*Boron Industry, Sources, and Evaporitic Andean Deposits: Geochemical Characteristics… DOI: http://dx.doi.org/10.5772/intechopen.90797*

contributions cause the enrichment in chloride and sodium, thus generating a more homogeneous composition of the solutions. The only samples that differ from this behavior are those of the northern sector, presenting a slightly higher anionic proportion in HCO3 and SO4. According to the results of the samples, the highest concentration of As and B in the brines is in the central-western sector of the salt, which is due to the predominantly hydrothermal origin of the recharge solutions. The lagoons of the central western sector are waters with a variable degree of chemical concentration. These lagoons are located mainly in the western zone of the salar, due to a slight slope of its surface toward the sector W, accumulating in this margin the scarce rainfall and also the solutions coming from the subsurface flow of the salar like that of its internal zone.

The predominance of water from inside or outside the saline nucleus of the salar determines the greater or lesser degree of concentration of the solutions, although they all share the same chemical type. In the southernmost zone, thermal waters emerge with a degree of concentration in solution similar to that of the brines that accumulate in the nearby lagoons, from which it follows that the concentration of the solutions comes in this area controlled by the interaction with the saline sediments of the salar. The saturation conditions (I.S.) of the solutions analyzed with respect to saline minerals of interest show a variable behavior; in the northern sector, the waters are clearly subsaturated with respect to gypsum and halite, while the waters of the bofedal are saturated with respect to calcite. On the other hand, the hot springs are subsaturated with respect to these three main saline minerals, although the degree of subsaturation is lower than that of the nonthermal springs. Finally, of the samples collected in the lagoons of the central sector, the two most diluted are in equilibrium with calcite and subsaturated with respect to gypsum and halite, while the most concentrated appears to be supersaturated with respect to calcite and gypsum and subsaturated with respect to halite.

#### **8. Conclusion**

to determine immediately, from the analysis of the initial solution, which evolutionary path should theoretically follow the solution from the precipitation of calcite and magnesium silicates. For its part, as an explanation of the presence of calcium sulfate and gypsum, since there is a clear tendency to balance in the samples that have F.I. greater than 2 m, in this case the existence of the sulfate source is the additional sulfur brought to the waters of the aquifer where it is oxidized transforming into sulfate from the sulfated minerals in the area. But, if the alkalinity is less than the sum of the calcium and magnesium concentrations (in meq/l), the solution will change its evolution toward the neutral saline route due to the precipitation of magnesium silicates, pH less than 9. The interesting thing about this method is that it allows you to immediately determine, from the analysis of the initial solution, which evolutionary pathway should theoretically follow the solution from the precipitation of calcite and magnesium silicates. If all alkali cations such as sulfate are removed, the amount of oxidized sulfate would be the difference between the total loss of alkali cations and the apparent loss of sulfate. From the visual observation in the area, there is a very close native sulfur, which is

transported by the winds; probably this is the process that generates the significant

2 must remain constant, as

The Salar de Quisquiro presents concentrations between F.I. 0.004 m and 2.54 m, and all sampled waters saturated in calcite and aragonite are presented. The other minerals closest to equilibrium are gypsum and later magnesite but far from precipitating. Since all waters are supersaturated in calcite, the next step is to consider alkalinity. If (alc) > 2(Ca2+), in the initial inlet water, then it increases regularly during evaporation, if only calcite precipitates. In other words, the activity

the concentration increases. If one of the solutes increases, then the other should decrease. In our case, the distribution of all incoming water must be converted into carbonate-rich brines. However, the evolution of the water represented in the triangular diagram (**Figure 3**) is of the Na-Cl-SO4 type with a pH lower than 9. The usual explanation for this anomaly is the precipitation of Mg silicates [69]. This suggests that the distribution of the incoming waters should become alkaline but that they are neutral brines. This induces evaporitic waters to follow two evolution paths. If during the evaporative process they are enriched with carbonates, becoming an alkaline brine of sodium carbonate, they will have a pH greater than 10. The other way is when the waters of input present more calcium than carbonate so that the solution is concentrated in calcium producing neutral brines with pH less than 9, as it is in our case. Therefore, the fundamental relationship if (alc) > 2((Ca2+)+2 (Mg2+)) does not depend on the nature of the weak anion of the acid associated with Ca and Mg, during the evaporation concentration process. Another explanation of the data is the existence of an excess sulfate of origin. In this model, additional sulfur is put into the waters of the aquifer where it oxidizes to sulfate and removes sulfate minerals. If every alkali cation is removed as sulfate from the amount of oxidized sulfate would be the difference between the total loss of alkali cations and apparent loss of sulfate. In observing the area very close to it, there is native sulfur. This is transported by the winds. These processes give a significant reduction in

The Salar de Aguas Calientes I has concentration waters that vary between 0.0237 m and 4.3195 m. The chemical nature of the waters shows (**Figure 3**) that its waters are of the Na-Cl type and it is directly related to the salt composition of the salt, whose sediments are mainly halite accompanied by gypsum and with the presence of borates in its central zone. The composition of all its waters seems to be linked to the saline composition of the sediments of the salt flat, since its contact

with both the surface waters that access the salars and the underground

product of the Ca2+ ions in solution in relation to CO3

reduction of alkalinity.

*Recent Advances in Boron-Containing Materials*

alkalinity.

**18**

Chilean salt flats have only ulexite as an economic mineral, these deposits being related to a shallow saline lake, whose main contributions in boron are from thermal sources. Boron in Andean salars is mainly linked to the Cenozoic volcanic rocks that prevail in the eastern Andean territory, particularly in recent or latent volcanic centers, and there is an increase in boron in areas of active latent volcanism, such as the hot springs of Salar de Surire [47] and Salar de Aguas Calientes I [48].

#### **Author details**

Ingrid Garcés Millas Department of Chemical Engineering and Minerals Process, Faculty of Engineering, University of Antofagasta, Antofagasta, Chile

\*Address all correspondence to<EMAIL_ADDRESS>
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Kistler RB, Helvaci C. Boron and borates. In: Carr DD, editor. Industrial Minerals and Rocks. 6ª ed. Sociedad de Minería, Metalurgia y Exploración, Inc.; 1994. pp. 171-186

[2] Garrett DE. Borates. In: Handbook of Deposits, Processing, Properties and Use. London: Academic Press; 1998. p. 483

[3] Helvacı C. Borates. In: Selley RC, Cocks LRM, Plimer IR, editors. Encyclopedia of Geology. Elsevier; 2005. pp. 510-522

[4] Garcés I, Reyes J, Geraldo C, Yunis F. Estudio experimental de la solubilidad de ulexita en agua y determinación de correlaciones generalizadas para medir su densidad, viscosidad e índice de refracción. Revista Innovación. 2003;**15**: 35-43. ISSN: 0716-6311

[5] USGS. Boron. In: Survey USG, editor. Mineral Commodity Summaries. 2019. pp. 36-37. Available at: https://prd-wret. s3-us-west-2.amazonaws.com/assets/ palladium/production/s3fs-public/ atoms/files/mcs-2019-boron.pdf

[6] Helvaci C, Palmer M. Origin and distribution of evaporate borates—The primary economic sources of boron. 2017. Available at: https://eprints.soton. ac.uk/413247/1/Helvaci\_revised\_April\_ 24.pdf

[7] Alonso R, de los Hoyos L. Boratos. Capitulo VII: otros minerales (Coord.) Liliana N. Castro y Ricardo Melgar. In: Nielson H, Sarudiansky R, editors. Minerales en la Agricultura en Latinoamérica. 1a. ed. Buenos Aires, Argentina. 2005. pp. 534-545, 578. ISBN: 987-22647-0-8

[8] Alonso R. Los yacimientos mundiales de boratos neógenos y claves para su prospección en los Andes Centrales. UNAS-Conicet. Conferencia en el marco de su incorporación como Académico Correspondiente Argentino a la Academia Nacional de Ciencias de Buenos Aires, Argentina; 2017

American Institute of Mining:

Inc.; 1985. p. 274

Tabla datos

Metallurgical and Petroleum Engineers,

*DOI: http://dx.doi.org/10.5772/intechopen.90797*

*Boron Industry, Sources, and Evaporitic Andean Deposits: Geochemical Characteristics…*

Química. EXPOQUIMIA'93. Barcelona,

[25] Dunai TJ, López GA, Juez-Larré J. Oligocene-Miocene age of aridity in the Atacama Desert revealed by exposure dating of erosion-sensitive landforms. Geology. 2005;**33**(4):321-324. DOI:

[26] Hall SR, Farber DL, Audin L, Finkel RC, Mériaux AS. Geochronology of pediment surfaces in southern Peru:

deformation of the Andean forearc. Tectonophysics. 2008;**459**(1):186-205. DOI: 10.1016/j.tecto.2007.11.073

[27] Hall SR, Farber DL, Audin L, Finkel RC. Recently active contractile deformation in the forearc of southern Peru. Earth and Planetary Science Letters. 2012;**337**:85-92. DOI: 10.1016/j.

[28] Kober F, Ivy-Ochs S, Schlunegger F,

Baur H, Kubik PW, Wieler R. Denudation rates and a topographydriven rainfall threshold in northern Chile: Multiple cosmogenic nuclide data

and sediment yield budgets.

Geomorphology. 2007;**83**(1):97-120. DOI: 10.1016/j.geomorph.2006.06.029

[29] Placzek CJ, Matmon A, Granger DE, Quade J, Niedermann S. Evidence for active landscape evolution in the hyperarid Atacama from multiple

terrestrial cosmogenic nuclides. Earth and Planetary Science Letters. 2010;**295**(1): 12-20. DOI: 10.1016/j.epsl.2010.03.006

[30] Benavente C, Zerathe S, Audin L, Hall R, Robert X, Delgado F, et al. Active transpressional tectonics in the Andean forearc of southern Peru quantified by 10Be surface exposure dating of an active fault scarp. Tectonics. 2017;**36**. DOI: 10.1002/

[31] Vila T. Geología de los depósitos

salinos andinos. Provincia de

2017TC004523

Implications for Quaternary

España. 1993. pp. 665-667

10.1130/G21184.1

epsl.2012.04.007

[17] Harben PW, Kuzvart M. Industrial Minerals, a Global Geology. Industrial Minerals Information Ltd.; 1997. p. 462

[18] USGS. Mineral Industry Surveys. Tables-only release. 2017. Available from: https://www.usgs.gov/centers/ nmic/boron-statistics-and-information

geoquímica de soluciones concentradas: Aplicación al estudio de la evolución de algunos salares tipo chilenos [tesis doctoral]. Zaragoza, España:

Universidad de Zaragoza; 2000. p. 225

[20] Munk LA, Hynek SA, Bradley D, Boutt D, Labay K, Jochens H. Lithium brines: A global perspective. Reviews in Economic Geology. 2016;**18**:339-365. Available from: https://pdfs.semantic scholar.org/3616/dd9db704d285b027c

[21] Tassara A. Segmentación andina desde el análisis flexural de la anomalía de Bouguer [unpub. MSc thesis]. Santiago de Chile: Universidad de Chile;

[22] Garcés I, Chong G. Yacimientos de Boro de Chile. Características, usos, mercados y aplicaciones industriales de los boratos. Rev. Innovación. 1993;**1**:

[23] Chong G, Garcés I. Antecedentes sobre los recursos económicos de los salares. In: Caracterización geológica química de los salares chilenos tipos y su consecuente importancia económica. Informe inédito. Fondecyt 786/87,

[24] Garcés I. Procesos de concentración de Boratos (ulexita) en depósitos chilenos. In: Proceedings of the 6° Congreso Mediterráneo de Ingeniería

[19] Garcés IM. Modelización

13185f4b6af3b9f2262.pdf

23-36. ISSN: 0716-6311

Santiago, Chile. 1988

**21**

1997. p. 140

[9] Alonso R. Ocurrencia, posición estratigráfica y génesis de los depósitos de boratos la Puna Argentina [tesis doctoral]. Salta, Argentina: Universidad Nacional de Salta; 1986. p. 196

[10] Alonso R. Los Boratos de la Puna. Edición Cámara de la Minería de Salta. Salta, Argentina. 1998. p. 196

[11] Alonso R, Viramonte J. La cuestión genética de los boratos de la Puna. In: Proceedings of the XII Congreso Geológico Argentino (Mendoza), Tomo V, Buenos Aires. 1993. pp. 187-194

[12] USGS. Mineral Commodities Summary. Boron. 2013. Available at: https://minerals.usgs.gov/minerals/ pubs/MineralCommoditiesSummary/ Boron/2013

[13] Parra R, Morales M. Estudio básico para la obtención de ácido bórico a partir de la ulexita y dióxido de carbono. Bolivian Journal of Chemistry. 2013; **30**(1):42-49

[14] Panorama de Mercado de Rocas y Minerales Industriales. Boratos. Ministerio de Energía y Minería. Presidencia de la Nación. Dirección de Asistencia al Productor Minero. Dirección Nacional de Promoción Minera. Argentina: Subsecretaría de Desarrollo Minero; 2018

[15] Chong G, Garcés I. Los yacimientos de boratos en Chile y su beneficio. Colegio de Ingenieros de Chile. 1989; **100**:37-47

[16] Barker J, Lefond S. Borates: Economic Geology and production. Society of Mining Engineers of the

*Boron Industry, Sources, and Evaporitic Andean Deposits: Geochemical Characteristics… DOI: http://dx.doi.org/10.5772/intechopen.90797*

American Institute of Mining: Metallurgical and Petroleum Engineers, Inc.; 1985. p. 274

**References**

1994. pp. 171-186

2005. pp. 510-522

35-43. ISSN: 0716-6311

p. 483

24.pdf

987-22647-0-8

**20**

[1] Kistler RB, Helvaci C. Boron and borates. In: Carr DD, editor. Industrial Minerals and Rocks. 6ª ed. Sociedad de Minería, Metalurgia y Exploración, Inc.;

*Recent Advances in Boron-Containing Materials*

de su incorporación como Académico Correspondiente Argentino a la Academia Nacional de Ciencias de Buenos Aires, Argentina; 2017

[9] Alonso R. Ocurrencia, posición estratigráfica y génesis de los depósitos de boratos la Puna Argentina [tesis doctoral]. Salta, Argentina: Universidad

Nacional de Salta; 1986. p. 196

Salta, Argentina. 1998. p. 196

[10] Alonso R. Los Boratos de la Puna. Edición Cámara de la Minería de Salta.

[11] Alonso R, Viramonte J. La cuestión genética de los boratos de la Puna. In: Proceedings of the XII Congreso Geológico Argentino (Mendoza),

Tomo V, Buenos Aires. 1993. pp. 187-194

[13] Parra R, Morales M. Estudio básico para la obtención de ácido bórico a partir de la ulexita y dióxido de carbono. Bolivian Journal of Chemistry. 2013;

[14] Panorama de Mercado de Rocas y Minerales Industriales. Boratos. Ministerio de Energía y Minería. Presidencia de la Nación. Dirección de Asistencia al Productor Minero. Dirección Nacional de Promoción Minera. Argentina: Subsecretaría de

[15] Chong G, Garcés I. Los yacimientos de boratos en Chile y su beneficio. Colegio de Ingenieros de Chile. 1989;

[16] Barker J, Lefond S. Borates: Economic Geology and production. Society of Mining Engineers of the

Desarrollo Minero; 2018

[12] USGS. Mineral Commodities Summary. Boron. 2013. Available at: https://minerals.usgs.gov/minerals/ pubs/MineralCommoditiesSummary/

Boron/2013

**30**(1):42-49

**100**:37-47

[2] Garrett DE. Borates. In: Handbook of Deposits, Processing, Properties and Use. London: Academic Press; 1998.

[3] Helvacı C. Borates. In: Selley RC, Cocks LRM, Plimer IR, editors. Encyclopedia of Geology. Elsevier;

[4] Garcés I, Reyes J, Geraldo C, Yunis F. Estudio experimental de la solubilidad de ulexita en agua y determinación de correlaciones generalizadas para medir su densidad, viscosidad e índice de refracción. Revista Innovación. 2003;**15**:

[5] USGS. Boron. In: Survey USG, editor. Mineral Commodity Summaries. 2019. pp. 36-37. Available at: https://prd-wret. s3-us-west-2.amazonaws.com/assets/ palladium/production/s3fs-public/ atoms/files/mcs-2019-boron.pdf

[6] Helvaci C, Palmer M. Origin and distribution of evaporate borates—The primary economic sources of boron. 2017. Available at: https://eprints.soton. ac.uk/413247/1/Helvaci\_revised\_April\_

[7] Alonso R, de los Hoyos L. Boratos. Capitulo VII: otros minerales (Coord.) Liliana N. Castro y Ricardo Melgar. In: Nielson H, Sarudiansky R, editors. Minerales en la Agricultura en Latinoamérica. 1a. ed. Buenos Aires, Argentina. 2005. pp. 534-545, 578. ISBN:

[8] Alonso R. Los yacimientos mundiales de boratos neógenos y claves para su prospección en los Andes Centrales. UNAS-Conicet. Conferencia en el marco [17] Harben PW, Kuzvart M. Industrial Minerals, a Global Geology. Industrial Minerals Information Ltd.; 1997. p. 462

[18] USGS. Mineral Industry Surveys. Tables-only release. 2017. Available from: https://www.usgs.gov/centers/ nmic/boron-statistics-and-information Tabla datos

[19] Garcés IM. Modelización geoquímica de soluciones concentradas: Aplicación al estudio de la evolución de algunos salares tipo chilenos [tesis doctoral]. Zaragoza, España: Universidad de Zaragoza; 2000. p. 225

[20] Munk LA, Hynek SA, Bradley D, Boutt D, Labay K, Jochens H. Lithium brines: A global perspective. Reviews in Economic Geology. 2016;**18**:339-365. Available from: https://pdfs.semantic scholar.org/3616/dd9db704d285b027c 13185f4b6af3b9f2262.pdf

[21] Tassara A. Segmentación andina desde el análisis flexural de la anomalía de Bouguer [unpub. MSc thesis]. Santiago de Chile: Universidad de Chile; 1997. p. 140

[22] Garcés I, Chong G. Yacimientos de Boro de Chile. Características, usos, mercados y aplicaciones industriales de los boratos. Rev. Innovación. 1993;**1**: 23-36. ISSN: 0716-6311

[23] Chong G, Garcés I. Antecedentes sobre los recursos económicos de los salares. In: Caracterización geológica química de los salares chilenos tipos y su consecuente importancia económica. Informe inédito. Fondecyt 786/87, Santiago, Chile. 1988

[24] Garcés I. Procesos de concentración de Boratos (ulexita) en depósitos chilenos. In: Proceedings of the 6° Congreso Mediterráneo de Ingeniería

Química. EXPOQUIMIA'93. Barcelona, España. 1993. pp. 665-667

[25] Dunai TJ, López GA, Juez-Larré J. Oligocene-Miocene age of aridity in the Atacama Desert revealed by exposure dating of erosion-sensitive landforms. Geology. 2005;**33**(4):321-324. DOI: 10.1130/G21184.1

[26] Hall SR, Farber DL, Audin L, Finkel RC, Mériaux AS. Geochronology of pediment surfaces in southern Peru: Implications for Quaternary deformation of the Andean forearc. Tectonophysics. 2008;**459**(1):186-205. DOI: 10.1016/j.tecto.2007.11.073

[27] Hall SR, Farber DL, Audin L, Finkel RC. Recently active contractile deformation in the forearc of southern Peru. Earth and Planetary Science Letters. 2012;**337**:85-92. DOI: 10.1016/j. epsl.2012.04.007

[28] Kober F, Ivy-Ochs S, Schlunegger F, Baur H, Kubik PW, Wieler R. Denudation rates and a topographydriven rainfall threshold in northern Chile: Multiple cosmogenic nuclide data and sediment yield budgets. Geomorphology. 2007;**83**(1):97-120. DOI: 10.1016/j.geomorph.2006.06.029

[29] Placzek CJ, Matmon A, Granger DE, Quade J, Niedermann S. Evidence for active landscape evolution in the hyperarid Atacama from multiple terrestrial cosmogenic nuclides. Earth and Planetary Science Letters. 2010;**295**(1): 12-20. DOI: 10.1016/j.epsl.2010.03.006

[30] Benavente C, Zerathe S, Audin L, Hall R, Robert X, Delgado F, et al. Active transpressional tectonics in the Andean forearc of southern Peru quantified by 10Be surface exposure dating of an active fault scarp. Tectonics. 2017;**36**. DOI: 10.1002/ 2017TC004523

[31] Vila T. Geología de los depósitos salinos andinos. Provincia de

Antofagasta, Chile: Instituto de Investigaciones Geológicas; 1975. Available from: http://www.andeange ology.equipu.cl/index.php/revista1/ article/viewFile/731/1065

[32] Garcés I. The sodium sulphate and ulexite deposits: Salar of Surire, Chile. In: Geertman RM, editor. Proceedings of 8th World Salt Symposium, Salt'2000. Vol. 2. Amsterdam: Elsevier; 2000. pp. 1159-1160

[33] Munk LA, Boutt D, Hynek S, Moran B. Hydrogeochemical fluxes and processes contributing to the formation of lithium-enriched brines in a hyperarid continental basin. Chemical Geology. 2018;**493**:37-57. DOI: 10.1016/ j.chemgeo.2018.05.013

[34] Risacher F, Alonso H, Salazar C. The origin of brines and salts in Chilean salars: A hydrochemical review. Earth-Science Reviews. 2003;**63**(3):249-293. DOI: 10.1016/S0012-8252(03)00037-0

[35] Garcés I. Aplicación del Modelo de Interacción Iónica de Pitzer para determinar Coeficientes de Actividad en Salmueras Naturales con Presencia de Boro. Información Tecnológica. 2019; **30**(2):283-292. DOI: 10.4067/ s0718-07642019000200283

[36] Risacher F, Alonso H, Salazar C. Geoquímica de aguas en cuencas cerradas: I, II, III regiones—Chile. Volumen I, II, III. Convenio de Cooperación DGA–UCN–IRD. S.I.T. N° 51. Santiago de Chile; 1999

[37] Li J, Wang F, Michalski G, Wilkins B. Atmospheric deposition across the Atacama Desert, Chile: Compositions, source distributions, and interannual comparisons. Chemical Geology. 2019;**525**:435-446. DOI: 10.1016/j.chemgeo.2019.07.037

[38] Warren JK. Non-potash salts: Borates, Na-sulphates, Na-carbonate, lithium salts, gypsum, halite and zolites. In: Evaporites. Cham: Springer; 2016. pp. 1187-1302. ISBN: 978-3-319-13512-0

Transporte y Telecomunicaciones; 1987.

*DOI: http://dx.doi.org/10.5772/intechopen.90797*

H2O system: A re-evaluation of the sulfate chemistry in the Spencer– Møller–Weare model. Geochimica et Cosmochimica Acta. 1999;**63**(9): 1305-1318. DOI: 10.1016/S0016-7037

(99)00102-7

*Boron Industry, Sources, and Evaporitic Andean Deposits: Geochemical Characteristics…*

90295-X

[55] Pabalan RT, Pitzer K.

Thermodynamics of concentrated electrolyte mixtures and the prediction

temperatures for mixtures in the system Na-K-Mg-Cl-SO4-OH-H2O. Geochimica

2429-2443. DOI: 10.1016/0016-7037(87)

[56] Spencer R, Moller N, Weare J. The prediction of mineral solubilities in natural waters: A chemical equilibrium model for the Na-K-Ca-Mg-Cl-SO4-H2O system at temperatures below 25°C. Geochimica et Cosmochimica Acta. 1990;**54**:575-590. DOI: 10.1016/

of mineral solubilities to high

et Cosmochimica Acta. 1987;**51**:

0016-7037(90)90354-N

1988. p. 310

8444-316-7

[57] Plummer L, Parkhurst DL, Fleming G, Dunkle S. Computer program incorporating Pitzer's

[58] Castellán GW. Fisicoquímica. Pearson Educación; 1987. ISBN: 978-96-

[59] Jander G, Friedrich JK. Análisis Volumétrico. Unión Tipográfica Editorial

Hispano Americana; 1961. p. 400

España; 2011. p. 688

[60] Pickering W. Química analítica moderna. Reverté S.A. 1a edición.

[61] Ball JW, Nordstrom DK. User's manual for WATEQ4F, with revised thermodynamic data base and test cases for calculating speciation of major, trace, and redox elements in natural waters. In: U.S. Geological Survey Open-File Report 91-183. 1991. p. 189

equations for calculation of geochemical reactions in brines. In: Water-Resources Investigation Report. WRI 88-4153.

ecosistema altoandino en peligro, frente a escenario del cambio climático. Rev.

[48] Garcés I, López P. Antecedentes Hidroquímicos del Salar de Aguas Calientes I (Chile). Revista Facultad de Ingeniería Universidad de Antioquia.

[49] Lindsay J, de Silva S, Trumbull R, Emmermann R, Wemmer K. La Pacana caldera, N. Chile: A reevaluation of the stratigraphy and volcanology of one of the world's largest resurgent calderas. Journal of Volcanology and Geothermal Research. 2001;**106**:145-173. DOI: 10.1016/S0377-0273(00)00270-5

[50] Alonso R. On the origin of La Puna borates. Acta Geológica Hispánica. 1999;

[51] Harvie C, Weare J-H. The prediction of mineral solubilities in natural waters: The Na-K-Mg-Ca-Cl-SO4-H2O system from zero to high concentration at 25°C. Geochimica et Cosmochimica Acta. 1980;**44**:981-997. DOI: 10.1016/

[47] Garcés I. Salar de Surire un

Nexo. 2011;**24**(1):43-49

2012;**62**:91-102

**34**:141-166

0016-7037(84)90098-X

[52] Harvie C, Eugster H, Weare J. Mineral equilibria in the six-component seawater system, Na-K-Mg-Ca-SO4-Cl-H2O at 25°C. II: compositions of the saturated solutions. Geochimica et Cosmochimica Acta. 1982;**46**:1603-1618. DOI: 10.1016/0016-7037(82)90317-9

[53] Harvie CE, Moller N, Weare J. The prediction of mineral solubilities in natural waters: The Na-K-Mg-Ca-H-Cl-SO4-OH-HCO3-CO3-CO2-H2O system to high ionic strengths at 25°C. Geochimica et Cosmochimica Acta. 1984;**48**:723-751. DOI: 10.1016/ 0016-7037(84)90098-X

[54] Marion GM, Farren RE. Mineral solubilities in the Na-K-Mg-Ca-Cl-SO4-

**23**

p. 24

[39] Risacher F, Fritz B. Origin of salts and brine evolution of Bolivian and Chilean salars. Aquatic Geochemistry. 2009;**15**(1–2):123-157. DOI: 10.1007/ s10498-008-9056-x

[40] Vila T. Geología de los depósitos salinos andinos. Provincia de Antofagasta [Tesis de Ciencias Geológicas]. Santiago de Chile: Universidad de Chile; 1974

[41] Alpers CN, Wittermore DO. Hydrogeochemistry and stable isotopes of ground and surface waters from two adjacent closed basins, Atacama Desert, northern Chile. Applied Geochemistry. 1990;**5**:719-734

[42] Gannat E, Schlund JM. Informe de la misión de estudio de las posibilidades de Chile en minerales potásicos. Informe Inédito, vol. 2 Santiago, Corp. Pom. Produc. y Bur. Rech. Geol. Min.; 1969

[43] Stoertz GE, Ericksen GE. Geology of salars in northern Chile. In: U.S. Geol. Surv. Prof. Paper 811. 1974. p. 65

[44] Ericksen GE, Salas OR. Geology and resources of salars in the Central Andes. In: Ericksen GE, Cañas PM, Reinemund JA, editors. Geology of the Andes and Its Relation to Hydrocarbon and Mineral Resources, Series. Vol. 11. Houston, Texas: Circum-Pacific Council for Energy and Mineral Resources; 1989. pp. 151-164

[45] Wisniak J, Garcés I. The rise and fall of the salitre (sodium nitrate) industry. Indian Journal of Chemical Technology. 2001;**8**(5):427-438. ISSN: 0971-457X (Print)

[46] Dirección General de Aguas (DGA). Balance Hídrico de Chile. Gobierno de Chile: Ministerio de Obras Públicas,

*Boron Industry, Sources, and Evaporitic Andean Deposits: Geochemical Characteristics… DOI: http://dx.doi.org/10.5772/intechopen.90797*

Transporte y Telecomunicaciones; 1987. p. 24

Antofagasta, Chile: Instituto de Investigaciones Geológicas; 1975. Available from: http://www.andeange ology.equipu.cl/index.php/revista1/

[32] Garcés I. The sodium sulphate and ulexite deposits: Salar of Surire, Chile. In: Geertman RM, editor. Proceedings of 8th World Salt Symposium, Salt'2000. Vol. 2. Amsterdam: Elsevier; 2000.

*Recent Advances in Boron-Containing Materials*

In: Evaporites. Cham: Springer; 2016. pp. 1187-1302. ISBN: 978-3-319-13512-0

[39] Risacher F, Fritz B. Origin of salts and brine evolution of Bolivian and Chilean salars. Aquatic Geochemistry. 2009;**15**(1–2):123-157. DOI: 10.1007/

[40] Vila T. Geología de los depósitos

salinos andinos. Provincia de Antofagasta [Tesis de Ciencias Geológicas]. Santiago de Chile: Universidad de Chile; 1974

[41] Alpers CN, Wittermore DO. Hydrogeochemistry and stable isotopes of ground and surface waters from two adjacent closed basins, Atacama Desert, northern Chile. Applied Geochemistry.

[42] Gannat E, Schlund JM. Informe de la misión de estudio de las posibilidades

[43] Stoertz GE, Ericksen GE. Geology of salars in northern Chile. In: U.S. Geol. Surv. Prof. Paper 811. 1974. p. 65

[44] Ericksen GE, Salas OR. Geology and resources of salars in the Central Andes.

Reinemund JA, editors. Geology of the Andes and Its Relation to Hydrocarbon and Mineral Resources, Series. Vol. 11. Houston, Texas: Circum-Pacific Council for Energy and Mineral Resources; 1989.

[45] Wisniak J, Garcés I. The rise and fall of the salitre (sodium nitrate) industry. Indian Journal of Chemical Technology. 2001;**8**(5):427-438. ISSN: 0971-457X

[46] Dirección General de Aguas (DGA). Balance Hídrico de Chile. Gobierno de Chile: Ministerio de Obras Públicas,

In: Ericksen GE, Cañas PM,

pp. 151-164

(Print)

de Chile en minerales potásicos. Informe Inédito, vol. 2 Santiago, Corp. Pom. Produc. y Bur. Rech. Geol. Min.;

s10498-008-9056-x

1990;**5**:719-734

1969

[33] Munk LA, Boutt D, Hynek S, Moran B. Hydrogeochemical fluxes and processes contributing to the formation of lithium-enriched brines in a hyperarid continental basin. Chemical Geology. 2018;**493**:37-57. DOI: 10.1016/

[34] Risacher F, Alonso H, Salazar C. The origin of brines and salts in Chilean salars: A hydrochemical review. Earth-Science Reviews. 2003;**63**(3):249-293. DOI: 10.1016/S0012-8252(03)00037-0

[35] Garcés I. Aplicación del Modelo de Interacción Iónica de Pitzer para

determinar Coeficientes de Actividad en Salmueras Naturales con Presencia de Boro. Información Tecnológica. 2019;

**30**(2):283-292. DOI: 10.4067/ s0718-07642019000200283

51. Santiago de Chile; 1999

[37] Li J, Wang F, Michalski G, Wilkins B. Atmospheric deposition across the Atacama Desert, Chile: Compositions, source distributions, and interannual comparisons. Chemical Geology. 2019;**525**:435-446. DOI: 10.1016/j.chemgeo.2019.07.037

[38] Warren JK. Non-potash salts: Borates, Na-sulphates, Na-carbonate, lithium salts, gypsum, halite and zolites.

**22**

[36] Risacher F, Alonso H, Salazar C. Geoquímica de aguas en cuencas cerradas: I, II, III regiones—Chile. Volumen I, II, III. Convenio de

Cooperación DGA–UCN–IRD. S.I.T. N°

j.chemgeo.2018.05.013

article/viewFile/731/1065

pp. 1159-1160

[47] Garcés I. Salar de Surire un ecosistema altoandino en peligro, frente a escenario del cambio climático. Rev. Nexo. 2011;**24**(1):43-49

[48] Garcés I, López P. Antecedentes Hidroquímicos del Salar de Aguas Calientes I (Chile). Revista Facultad de Ingeniería Universidad de Antioquia. 2012;**62**:91-102

[49] Lindsay J, de Silva S, Trumbull R, Emmermann R, Wemmer K. La Pacana caldera, N. Chile: A reevaluation of the stratigraphy and volcanology of one of the world's largest resurgent calderas. Journal of Volcanology and Geothermal Research. 2001;**106**:145-173. DOI: 10.1016/S0377-0273(00)00270-5

[50] Alonso R. On the origin of La Puna borates. Acta Geológica Hispánica. 1999; **34**:141-166

[51] Harvie C, Weare J-H. The prediction of mineral solubilities in natural waters: The Na-K-Mg-Ca-Cl-SO4-H2O system from zero to high concentration at 25°C. Geochimica et Cosmochimica Acta. 1980;**44**:981-997. DOI: 10.1016/ 0016-7037(84)90098-X

[52] Harvie C, Eugster H, Weare J. Mineral equilibria in the six-component seawater system, Na-K-Mg-Ca-SO4-Cl-H2O at 25°C. II: compositions of the saturated solutions. Geochimica et Cosmochimica Acta. 1982;**46**:1603-1618. DOI: 10.1016/0016-7037(82)90317-9

[53] Harvie CE, Moller N, Weare J. The prediction of mineral solubilities in natural waters: The Na-K-Mg-Ca-H-Cl-SO4-OH-HCO3-CO3-CO2-H2O system to high ionic strengths at 25°C. Geochimica et Cosmochimica Acta. 1984;**48**:723-751. DOI: 10.1016/ 0016-7037(84)90098-X

[54] Marion GM, Farren RE. Mineral solubilities in the Na-K-Mg-Ca-Cl-SO4H2O system: A re-evaluation of the sulfate chemistry in the Spencer– Møller–Weare model. Geochimica et Cosmochimica Acta. 1999;**63**(9): 1305-1318. DOI: 10.1016/S0016-7037 (99)00102-7

[55] Pabalan RT, Pitzer K. Thermodynamics of concentrated electrolyte mixtures and the prediction of mineral solubilities to high temperatures for mixtures in the system Na-K-Mg-Cl-SO4-OH-H2O. Geochimica et Cosmochimica Acta. 1987;**51**: 2429-2443. DOI: 10.1016/0016-7037(87) 90295-X

[56] Spencer R, Moller N, Weare J. The prediction of mineral solubilities in natural waters: A chemical equilibrium model for the Na-K-Ca-Mg-Cl-SO4-H2O system at temperatures below 25°C. Geochimica et Cosmochimica Acta. 1990;**54**:575-590. DOI: 10.1016/ 0016-7037(90)90354-N

[57] Plummer L, Parkhurst DL, Fleming G, Dunkle S. Computer program incorporating Pitzer's equations for calculation of geochemical reactions in brines. In: Water-Resources Investigation Report. WRI 88-4153. 1988. p. 310

[58] Castellán GW. Fisicoquímica. Pearson Educación; 1987. ISBN: 978-96- 8444-316-7

[59] Jander G, Friedrich JK. Análisis Volumétrico. Unión Tipográfica Editorial Hispano Americana; 1961. p. 400

[60] Pickering W. Química analítica moderna. Reverté S.A. 1a edición. España; 2011. p. 688

[61] Ball JW, Nordstrom DK. User's manual for WATEQ4F, with revised thermodynamic data base and test cases for calculating speciation of major, trace, and redox elements in natural waters. In: U.S. Geological Survey Open-File Report 91-183. 1991. p. 189

[62] Jenne EA, Ball JW, Burchard JM, Vivit DV, Barks JH. Geochemical modeling: Apparent solubility controls on Ba, Zn, Cd, Pb and F in waters of the Missouri Tri-State mining area. In: Hemphill DD, editor. Trace Substances in Environmental Health. Vol. 14. Columbia, Montana: University of Missouri; 1980. pp. 353-361

[63] Dickson AG. pH scales and protontransfer reactions in saline media such as sea water. Geochimica et Cosmochimica Acta. 1984;**48**: 2299-2308. DOI: 10.1016/0016-7037 (84)90225-4

[64] Markus Y. Determination of pH in highly saline waters. Pure and Applied Chemistry. 1989;**61**:1133-1138. DOI: 10.1351/pac198961061133

[65] Lazar B, Starinski A, Katz A, Sass E, Ben-Yaakov S. The carbonate system in hypersaline solutions: alkalinity and CaCO3 solubility of evaporated seawater. Limnology and Oceanography. 1983;**28**:978-986. DOI: 10.4319/lo.19<IP_ADDRESS>8

[66] López PL, Garcés I, Auqué LF, Gómez J, Gimeno MJ, Lapuente MP. Características geoquímicas y aspectos geológicos del salar de Huasco (Chile). Boletín Geológico y Minero. 1999;**110**: 297-316

[67] Pengsheng S, Yan Y. Thermodynamics and phase diagram of the Salt Lake brine system at 298.15 K: V. Model for the system Li+ , Na+ , K+ , Mg2+/Cl, SO4 2, H2O and its applications. Calphad. 2003;**27**(4): 343-352. DOI: 10.1016/j. calphad.2004.02.001

[68] Gao F, Zheng M, Song P, Bu L, Wang Y. The 273.15-K-isothermal evaporation experiment of lithium brine from the Zhabei Salt Lake, Tibet, and its geochemical significance. Aquatic Geochemistry. 2012;**18**(4):343-356. DOI: 10.1007/s10498-012-9168-1

[69] Hardie LA, Eugster HP. The evolution of closed-basin brines. Mineralogical Society of America Special Paper. 1970;**3**:273-290

**25**

**Chapter 2**

**Abstract**

cine, are also reported.

**1. Introduction**

nanomedicine, cancer, drugs

Functionalized Boron Nitride

Applications in Biotechnology

*Milene Adriane Luciano and Lidia Maria de Andrade*

*Hélio Ribeiro, Paula von Cardoso Randow, Diego N. Vilela,*

Due to its interesting chemical, physical, and biological properties, boron nitride has received considerable attention by the scientific and technological communities. However, there is a strong dependency of its structural quality and compatibility in different host systems, regarding its potential applications. The use of these different nanostructures involves several challenges due to their low dispersibility in water and organic solvents; thus, its chemical modification is an important step that gives them specificity. Therefore, the ability to control their surface (physically or chemically) is essential for exploring and building blocks in the nanoengineering of supramolecular structures. In this chapter, we report different boron nitride functionalization processes, as well as their important uses as adjuvants in vaccines, brachytherapy, or drug delivery. Besides some important theoretical studies that have demonstrated the different functionalization possibilities for use in nanomedi-

**Keywords:** hexagonal boron nitride, boron nitride nanotubes, functionalization,

Boron nitride (BN) is a covalent solid constituted by equal numbers of boron and nitrogen atoms, and its well-known crystalline forms are hexagonal boron nitride (h-BN), diamond-like cubic BN (c-BN), and wurtzite BN (w-BN) [1]. In particular, h-BN is the most stable BN phase under standard conditions that

for boron atoms, and bond angle expected between the B-N-B or N-B-N is 120° that forms a perfect hexagonal ring bond network such as graphite, whereas the 2D layers are held together by weak van der Waals forces [1, 2]. Due to its similar structure with graphite, h-BN has common properties with it, like anisotropy along and perpendicular to a basal plane, high mechanical strength and thermal conductivity, and excellent lubrication [1]. Due to its reduced electron delocalization in the π BN bonds, it has a large bandgap making it an electrical insulating nanomaterial; however, h-BN is used as a lubricant (weakly held layers can slide over each other) and can have semiconductor properties. h-BN is also highly thermally and chemically stable and thus is also widely used for durable high-temperature crucibles, antioxidation lubricants, and protective coatings [1] and also has a wide range application in nanomedicine and biotechnology such as cancer therapies [3],

hybridization is observed

presents two-dimensional (2D) layered structure. The sp2

#### **Chapter 2**

[62] Jenne EA, Ball JW, Burchard JM, Vivit DV, Barks JH. Geochemical modeling: Apparent solubility controls on Ba, Zn, Cd, Pb and F in waters of the Missouri Tri-State mining area. In: Hemphill DD, editor. Trace Substances in Environmental Health. Vol. 14. Columbia, Montana: University of Missouri; 1980. pp. 353-361

*Recent Advances in Boron-Containing Materials*

[69] Hardie LA, Eugster HP. The evolution of closed-basin brines. Mineralogical Society of America Special Paper. 1970;**3**:273-290

[63] Dickson AG. pH scales and protontransfer reactions in saline media such

[64] Markus Y. Determination of pH in highly saline waters. Pure and Applied Chemistry. 1989;**61**:1133-1138. DOI:

[65] Lazar B, Starinski A, Katz A, Sass E, Ben-Yaakov S. The carbonate system in hypersaline solutions: alkalinity and CaCO3 solubility of evaporated seawater. Limnology and

Oceanography. 1983;**28**:978-986. DOI:

[66] López PL, Garcés I, Auqué LF, Gómez J, Gimeno MJ, Lapuente MP. Características geoquímicas y aspectos geológicos del salar de Huasco (Chile). Boletín Geológico y Minero. 1999;**110**:

Thermodynamics and phase diagram of the Salt Lake brine system at 298.15 K:

2, H2O and its

, Na+ , K+ ,

as sea water. Geochimica et Cosmochimica Acta. 1984;**48**: 2299-2308. DOI: 10.1016/0016-7037

10.1351/pac198961061133

10.4319/lo.19<IP_ADDRESS>8

[67] Pengsheng S, Yan Y.

V. Model for the system Li+

10.1007/s10498-012-9168-1

343-352. DOI: 10.1016/j. calphad.2004.02.001

applications. Calphad. 2003;**27**(4):

[68] Gao F, Zheng M, Song P, Bu L, Wang Y. The 273.15-K-isothermal evaporation experiment of lithium brine from the Zhabei Salt Lake, Tibet, and its geochemical significance. Aquatic Geochemistry. 2012;**18**(4):343-356. DOI:

297-316

**24**

Mg2+/Cl, SO4

(84)90225-4

## Functionalized Boron Nitride Applications in Biotechnology

*Hélio Ribeiro, Paula von Cardoso Randow, Diego N. Vilela, Milene Adriane Luciano and Lidia Maria de Andrade*

#### **Abstract**

Due to its interesting chemical, physical, and biological properties, boron nitride has received considerable attention by the scientific and technological communities. However, there is a strong dependency of its structural quality and compatibility in different host systems, regarding its potential applications. The use of these different nanostructures involves several challenges due to their low dispersibility in water and organic solvents; thus, its chemical modification is an important step that gives them specificity. Therefore, the ability to control their surface (physically or chemically) is essential for exploring and building blocks in the nanoengineering of supramolecular structures. In this chapter, we report different boron nitride functionalization processes, as well as their important uses as adjuvants in vaccines, brachytherapy, or drug delivery. Besides some important theoretical studies that have demonstrated the different functionalization possibilities for use in nanomedicine, are also reported.

**Keywords:** hexagonal boron nitride, boron nitride nanotubes, functionalization, nanomedicine, cancer, drugs

#### **1. Introduction**

Boron nitride (BN) is a covalent solid constituted by equal numbers of boron and nitrogen atoms, and its well-known crystalline forms are hexagonal boron nitride (h-BN), diamond-like cubic BN (c-BN), and wurtzite BN (w-BN) [1]. In particular, h-BN is the most stable BN phase under standard conditions that presents two-dimensional (2D) layered structure. The sp2 hybridization is observed for boron atoms, and bond angle expected between the B-N-B or N-B-N is 120° that forms a perfect hexagonal ring bond network such as graphite, whereas the 2D layers are held together by weak van der Waals forces [1, 2]. Due to its similar structure with graphite, h-BN has common properties with it, like anisotropy along and perpendicular to a basal plane, high mechanical strength and thermal conductivity, and excellent lubrication [1]. Due to its reduced electron delocalization in the π BN bonds, it has a large bandgap making it an electrical insulating nanomaterial; however, h-BN is used as a lubricant (weakly held layers can slide over each other) and can have semiconductor properties. h-BN is also highly thermally and chemically stable and thus is also widely used for durable high-temperature crucibles, antioxidation lubricants, and protective coatings [1] and also has a wide range application in nanomedicine and biotechnology such as cancer therapies [3],

drug delivery [4, 5], biosensing [6–8], adjuvant in vaccines [9], and intracellular delivery [10, 11]. Hexagonal boron nitride also can be incorporated in ceramics, alloys, resins, plastics, and rubbers to give them thermal and chemical stability and mechanical resistance as well [12–15]. BN nanomaterials (**Figures 1** and **2**), such as carbon nanotubes (CNT) and graphene, also are awakened as new perspectives in prophylactic, diagnostic, and therapeutic areas. However, the use of them depends strongly of its chemical and physical modification surfaces that display an important role in their compatibility different host environments.

Its modification surfaces results in homogeneous dispersion medium with minimum restacking or agglomeration which guarantees biocompatibility in different biological or inorganic systems. The nanostructure dispersions in different medium of interest are fundamental to their potential applications [16]. The nanoengineering interfaces between host (organic or inorganic) systems and these nanostructures involve several challenges that need to be overcome. For instance, the restacking or agglomeration process of them does not allow transferring their expected properties to the host system, resulting in an inhomogeneous medium with minimum of compatibility. This undesirable phenomenon of surface can be overcome by physical or chemical modification methodologies, such as covalent or non-covalent functionalization. Thus, our choices will depend on the nanostructure and system desired. There are several types of covalent functionalization, and different functional groups can be chosen, according to their selectivity [16]. In this case, different organic or inorganic functional groups or nanoparticles can be anchored by strong covalent bonds. For instance, it can be introduced on surfaces of oxidized CNTs or graphene oxide (GO), functional groups such as alkoxy (−OR), amino (−NH2), amine (−NHR), alkyl (−R) [17, 18], heteroatom doping, metallic nanoparticles, biomolecules, and biopolymers, among others. These modification

#### **Figure 1.**

*TEM images of (a, b) h-BN in different magnitudes, (c) multilayered BNTs. (d, e) AFM image and profile of h-BN nanosheets. (Images courtesy of the UFMG Microscopy Center).*

**27**

**Figure 2.**

*Functionalized Boron Nitride Applications in Biotechnology*

processes alter significantly their surface interactions, leading them to a large range

*BNNT and h-BN scheme not functionalized (a, b) and functionalized with different functional groups (c, d).*

On the other hand, non-covalent functionalization of nanoparticles is strongly dependent on their physical interaction with host system through intermolecular forces, such as van der Waals, hydrophilic, hydrophobic, hydrogen bonding, and π-π interactions, among others [19]. Using advantages of these physical interactions of molecules (conjugated, surfactants, etc.), they form homogenously dispersion into different medium with controlled physicochemical properties [20]. The study of different modification surface and their potential applications is very important. Several studies have presented different types of covalent and non-covalent functionalization methodologies in different nanoparticles with several demands, such as in cellulose films or fibers [21, 22], chitosan [23], polyethylenimine-grafted nanoribbon (for recognition of microRNA) [8], vinyl acetate copolymer [20], octadecylamine [1], glucose oxidase biosensing [24], poly (ethylene glycol) [25], DNA [26], and metallic nanoparticles, among others. The most important issue for success and performance of these compounds is the choice of the best tailored functionalization process (bio-nanoengineering) for each type of inorganic or biological system. The physical-chemical modification is an essential step for their relevant applications, leading to nanocomplex chemically stable, well dispersed, and biocompatible with the biological environment of interest. Thus, it is possible to produce smart nano-systems with advanced applications in biotechnology and biomedical areas, such as ecological packaging, bio-robots, and tumor markers for diagnosis and therapy. In this chapter, we propose a brief report about the main methods of functionalization of boron nitride and their advances and potential

**2. Boron nitride functionalization and its implications in nanomedicine**

Hexagonal boron nitride is thermal and chemically layered structure more stable than graphitic carbon structures. Due to its excellent chemical stability, a better biological performance is expected [27]. The key for application of h-BN in different

of solubility in water, copolymers, or organic solvents [16].

applications in biotechnology and nanomedicine.

*DOI: http://dx.doi.org/10.5772/intechopen.80849*

*Functionalized Boron Nitride Applications in Biotechnology DOI: http://dx.doi.org/10.5772/intechopen.80849*

*Recent Advances in Boron-Containing Materials*

drug delivery [4, 5], biosensing [6–8], adjuvant in vaccines [9], and intracellular delivery [10, 11]. Hexagonal boron nitride also can be incorporated in ceramics, alloys, resins, plastics, and rubbers to give them thermal and chemical stability and mechanical resistance as well [12–15]. BN nanomaterials (**Figures 1** and **2**), such as carbon nanotubes (CNT) and graphene, also are awakened as new perspectives in prophylactic, diagnostic, and therapeutic areas. However, the use of them depends strongly of its chemical and physical modification surfaces that display an impor-

Its modification surfaces results in homogeneous dispersion medium with minimum restacking or agglomeration which guarantees biocompatibility in different biological or inorganic systems. The nanostructure dispersions in different medium of interest are fundamental to their potential applications [16]. The nanoengineering interfaces between host (organic or inorganic) systems and these nanostructures involve several challenges that need to be overcome. For instance, the restacking or agglomeration process of them does not allow transferring their expected properties to the host system, resulting in an inhomogeneous medium with minimum of compatibility. This undesirable phenomenon of surface can be overcome by physical or chemical modification methodologies, such as covalent or non-covalent functionalization. Thus, our choices will depend on the nanostructure and system desired. There are several types of covalent functionalization, and different functional groups can be chosen, according to their selectivity [16]. In this case, different organic or inorganic functional groups or nanoparticles can be anchored by strong covalent bonds. For instance, it can be introduced on surfaces of oxidized CNTs or graphene oxide (GO), functional groups such as alkoxy (−OR), amino (−NH2), amine (−NHR), alkyl (−R) [17, 18], heteroatom doping, metallic nanoparticles, biomolecules, and biopolymers, among others. These modification

*TEM images of (a, b) h-BN in different magnitudes, (c) multilayered BNTs. (d, e) AFM image and profile of*

*h-BN nanosheets. (Images courtesy of the UFMG Microscopy Center).*

tant role in their compatibility different host environments.

**26**

**Figure 1.**

**Figure 2.** *BNNT and h-BN scheme not functionalized (a, b) and functionalized with different functional groups (c, d).*

processes alter significantly their surface interactions, leading them to a large range of solubility in water, copolymers, or organic solvents [16].

On the other hand, non-covalent functionalization of nanoparticles is strongly dependent on their physical interaction with host system through intermolecular forces, such as van der Waals, hydrophilic, hydrophobic, hydrogen bonding, and π-π interactions, among others [19]. Using advantages of these physical interactions of molecules (conjugated, surfactants, etc.), they form homogenously dispersion into different medium with controlled physicochemical properties [20]. The study of different modification surface and their potential applications is very important. Several studies have presented different types of covalent and non-covalent functionalization methodologies in different nanoparticles with several demands, such as in cellulose films or fibers [21, 22], chitosan [23], polyethylenimine-grafted nanoribbon (for recognition of microRNA) [8], vinyl acetate copolymer [20], octadecylamine [1], glucose oxidase biosensing [24], poly (ethylene glycol) [25], DNA [26], and metallic nanoparticles, among others. The most important issue for success and performance of these compounds is the choice of the best tailored functionalization process (bio-nanoengineering) for each type of inorganic or biological system. The physical-chemical modification is an essential step for their relevant applications, leading to nanocomplex chemically stable, well dispersed, and biocompatible with the biological environment of interest. Thus, it is possible to produce smart nano-systems with advanced applications in biotechnology and biomedical areas, such as ecological packaging, bio-robots, and tumor markers for diagnosis and therapy. In this chapter, we propose a brief report about the main methods of functionalization of boron nitride and their advances and potential applications in biotechnology and nanomedicine.

#### **2. Boron nitride functionalization and its implications in nanomedicine**

Hexagonal boron nitride is thermal and chemically layered structure more stable than graphitic carbon structures. Due to its excellent chemical stability, a better biological performance is expected [27]. The key for application of h-BN in different

systems is its dispersion by the introduction of specific agents (such as surfactants) or by some covalent attachments [28]. The adequate modification process provides specific surfaces that allow its better solubility or dispersion in different solvents media playing an important role regarding selectivity, for instance, in biological systems [28]. These nanoparticles can be coated with biological molecules to facilitate their interaction with a living system, binding to a specific target, like tumor cells [29]. Regarding the tumor targeting strategies, the enhanced permeability and retention (EPR) effect of nanomaterials is a key mechanism for solid tumor targeting, and it is considered a gold standard for novel radioisotopes design [30]. There are two different types of possible modifications. One is to attach, covalently, a molecule or molecular structure, and the second approach is through physical adsorption onto BN or h-BN surface nanostructure. In addition to improve solubility and dispersion, an important issue that needs to be addressed is the toxicity of boron nitride materials and their behavior in a biological system. The primary objective of toxicology studies is to evaluate the safety of potential drug candidates, using animal models and validated procedures to access genetic toxicology, acute and sub-chronic toxicology, and absorption, distribution, metabolism, and excretion (ADME) studies [31]. The ability to design, format, and run assays that are specific, sensitive, and robust is crucial in biomedical research and plays an important role in launching a drug development project to a successful outcome. One of the most important prerequisites that a new drug must fulfill is nontoxicity. Cell culture can be used to access toxicity and cytocompatibility of BN, detecting several parameters such cytosolic enzyme release, cell growth, and cloning efficiency. Many factors can be defined directly related to chemical kinetics like absorption rates, membrane permeability, intracellular synthetic pathways, biotransformation, oxidative stress, or apoptosis/necrosis induction, distribution, and excretion [32, 33]. The modulation of immune cell response can be evaluated at gene and protein levels, mainly regarding the expression of cytokines and chemokines [33].

A study showed that important cytotoxic effects of pure BNNTs on several cell lines were observed with a concentration of 20 μg/mL. According to this viability test, the levels of toxicity and morphological alterations were cell-type dependent and related to the absence of a biomolecule, causing acute toxicity in cell cultures, due to the increased nanomaterial accumulation [34].

In an interesting study, Ciofani et al. [10] proposed a technique to obtain BNNT stable dispersions for biological applications, dissolving BNNT powder in polyethylenimine (PEI) water solutions via an ultrasonication process. PEI is a cationic polymer for nucleic acid delivery with a high transfection efficiency, enhanced cellular uptake, and endosomal escape. In this in vitro testing performed on human neuroblastoma cell line (SH-SY5Y), PEI-coated BNNTs showed good cell viability in the culture medium. Another study demonstrated that pectin-coated BNNTs (P-BNNTs) are nontoxic for macrophages up to 50 μg/mL after 24 h of incubation. According to this study, cytokine expression was not affected by the administration of the P-BNNT, and its uptake by macrophages did not cause any cell membrane impairment, adverse effects, or inflammation processes in the cell [33]. BN coated with glycol-chitosan (GC) assay was performed to evaluate the BNNT interactions with biological systems and determine their biosafety, using human vein endothelial cells (HUVECs). Various parameters were observed such as cell toxicity, proliferation, cytoskeleton integrity, cell activation, and DNA damage. At the highest concentration, only a small reduction in cell viability and the increase of a vascular adhesion molecule (a marker of cell activation) expression were identified. According to that study, these findings show that GC-BNNTs do not affect endothelial cell biology and can be further investigated for vascular targeting, imaging, and drug delivery [35].

**29**

*Functionalized Boron Nitride Applications in Biotechnology*

effects on animal stem cell biology or on tissue regeneration [40].

As the cytotoxicity and biocompatibility of nanomaterials are being elucidated, new approaches overcome this first phase of research, leading to new discoveries and opening doors to novel alternatives. The antimicrobial activity of nanoparticles was investigated on different microorganisms in a study with h-BN. It was demonstrated that the h-BN has a bacteriostatic effect and shows a high antibiofilm activity on preformed biofilm [38]. PEI-BNNTs and other surfactant-coated BNNTs were also examined to elucidate their antibacterial activity. The optical density of bacterial growth curves and the transmission electron microscopy morphology images revealed that PEI-BNNTs exhibit strong microbial activity against *Escherichia coli* and *Staphylococcus aureus* [41]. Because of its low toxicity, high mechanical strength, and chemical stability, BNNTs also are considered to be a promising bioactive material for bone tissue engineering, improving polymers, composites, and scaffold properties [42]. In a study, akermanite (AKM), a bioactive material, was reinforced with boron nitride nanosheets (BNNSs) to ameliorate its mechanical features [43]. Significantly enhancement in compressive strength, fracture toughness, and an overall favorable cytocompatibility characteristics were found. Analysis of osteoblast gene expression and alkaline phosphatase activity measurement suggest that

Cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (ODNs) are molecules that present promising therapeutic properties due to their capability of stimulating innate and adaptive immune responses, activating Toll-like receptor 9 (TRL-9), leading to induction of proinflammatory cytokines [36]. The CpG ODNs delivery system was developed by the functionalization of boron nitride nanospheres with PEI. The complex BNNs-PEI showed enhanced dispersity and stability in aqueous solution. Although PEI itself can be used as a drug delivery carrier, the complex BNNs-PEI exhibited much higher efficiency than the PEI alone, increased CpG ODNs' cellular uptake and induced higher expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α) from peripheral blood mononuclear cells. No obvious cytotoxicity was observed with concentrations up to 100 μg/mL [35]. It was demonstrated that the complex PEI-BNNTs is internalized through an energy-dependent process via endocytosis pathway. PEI coating influences the behavior of BNNTs as it enhances the chemical reactivity of the nanotubes, allowing the interaction with a biological system [37]. In another cell viability assay [36], the MRC-5 culture, a diploid cell line derived from human fetal lung, normally used as a model for early cytotoxicity studies was treated for 48 h with samarium doped boron nitride nanotubes (Sm- BNNTs). This study demonstrated that even at the highest concentration, the cell viability was higher than 70%. This result reassures the findings of previous studies [29, 37, 38], confirming that, in concentrations below 200 μg/mL, BNNTs showed low cytotoxicity, and BNNTs do not appear to inhibit cell growth or induce apoptotic pathways in the cells. It should be noted that the high purity and quality of BNNTs are crucial for their nontoxicity [11, 36]. Many studies were conducted to determine possible toxicity to metabolism and liver morphology, as well as to renal function. A biodistribution study shows a significant elimination of BNNTs by renal excretion and accumulation in the liver, spleen, and intestines [36]. Ciofani et al. results indicate a similar pharmacokinetic behavior in an in vivo investigation of BNNTs in rabbits, with relatively high clearance of GC-BNNTs from the blood, with quick distribution and excretion [39]. The hematological parameters were monitored for up to 7 days. During the observation period, neither unusual behavior including sweating, excitement, trembling, head nodding, or temperature changes was observed. The study showed excellent hematological results without evidence of adverse effect, liver or kidney impairment [18]. A biocompatibility study with planarians indicated that gum Arabic-coated BNNTs do not induce oxidative DNA damage and apoptosis and did not show adverse

*DOI: http://dx.doi.org/10.5772/intechopen.80849*

*Recent Advances in Boron-Containing Materials*

regarding the expression of cytokines and chemokines [33].

due to the increased nanomaterial accumulation [34].

A study showed that important cytotoxic effects of pure BNNTs on several cell lines were observed with a concentration of 20 μg/mL. According to this viability test, the levels of toxicity and morphological alterations were cell-type dependent and related to the absence of a biomolecule, causing acute toxicity in cell cultures,

In an interesting study, Ciofani et al. [10] proposed a technique to obtain BNNT stable dispersions for biological applications, dissolving BNNT powder in polyethylenimine (PEI) water solutions via an ultrasonication process. PEI is a cationic polymer for nucleic acid delivery with a high transfection efficiency, enhanced cellular uptake, and endosomal escape. In this in vitro testing performed on human neuroblastoma cell line (SH-SY5Y), PEI-coated BNNTs showed good cell viability in the culture medium. Another study demonstrated that pectin-coated BNNTs (P-BNNTs) are nontoxic for macrophages up to 50 μg/mL after 24 h of incubation. According to this study, cytokine expression was not affected by the administration of the P-BNNT, and its uptake by macrophages did not cause any cell membrane impairment, adverse effects, or inflammation processes in the cell [33]. BN coated with glycol-chitosan (GC) assay was performed to evaluate the BNNT interactions with biological systems and determine their biosafety, using human vein endothelial cells (HUVECs). Various parameters were observed such as cell toxicity, proliferation, cytoskeleton integrity, cell activation, and DNA damage. At the highest concentration, only a small reduction in cell viability and the increase of a vascular adhesion molecule (a marker of cell activation) expression were identified. According to that study, these findings show that GC-BNNTs do not affect endothelial cell biology and can be further investigated for vascular targeting, imaging, and

systems is its dispersion by the introduction of specific agents (such as surfactants) or by some covalent attachments [28]. The adequate modification process provides specific surfaces that allow its better solubility or dispersion in different solvents media playing an important role regarding selectivity, for instance, in biological systems [28]. These nanoparticles can be coated with biological molecules to facilitate their interaction with a living system, binding to a specific target, like tumor cells [29]. Regarding the tumor targeting strategies, the enhanced permeability and retention (EPR) effect of nanomaterials is a key mechanism for solid tumor targeting, and it is considered a gold standard for novel radioisotopes design [30]. There are two different types of possible modifications. One is to attach, covalently, a molecule or molecular structure, and the second approach is through physical adsorption onto BN or h-BN surface nanostructure. In addition to improve solubility and dispersion, an important issue that needs to be addressed is the toxicity of boron nitride materials and their behavior in a biological system. The primary objective of toxicology studies is to evaluate the safety of potential drug candidates, using animal models and validated procedures to access genetic toxicology, acute and sub-chronic toxicology, and absorption, distribution, metabolism, and excretion (ADME) studies [31]. The ability to design, format, and run assays that are specific, sensitive, and robust is crucial in biomedical research and plays an important role in launching a drug development project to a successful outcome. One of the most important prerequisites that a new drug must fulfill is nontoxicity. Cell culture can be used to access toxicity and cytocompatibility of BN, detecting several parameters such cytosolic enzyme release, cell growth, and cloning efficiency. Many factors can be defined directly related to chemical kinetics like absorption rates, membrane permeability, intracellular synthetic pathways, biotransformation, oxidative stress, or apoptosis/necrosis induction, distribution, and excretion [32, 33]. The modulation of immune cell response can be evaluated at gene and protein levels, mainly

**28**

drug delivery [35].

Cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (ODNs) are molecules that present promising therapeutic properties due to their capability of stimulating innate and adaptive immune responses, activating Toll-like receptor 9 (TRL-9), leading to induction of proinflammatory cytokines [36]. The CpG ODNs delivery system was developed by the functionalization of boron nitride nanospheres with PEI. The complex BNNs-PEI showed enhanced dispersity and stability in aqueous solution. Although PEI itself can be used as a drug delivery carrier, the complex BNNs-PEI exhibited much higher efficiency than the PEI alone, increased CpG ODNs' cellular uptake and induced higher expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α) from peripheral blood mononuclear cells. No obvious cytotoxicity was observed with concentrations up to 100 μg/mL [35].

It was demonstrated that the complex PEI-BNNTs is internalized through an energy-dependent process via endocytosis pathway. PEI coating influences the behavior of BNNTs as it enhances the chemical reactivity of the nanotubes, allowing the interaction with a biological system [37]. In another cell viability assay [36], the MRC-5 culture, a diploid cell line derived from human fetal lung, normally used as a model for early cytotoxicity studies was treated for 48 h with samarium doped boron nitride nanotubes (Sm- BNNTs). This study demonstrated that even at the highest concentration, the cell viability was higher than 70%. This result reassures the findings of previous studies [29, 37, 38], confirming that, in concentrations below 200 μg/mL, BNNTs showed low cytotoxicity, and BNNTs do not appear to inhibit cell growth or induce apoptotic pathways in the cells. It should be noted that the high purity and quality of BNNTs are crucial for their nontoxicity [11, 36]. Many studies were conducted to determine possible toxicity to metabolism and liver morphology, as well as to renal function. A biodistribution study shows a significant elimination of BNNTs by renal excretion and accumulation in the liver, spleen, and intestines [36]. Ciofani et al. results indicate a similar pharmacokinetic behavior in an in vivo investigation of BNNTs in rabbits, with relatively high clearance of GC-BNNTs from the blood, with quick distribution and excretion [39]. The hematological parameters were monitored for up to 7 days. During the observation period, neither unusual behavior including sweating, excitement, trembling, head nodding, or temperature changes was observed. The study showed excellent hematological results without evidence of adverse effect, liver or kidney impairment [18]. A biocompatibility study with planarians indicated that gum Arabic-coated BNNTs do not induce oxidative DNA damage and apoptosis and did not show adverse effects on animal stem cell biology or on tissue regeneration [40].

As the cytotoxicity and biocompatibility of nanomaterials are being elucidated, new approaches overcome this first phase of research, leading to new discoveries and opening doors to novel alternatives. The antimicrobial activity of nanoparticles was investigated on different microorganisms in a study with h-BN. It was demonstrated that the h-BN has a bacteriostatic effect and shows a high antibiofilm activity on preformed biofilm [38]. PEI-BNNTs and other surfactant-coated BNNTs were also examined to elucidate their antibacterial activity. The optical density of bacterial growth curves and the transmission electron microscopy morphology images revealed that PEI-BNNTs exhibit strong microbial activity against *Escherichia coli* and *Staphylococcus aureus* [41]. Because of its low toxicity, high mechanical strength, and chemical stability, BNNTs also are considered to be a promising bioactive material for bone tissue engineering, improving polymers, composites, and scaffold properties [42]. In a study, akermanite (AKM), a bioactive material, was reinforced with boron nitride nanosheets (BNNSs) to ameliorate its mechanical features [43]. Significantly enhancement in compressive strength, fracture toughness, and an overall favorable cytocompatibility characteristics were found. Analysis of osteoblast gene expression and alkaline phosphatase activity measurement suggest that

nanomaterials have a great potential in the orthopedic implant field [28]. Chitosanbased scaffolds are thoroughly studied owing to their biocompatibility and antimicrobial activity. Hydroxylated BNNTs (BNNT-OH) were included into a chitosan scaffold and tested for their mechanical strength. The results of this study indicated that the inclusion of BNNT-OH increased mechanical strength and induced cell proliferation and adhesion decreased the scaffold degradation rate when compared to chitosan-only scaffold and did not cause toxicity to human dermal fibroblast cells [42]. Despite of some different experimental approaches and nanomaterial complexity, most of the studies show very good response of cells and organisms toward boron nitride nanocompounds. Researches about boron nitride applications in biotechnology are at full expansion, and nanomaterial biocompatibility and biosafety require further investigation.

#### **2.1 Functionalized BN as a candidate for imaging and cancer therapy**

Nowadays, some challenges regarding the earliest tumor diagnosis and treatment have been discussed considering that time represents a critical point between death and surviving. In this way, nanotechnology appears as promising tool due to its small size and remarkable physical-chemical characteristics as well, opening the as-called nanomedicine era. Traditional imaging resources to identify tumor sites have been applying ionizing radiation equipment. One of the most used is computed tomography followed by scintigraphy such as positron emission tomography coupled with computed tomography images (PET-CT). Likewise, non-ionizing radiation tools are applied such as magnetic resonance image (MRI). However, even though all these strategies possess high-image resolution, they are not completely able to detect smaller precocious tumors a primary indicative of micrometastasis.

There are several efforts to enhance the quality of images especially those taken from MRI. Notwithstanding, technical advances in nanotechnology are creating novel classes of MRI contrast-enhancing agents offering much higher relaxivities than most current clinical contrast agents, which translates into greater MRI contrast enhancement. These nanoscale agents also have the potential to revolutionize in vivo applications of contrast-enhanced MRI since they offer the multiple advantages of low toxicities, extremely high relaxivities, and cell internalization capabilities [44]. One of these nanomaterials presenting good possibilities to enhance MRI contrast is boron nitride nanotubes (BNNTs) containing Fe paramagnetic impurities. One drawback of pristine BNNT is its high hydrophobicity, and to overcome the low solubility of pristine BNNTs in aqueous solution, they can be wrapped with poly-L-lysine creating a PLL-BNNT. This soluble BNNT containing Fe has demonstrated values of transverse relaxivities comparable to commercial superparamagnetic iron oxide nanoparticles suggesting Fe-BNNT as a potential magnetic-enhanced contrast agent for MRI images at a field of 3 T [45]. Much has been investigated to improve the beneficial effects of radiotherapy especially in that case where radioresistant behavior is observed [46]. Radiotherapy is one of the most largely and effective tools to treat cancer using different approaches among then 10B through the boron neutron capture therapy (BNCT). The fundamental concept of boron neutron capture therapy is the production of high-linear energy transfer (LET) particles when one "tags" or "labels" a tumor cell with a compound having a large cross section capable of capturing a neutron. After neutron capture it goes into excited state releasing local energy driving heavy ion products over short distances comparable to the dimensions of cells ~20 μm [47]. The BNCT reaction is presented in **Figure 3**.

BNNTs have been thought as a possible candidate to BNCT due to their considerable high B density. Preliminary in vitro studies have suggested

**31**

*Functionalized Boron Nitride Applications in Biotechnology*

folate-functionalized BNNTs (FA-BNNT) as a potential boron delivery agent to malignant glioblastoma cells whose results have confirmed a strong and selective uptake of these nanotube vectors by human glioblastoma multiforme T98G cells and for cervix tumor cell line HeLa, but not by normal human fibroblasts [48, 49]. PEGylated BNNT was evaluated as a BNCT strategy in B16 melanoma cell line compared with the conventional B carrier sodium borocaptate (BSH). Although PEGylated BNNT have shown three times higher cellular uptake than BSH, the concentration of 10B delivered wasn't enough to perform BNCT as well as gold nanoparticles functionalized with carboranes as a 10B donator. Even though these nanoparticles have demonstrated high accumulation of B atoms inside cells, they have failure in therapeutic window for BNCT, then requiring improvements in their

*Li nuclei*

*BNCT reaction scheme. 10B bombarded by thermal neutrons resulting in a nuclear reaction where 7*

*and α particles are released offering a lethal effect localized within a tumor cell.*

Other applications of BNs in the field of cancer treatment due to their physical properties have been proposed. One of them presents a new boron-containing chlorin derivative as an agent for photodynamic therapy (PDT) and BNCT. Using in vivo xenographic tumor model, the results have shown significant tumor growth inhibition suggesting this nanocompound as a promising agent for PDT and for BNCT as well [52]. Radioisotopes can be used as image resource in nuclear medicine and in some cases as a therapy agent too. BNNT doped with samarium 152, a radioactive isotope from a rare earth metal of the lanthanide group, has shown low toxicity in MRC-5 fibroblasts suggesting this nanomaterial as a potential nanosized β-emission source for nuclear medicine therapy especially for bone metastasis treatment [30]. Another widely used pathway to cancer treatment is chemotherapy. Despite efficient outcomes of chemotherapeutical agents, side effects are usual, and, in some cases, *enhanced permeability and retention* (*EPR*) *effect is hampered*. *Doxorubicin* (*DOX*) *and* paclitaxel *are a broad-spectrum antitumor drugs widely used for the treatment of several kinds of cancers, including prostate, breast and ovarian*. *As an attempt to improve chemotherapy effects*, different types of nanocarriers are under investigation especially as selectively drug deliver, commonly using liposomes and carbon nanotubes (CNTs). The utility of BNNTs@NaGdF4:Eu composites as a targeted cancer therapeutic for chemotherapy drug delivery, used to load doxorubicin in the absence and presence of a magnetic field, has been demonstrated. By using human prostate cancer LNCaP cell line, the BNNTs@NaGdF4:Eu composite shows a loading efficiency of doxorubicin of about 30% when a magnetic field is applied [53]. Besides, the administration of hollow BN spheres with paclitaxel leads to synergetic effects in the suppression of tumor growth of human prostate cancer as in vitro as

*DOI: http://dx.doi.org/10.5772/intechopen.80849*

design as a 10B source [50, 51].

**Figure 3.**

in vivo mainly due to apoptosis death [54].

**Figure 3.**

*Recent Advances in Boron-Containing Materials*

biosafety require further investigation.

nanomaterials have a great potential in the orthopedic implant field [28]. Chitosanbased scaffolds are thoroughly studied owing to their biocompatibility and antimicrobial activity. Hydroxylated BNNTs (BNNT-OH) were included into a chitosan scaffold and tested for their mechanical strength. The results of this study indicated that the inclusion of BNNT-OH increased mechanical strength and induced cell proliferation and adhesion decreased the scaffold degradation rate when compared to chitosan-only scaffold and did not cause toxicity to human dermal fibroblast cells [42]. Despite of some different experimental approaches and nanomaterial complexity, most of the studies show very good response of cells and organisms toward boron nitride nanocompounds. Researches about boron nitride applications in biotechnology are at full expansion, and nanomaterial biocompatibility and

**2.1 Functionalized BN as a candidate for imaging and cancer therapy**

Nowadays, some challenges regarding the earliest tumor diagnosis and treatment have been discussed considering that time represents a critical point between death and surviving. In this way, nanotechnology appears as promising tool due to its small size and remarkable physical-chemical characteristics as well, opening the as-called nanomedicine era. Traditional imaging resources to identify tumor sites have been applying ionizing radiation equipment. One of the most used is computed tomography followed by scintigraphy such as positron emission tomography coupled with computed tomography images (PET-CT). Likewise, non-ionizing radiation tools are applied such as magnetic resonance image (MRI). However, even though all these strategies possess high-image resolution, they are not completely able to detect smaller precocious tumors a primary indicative of micrometastasis. There are several efforts to enhance the quality of images especially those taken from MRI. Notwithstanding, technical advances in nanotechnology are creating novel classes of MRI contrast-enhancing agents offering much higher relaxivities than most current clinical contrast agents, which translates into greater MRI contrast enhancement. These nanoscale agents also have the potential to revolutionize in vivo applications of contrast-enhanced MRI since they offer the multiple advantages of low toxicities, extremely high relaxivities, and cell internalization capabilities [44]. One of these nanomaterials presenting good possibilities to enhance MRI contrast is boron nitride nanotubes (BNNTs) containing Fe paramagnetic impurities. One drawback of pristine BNNT is its high hydrophobicity, and to overcome the low solubility of pristine BNNTs in aqueous solution, they can be wrapped with poly-L-lysine creating a PLL-BNNT. This soluble BNNT containing Fe has demonstrated values of transverse relaxivities comparable to commercial superparamagnetic iron oxide nanoparticles suggesting Fe-BNNT as a potential magnetic-enhanced contrast agent for MRI images at a field of 3 T [45]. Much has been investigated to improve the beneficial effects of radiotherapy especially in that case where radioresistant behavior is observed [46]. Radiotherapy is one of the most largely and effective tools to treat cancer using different approaches among then 10B through the boron neutron capture therapy (BNCT). The fundamental concept of boron neutron capture therapy is the production of high-linear energy transfer (LET) particles when one "tags" or "labels" a tumor cell with a compound having a large cross section capable of capturing a neutron. After neutron capture it goes into excited state releasing local energy driving heavy ion products over short distances comparable to the dimensions of cells ~20 μm [47]. The BNCT reaction is

BNNTs have been thought as a possible candidate to BNCT due to their considerable high B density. Preliminary in vitro studies have suggested

**30**

presented in **Figure 3**.

*BNCT reaction scheme. 10B bombarded by thermal neutrons resulting in a nuclear reaction where 7 Li nuclei and α particles are released offering a lethal effect localized within a tumor cell.*

folate-functionalized BNNTs (FA-BNNT) as a potential boron delivery agent to malignant glioblastoma cells whose results have confirmed a strong and selective uptake of these nanotube vectors by human glioblastoma multiforme T98G cells and for cervix tumor cell line HeLa, but not by normal human fibroblasts [48, 49]. PEGylated BNNT was evaluated as a BNCT strategy in B16 melanoma cell line compared with the conventional B carrier sodium borocaptate (BSH). Although PEGylated BNNT have shown three times higher cellular uptake than BSH, the concentration of 10B delivered wasn't enough to perform BNCT as well as gold nanoparticles functionalized with carboranes as a 10B donator. Even though these nanoparticles have demonstrated high accumulation of B atoms inside cells, they have failure in therapeutic window for BNCT, then requiring improvements in their design as a 10B source [50, 51].

Other applications of BNs in the field of cancer treatment due to their physical properties have been proposed. One of them presents a new boron-containing chlorin derivative as an agent for photodynamic therapy (PDT) and BNCT. Using in vivo xenographic tumor model, the results have shown significant tumor growth inhibition suggesting this nanocompound as a promising agent for PDT and for BNCT as well [52]. Radioisotopes can be used as image resource in nuclear medicine and in some cases as a therapy agent too. BNNT doped with samarium 152, a radioactive isotope from a rare earth metal of the lanthanide group, has shown low toxicity in MRC-5 fibroblasts suggesting this nanomaterial as a potential nanosized β-emission source for nuclear medicine therapy especially for bone metastasis treatment [30].

Another widely used pathway to cancer treatment is chemotherapy. Despite efficient outcomes of chemotherapeutical agents, side effects are usual, and, in some cases, *enhanced permeability and retention* (*EPR*) *effect is hampered*. *Doxorubicin* (*DOX*) *and* paclitaxel *are a broad-spectrum antitumor drugs widely used for the treatment of several kinds of cancers, including prostate, breast and ovarian*. *As an attempt to improve chemotherapy effects*, different types of nanocarriers are under investigation especially as selectively drug deliver, commonly using liposomes and carbon nanotubes (CNTs). The utility of BNNTs@NaGdF4:Eu composites as a targeted cancer therapeutic for chemotherapy drug delivery, used to load doxorubicin in the absence and presence of a magnetic field, has been demonstrated. By using human prostate cancer LNCaP cell line, the BNNTs@NaGdF4:Eu composite shows a loading efficiency of doxorubicin of about 30% when a magnetic field is applied [53]. Besides, the administration of hollow BN spheres with paclitaxel leads to synergetic effects in the suppression of tumor growth of human prostate cancer as in vitro as in vivo mainly due to apoptosis death [54].

Despite BNNTs possess extraordinary physical-chemical properties highlighting the potential applications of these nanomaterials in nanomedicine, they have been poorly exploited [55, 56]. The safety and cytobiocompatibility of boron nitride compounds have been reported in vitro using glioblastoma multiforme T98G cells [48], human MRC-5 fibroblast cells [48], human cervix tumor cell line HeLa [49], melanoma B16 cells [50], rat-derived osteosarcoma cell line UMR-106 [51], human neuroblastoma cells SH-SY5Y [37, 57], and human embryonic kidney cell line HEK 293 [11]. However, based on the fact that nanotubes present some similarities with asbestos lung cancer, human lung cancer cells (A549), alveolar macrophages (RAW264.7), fibroblast cells (3T3-L1), and human embryonic kidney cells (HEK293) were also exposed to BNNTs to verify cytotoxicity regarding BN compounds. In fact, the results indicate that BNNTs are cytotoxic in vitro even at low concentration in a time and dose-dependent manner promoting morphological alterations and decreased cellular viability [34].

Nanomaterials applied in medicine are a controversial issue requiring further investigations, especially due to a potential toxicity and environmental consequences regarding B compound disposal, and their biological responses need to be examined like extensively related CNT cytotoxicity reports. Recent progress in the field of nanomedicine research has offered good alternatives on this matter, especially those targeting tumor cells with metal nanoparticles [58]. For a while, the insipient results highlight a promising future for nanomedicine leading to new therapeutic approaches. For instance, graphene oxide may be an effective nontoxic therapeutic strategy for the eradication of cancer stem cells, via differentiationbased nanotherapy [59]. As described above, boron nitride represents one of the most promising nanomaterials in nanomedicine since some drawbacks can be overcome such as improvement of solubility in aqueous solution, high 10B concentrations releasing, allowing their use for BNCT and reducing of cytotoxicity. Moreover, further preclinical investigations will provide the safety and efficacy of BN for image and therapy leading to a more deeply knowledge about biodistribution, clearance, and side effects regarding dose, time, and administration pathways.

#### **3. Computational simulation perspectives of boron nitride nanotubes using as drug carriers for cancer treatment**

The advances in nanotechnology have stimulated a large production and storage of information coming from different sources, such as high-processing DNA sequencers, nuclear magnetic resonance, X-ray crystallography, electron microscopy images, and spectroscopic data, among others [60]. This large number of information about different systems needs to be quickly processed and understood in terms of structure, morphology function, and properties being solved by computational simulation (CS) with efficiency and high degree of accuracy [60]. CS has been widely used in studies of aggregation, folding, functionality, and nanoengineering platforms for several proteins, tertiary structures of RNA, and nanostructures surfaces and arises in the development of new techniques and diagnosis and therapy [61]. Thermodynamic properties such as enthalpy, entropy, and free energy of protein conformations also have been used to predict different protein and DNA structures [62], with atomic details applied in complex organisms [63]. By molecular dynamic simulation (MDS), several researchers have investigated the behavior of different nanoparticles, clusters, biomolecules, polymers, ceramics, metal alloys, composites, and fuel systems in relative short-time operation, compared to other non-computational methods. Numerical simulations based on preestablished mathematical models that involve quantum mechanics, molecular mechanics, Monte-Carlo, or a hybrid thereof have been used as well [64].

**33**

*Functionalized Boron Nitride Applications in Biotechnology*

Quantum mechanics provides the accurate description of the energy about system electronic distribution. However, this description may have some restrictions, such as the size of the system (< 500 atoms) and requires high computational power, due to the large correlation in many electron interactions [65]. This limitation can be overcome by the density functional theory (DFT), to solve many body systems, for example, ionization energy calculations and band theory analysis. In this approach is considered an ab initio method because it does not require initial parameterizations, making this technique faster when used electronic density approximations are used, such as Car-Parrinello and Born-Oppenheimer methods [66]. In the case of molecular mechanics, the potential energy is described in geometric terms by force fields inherent to the molecules, in their internal and external interactions [64]. This approach acts empirically on the integration of potential energies resulted from the intramolecular interactions and intermolecular where the energy of each components or entity must be explicitly parameterized according to the specific equilibrium between atoms and their geometry imposed by their structures [65]. The Monte-Carlo method provides spatial conformation based on the atoms' distribution probabilities predicted by the Boltzmann equilibrium in each random Cartesian coordinate. The selected conformation positions within a tridimensional space, regarding to its rotation, torsion, or twist which needs to be lower than its initial conformation in study [65]. About the computational methods used in nanotechnology, we can highlight several studies in different nanostructures, such as h-BN and BNNTs, explored in several technology areas such as DNA sequencing [66–70], water treatment [71–74], piezoelectric properties [75, 76], and drug delivery [77–79], among others. For instance, the cisplatin (CP) is a well-known agent chemotherapeutic that acts directly on DNA causing defects in the cell repair mechanism and leading to apoptosis. This drug is widely used in treatment of several types of cancer, such as lymphomas, sarcomas, and carcinomas, as well as in the treatment of other types of cancer that are affecting the head and neck, bladder, lung, ovaries, and testicles [80]. However, its cellular uptake sometime is accompanied by large side effects and development of resistance, causing allergic reactions, low immunity to infections, hemorrhages, kidney problems, and gastrointestinal disorders among other effects [80]. Similarly, the doxorubicin is a type of anthracycline that acts in the DNA structure preventing its replication, with important role in relation to other chemotherapeutics that present restrictions, such as cytotoxicity, accumulating irreversibly and compromising muscular tissues, mainly cardiac [81]. The expectation about the use of nanocarriers is related to the possibility whether they eliminate or reduce the harm effects in relation to conventional drugs [82]. From here, we will explore some interesting works about MDS applications considering the potential

*DOI: http://dx.doi.org/10.5772/intechopen.80849*

drug carrier as vector in cancer treatments.

For instance, Khatti and Hashemianzadeh focused their efforts on the diffusion process of water in loading of drugs inside the BNNT [83]. Their study was about single-walled zigzag BNNT (18,0) sample with length 40 Å and diameter 14 Å to represent the system. They use BNNT containing 18 hydroxyl groups (-OH) at the end and another one with saturated -OH groups at the same position. The model systems were solvated in an aqueous solution with a TIP3P in octagonal box over 12 Å. All systems were solvated with 7544 water molecules in total [83]. The simulations were performed with different combinations that also include the carboplatin (CPt) molecule. The MDS studies were carried out by the AMBER 12 package with SANDER module (at 300 K and 1 atm) using SHAKE algorithm, where each simulation included 5000 steps of solvent/solute running through 10 ns to the step

The results showed that the electrostatic interaction -OH groups in BNNT cause

of 2 fs [83]. The diffusion coefficient (D) results can be seen in **Table 1**.

different diffusion behaviors in water compared to BNNT nonfunctionalized.

#### *Functionalized Boron Nitride Applications in Biotechnology DOI: http://dx.doi.org/10.5772/intechopen.80849*

*Recent Advances in Boron-Containing Materials*

Despite BNNTs possess extraordinary physical-chemical properties highlighting the potential applications of these nanomaterials in nanomedicine, they have been poorly exploited [55, 56]. The safety and cytobiocompatibility of boron nitride compounds have been reported in vitro using glioblastoma multiforme T98G cells [48], human MRC-5 fibroblast cells [48], human cervix tumor cell line HeLa [49], melanoma B16 cells [50], rat-derived osteosarcoma cell line UMR-106 [51], human neuroblastoma cells SH-SY5Y [37, 57], and human embryonic kidney cell line HEK 293 [11]. However, based on the fact that nanotubes present some similarities with asbestos lung cancer, human lung cancer cells (A549), alveolar macrophages (RAW264.7), fibroblast cells (3T3-L1), and human embryonic kidney cells (HEK293) were also exposed to BNNTs to verify cytotoxicity regarding BN compounds. In fact, the results indicate that BNNTs are cytotoxic in vitro even at low concentration in a time and dose-dependent manner

promoting morphological alterations and decreased cellular viability [34].

Nanomaterials applied in medicine are a controversial issue requiring further investigations, especially due to a potential toxicity and environmental consequences regarding B compound disposal, and their biological responses need to be examined like extensively related CNT cytotoxicity reports. Recent progress in the field of nanomedicine research has offered good alternatives on this matter, especially those targeting tumor cells with metal nanoparticles [58]. For a while, the insipient results highlight a promising future for nanomedicine leading to new therapeutic approaches. For instance, graphene oxide may be an effective nontoxic therapeutic strategy for the eradication of cancer stem cells, via differentiationbased nanotherapy [59]. As described above, boron nitride represents one of the most promising nanomaterials in nanomedicine since some drawbacks can be overcome such as improvement of solubility in aqueous solution, high 10B concentrations releasing, allowing their use for BNCT and reducing of cytotoxicity. Moreover, further preclinical investigations will provide the safety and efficacy of BN for image and therapy leading to a more deeply knowledge about biodistribution, clearance, and side effects regarding dose, time, and administration pathways.

**3. Computational simulation perspectives of boron nitride nanotubes**

The advances in nanotechnology have stimulated a large production and storage of information coming from different sources, such as high-processing DNA sequencers, nuclear magnetic resonance, X-ray crystallography, electron microscopy images, and spectroscopic data, among others [60]. This large number of information about different systems needs to be quickly processed and understood in terms of structure, morphology function, and properties being solved by computational simulation (CS) with efficiency and high degree of accuracy [60]. CS has been widely used in studies of aggregation, folding, functionality, and nanoengineering platforms for several proteins, tertiary structures of RNA, and nanostructures surfaces and arises in the development of new techniques and diagnosis and therapy [61]. Thermodynamic properties such as enthalpy, entropy, and free energy of protein conformations also have been used to predict different protein and DNA structures [62], with atomic details applied in complex organisms [63]. By molecular dynamic simulation (MDS), several researchers have investigated the behavior of different nanoparticles, clusters, biomolecules, polymers, ceramics, metal alloys, composites, and fuel systems in relative short-time operation, compared to other non-computational methods. Numerical simulations based on preestablished mathematical models that involve quantum mechanics, molecular mechanics,

**using as drug carriers for cancer treatment**

Monte-Carlo, or a hybrid thereof have been used as well [64].

**32**

Quantum mechanics provides the accurate description of the energy about system electronic distribution. However, this description may have some restrictions, such as the size of the system (< 500 atoms) and requires high computational power, due to the large correlation in many electron interactions [65]. This limitation can be overcome by the density functional theory (DFT), to solve many body systems, for example, ionization energy calculations and band theory analysis. In this approach is considered an ab initio method because it does not require initial parameterizations, making this technique faster when used electronic density approximations are used, such as Car-Parrinello and Born-Oppenheimer methods [66]. In the case of molecular mechanics, the potential energy is described in geometric terms by force fields inherent to the molecules, in their internal and external interactions [64]. This approach acts empirically on the integration of potential energies resulted from the intramolecular interactions and intermolecular where the energy of each components or entity must be explicitly parameterized according to the specific equilibrium between atoms and their geometry imposed by their structures [65]. The Monte-Carlo method provides spatial conformation based on the atoms' distribution probabilities predicted by the Boltzmann equilibrium in each random Cartesian coordinate. The selected conformation positions within a tridimensional space, regarding to its rotation, torsion, or twist which needs to be lower than its initial conformation in study [65]. About the computational methods used in nanotechnology, we can highlight several studies in different nanostructures, such as h-BN and BNNTs, explored in several technology areas such as DNA sequencing [66–70], water treatment [71–74], piezoelectric properties [75, 76], and drug delivery [77–79], among others. For instance, the cisplatin (CP) is a well-known agent chemotherapeutic that acts directly on DNA causing defects in the cell repair mechanism and leading to apoptosis. This drug is widely used in treatment of several types of cancer, such as lymphomas, sarcomas, and carcinomas, as well as in the treatment of other types of cancer that are affecting the head and neck, bladder, lung, ovaries, and testicles [80]. However, its cellular uptake sometime is accompanied by large side effects and development of resistance, causing allergic reactions, low immunity to infections, hemorrhages, kidney problems, and gastrointestinal disorders among other effects [80]. Similarly, the doxorubicin is a type of anthracycline that acts in the DNA structure preventing its replication, with important role in relation to other chemotherapeutics that present restrictions, such as cytotoxicity, accumulating irreversibly and compromising muscular tissues, mainly cardiac [81]. The expectation about the use of nanocarriers is related to the possibility whether they eliminate or reduce the harm effects in relation to conventional drugs [82]. From here, we will explore some interesting works about MDS applications considering the potential drug carrier as vector in cancer treatments.

For instance, Khatti and Hashemianzadeh focused their efforts on the diffusion process of water in loading of drugs inside the BNNT [83]. Their study was about single-walled zigzag BNNT (18,0) sample with length 40 Å and diameter 14 Å to represent the system. They use BNNT containing 18 hydroxyl groups (-OH) at the end and another one with saturated -OH groups at the same position. The model systems were solvated in an aqueous solution with a TIP3P in octagonal box over 12 Å. All systems were solvated with 7544 water molecules in total [83]. The simulations were performed with different combinations that also include the carboplatin (CPt) molecule. The MDS studies were carried out by the AMBER 12 package with SANDER module (at 300 K and 1 atm) using SHAKE algorithm, where each simulation included 5000 steps of solvent/solute running through 10 ns to the step of 2 fs [83]. The diffusion coefficient (D) results can be seen in **Table 1**.

The results showed that the electrostatic interaction -OH groups in BNNT cause different diffusion behaviors in water compared to BNNT nonfunctionalized.

#### **Table 1.**

*Diffusion coefficient (D) prediction of different BNNT systems in different combinations studied by Khatti and Hashemianzadeh (2016) [83].*

Therefore, the drug diffusivity into the nanotube can be related to the diffusive behavior of water molecules inside the tube. The increase of the diffusion rate of water molecules in BNNT-OH is observed according to the diffusion coefficient values. These results showed us that the penetration rate of the drug in BNNT-OH is larger than that nonfunctionalized BNNT, and the electrostatic interactions between carboplatin and hydroxyl groups on the tube edge enhance the permeation rate of the drugs into the nanotube cavity [83]. By MSD study, they observed that hydrogen bonds at the extremities of BNNT produce dipole-dipole interactions between hydrophilic CPt and -OH groups, which allow an efficient condition for the encapsulation of this drug. The hydroxyl groups also maintain the stability of the BNNT and prevent its aggregation into the solutions [83]. An encapsulation scheme of CPt molecules encapsulation into BNNT-OH can be visualized in **Figure 4**.

Nanotube structures are of great interest in nanomedicine as a vector in drug delivery; they can access the cell carrying large amounts of drugs due to their possibility endohedral functionalized surfaces [77]. From this juncture, several works have performed different theoretical methods of BNNT stability by drug encapsulation. For instance, the azomethine (AZ) prevents the carboplatin deactivation process, prematurely before the CPt achieves the cancer cell [77]. Studies have demonstrated that BNNT-OH acts as nanocarriers drugs for CPt complex. **Figure 5** shows a scheme of BNNT endohedrally functionalized with carboplatin, and the DNA linked covalently to the CPt complex.

Duverger et al. used DFT simulations to study the interactions between BNNT-OH in azomethine and an anticancer agent (Pt (IV) complex) linked with an amino-derivative chain. The geometry of the azomethine/Pt/amine system was optimized by different molecular configurations on the inner and outer surfaces of the BNNT. The authors also showed that the molecular chemisorption is possible only when the azomethine is present above two adjacent B and N atoms of a hexagon structure. The attachment of an azomethine and subsequent drug did not perturb the cycloaddition process. These theoretical results showed that the therapeutic Pt (IV) complex was not affected when it was attached onto BNNTs [84]. In another work, Khalifi et al. also demonstrated theoretical results about the use of BNNT particles as carrying drug insertion into to the lipid bilayer [85]. They studied a single-walled BNNT armchair (10,10) with diameter 13.94 Å and length 21.32 Å (also saturated with -OH groups) with its extremities encapsulated with carboplatin (CPt) in ionized solvated ambient to mimic a biological environment. The BNNT-CPt complex can move freely, and a bilipid membrane (BM) is formed by 656 molecules of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. It was applying DFT method conjugated with classical molecular mechanics [85]. The rapid diffusion of the BNNT-CPt complex toward BM with increased BNNT-CPt hydrophilicity due to surface of BNNT-OH was observed. This diffusion process was energetically favorable to the system due to the contribution of different energy component combinations. According to these results, the possibility of BNNT-OH as a specific ligand for cancer cells allows the more precise encapsulated drug delivery in cell membranes [85].

**35**

**4. Conclusion**

*great promises of nanobiotechnology.*

**Figure 5.**

**Figure 4.**

In this chapter we highlighted some experimental and theoretical works under different BN functionalization structures with potential biomedical applications. However, the most important aspect for success and an optimal performance about these compounds are the choice of the best tailored modification process for each biological system in study. Their physical-chemical modification is an essential step for relevant applications, leading to different systems chemically stable, dispersed,

*Theoretical prediction of BNNT (sticks and wires) by delivering CPt molecules directly into DNA, one of the*

*Functionalized Boron Nitride Applications in Biotechnology*

*CPt molecule encapsulated by BNNT-OH (a) and electrostatic force field of BNNT (b).*

*DOI: http://dx.doi.org/10.5772/intechopen.80849*

*Functionalized Boron Nitride Applications in Biotechnology DOI: http://dx.doi.org/10.5772/intechopen.80849*

*Recent Advances in Boron-Containing Materials*

Therefore, the drug diffusivity into the nanotube can be related to the diffusive behavior of water molecules inside the tube. The increase of the diffusion rate of water molecules in BNNT-OH is observed according to the diffusion coefficient values. These results showed us that the penetration rate of the drug in BNNT-OH is larger than that nonfunctionalized BNNT, and the electrostatic interactions between carboplatin and hydroxyl groups on the tube edge enhance the permeation rate of the drugs into the nanotube cavity [83]. By MSD study, they observed that hydrogen bonds at the extremities of BNNT produce dipole-dipole interactions between hydrophilic CPt and -OH groups, which allow an efficient condition for the encapsulation of this drug. The hydroxyl groups also maintain the stability of the BNNT and prevent its aggregation into the solutions [83]. An encapsulation scheme of CPt

*Diffusion coefficient (D) prediction of different BNNT systems in different combinations studied by Khatti*

**System D (cm2**

BNNT/water 0.440 BNNT-OH/water 0.600 BNNT-CPt/water 0.560 BNNT-OH/CPt 1.890

 **s−1 × 105 )**

molecules encapsulation into BNNT-OH can be visualized in **Figure 4**.

Nanotube structures are of great interest in nanomedicine as a vector in drug delivery; they can access the cell carrying large amounts of drugs due to their possibility endohedral functionalized surfaces [77]. From this juncture, several works have performed different theoretical methods of BNNT stability by drug encapsulation. For instance, the azomethine (AZ) prevents the carboplatin deactivation process, prematurely before the CPt achieves the cancer cell [77]. Studies have demonstrated that BNNT-OH acts as nanocarriers drugs for CPt complex. **Figure 5** shows a scheme of BNNT endohedrally functionalized with carboplatin, and the DNA linked covalently

Duverger et al. used DFT simulations to study the interactions between BNNT-OH in azomethine and an anticancer agent (Pt (IV) complex) linked with an amino-derivative chain. The geometry of the azomethine/Pt/amine system was optimized by different molecular configurations on the inner and outer surfaces of the BNNT. The authors also showed that the molecular chemisorption is possible only when the azomethine is present above two adjacent B and N atoms of a hexagon structure. The attachment of an azomethine and subsequent drug did not perturb the cycloaddition process. These theoretical results showed that the therapeutic Pt (IV) complex was not affected when it was attached onto BNNTs [84]. In another work, Khalifi et al. also demonstrated theoretical results about the use of BNNT particles as carrying drug insertion into to the lipid bilayer [85]. They studied a single-walled BNNT armchair (10,10) with diameter 13.94 Å and length 21.32 Å (also saturated with -OH groups) with its extremities encapsulated with carboplatin (CPt) in ionized solvated ambient to mimic a biological environment. The BNNT-CPt complex can move freely, and a bilipid membrane (BM) is formed by 656 molecules of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. It was applying DFT method conjugated with classical molecular mechanics [85]. The rapid diffusion of the BNNT-CPt complex toward BM with increased BNNT-CPt hydrophilicity due to surface of BNNT-OH was observed. This diffusion process was energetically favorable to the system due to the contribution of different energy component combinations. According to these results, the possibility of BNNT-OH as a specific ligand for cancer cells allows the more precise encapsulated drug delivery in cell membranes [85].

**34**

to the CPt complex.

**Table 1.**

*and Hashemianzadeh (2016) [83].*

#### **Figure 5.**

*Theoretical prediction of BNNT (sticks and wires) by delivering CPt molecules directly into DNA, one of the great promises of nanobiotechnology.*

#### **4. Conclusion**

In this chapter we highlighted some experimental and theoretical works under different BN functionalization structures with potential biomedical applications. However, the most important aspect for success and an optimal performance about these compounds are the choice of the best tailored modification process for each biological system in study. Their physical-chemical modification is an essential step for relevant applications, leading to different systems chemically stable, dispersed,

and compatible with the environment of interest. Thus, it is also possible to produce nano-templates with advanced applications in biotechnology. Clearly, computational simulation is an important support tool in science that contributes to reduce time, costs, and risks. In the case of cancer, several types of drugs already exist; however, their delivery to their specific sites remains a big challenge and leads to undesirable consequences. Thus, the computational methods in conjunction with nanotechnology can optimize parameters and procedures maybe improving diagnosis and treatment, the chances of cure. Based on all what have had proposed and investigated, boron nitride arises as a promising nanomaterial for several application even in nanomedicine and nanobiology.

#### **Acknowledgements**

The authors thank the researcher Wellington M. Silva (CDTN) and the Microscopy Center of the Federal University of Minas Gerais for the courtesy microscopy images. All images are produced exclusively for this work.

#### **Conflict of interest**

The authors also declare that there is no conflict of interest in this work.

#### **Author details**

Hélio Ribeiro1 \*, Paula von Cardoso Randow2 , Diego N. Vilela3 , Milene Adriane Luciano1 and Lidia Maria de Andrade4

1 Departamento de Química Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

2 Fundação Ezequiel Dias, Belo Horizonte, Brazil

3 Centro Universitário Barão de Mauá, Ribeirão Preto, Brazil

4 Nanobiomedical Research Group, Departamento de Física, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**37**

*Functionalized Boron Nitride Applications in Biotechnology*

graphene nanoribbon for cellular delivery of locked nucleic acid modified molecular beacon for

biomaterials.2011.02.001

hv.29589

jnn.2008.339

DOI: 10.1021/ja807334b

recognition of microRNA. Biomaterials. 2011;**32**(15):3875-3882. DOI: 10.1016/j.

[9] Zhu M, Wang R, Nie G. Applications of nanomaterials as vaccine adjuvants. Human Vaccines & Immunotherapeutics. 2014;**10**(9):2761-2774. DOI: 10.4161/

[10] Ciofani G, Raffa V, Menciassi A, Dario P. Preparation of boron nitride nanotubes aqueous dispersions for biological pplications. Journal of Nanoscience and Nanotechnology. 2008;**8**(12):6223-6231. DOI: 10.1166/

[11] Chen X, Wu P, Rousseas M, Okawa D, Gartner Z, Zettl A, et al. Boron nitride nanotubes are noncytotoxic and can be functionalized for interaction with proteins and cells. Journal of the American Chemical Society. 2009;**131**(3):890-891.

[12] Ribeiro H, Trigueiro J, Silva W, Woellner C, Owuor P, Cristian Chipara A, et al. Hybrid MoS2/h-BN nanofillers as synergic heat dissipation and reinforcement additives in epoxy nanocomposites. ACS Applied Materials

& Interfaces. 2017. DOI: 10.1021/ acsami.7b09945. https://pubs.acs.org/

[13] Ribeiro H, Trigueiro J, Lopes M, Pedrotti J, Woellner C, Silva W, et al. Enhanced thermal conductivity and mechanical properties of hybrid MoS2/ h-BN polyurethane nanocomposites. Journal of Applied Polymer Science. 2018;**135**(30):46560. DOI: 10.1002/

[14] Ribeiro H, Trigueiro J, Owuor P, Machado L, Woellner C, Pedrotti J, et al. Hybrid 2D nanostructures for

doi/10.1021/acsami.7b09945

app.46560

*DOI: http://dx.doi.org/10.5772/intechopen.80849*

[1] Weng Q, Wang X, Wang X, Bando Y, Golberg D. Functionalized hexagonal boron nitride nanomaterials: Emerging properties and applications. Chemical Society Reviews. 2016;**45**(14):3989-4012.

[2] Taha-Tijerina J, Narayanan T, Gao G, Rohde M, Tsentalovich D, Pasquali M, et al. Electrically insulating thermal nano-oils using 2D fillers. ACS Nano. 2012;**6**(2):1214-1220. DOI: 10.1021/

[3] Hong Y, Lee E, Choi J, Oh S, Haam S, Huh Y, et al. Gold nanorod-mediated photothermal modulation for localized ablation of cancer cells. Journal of Nanomaterials. 2012;**2012**:1-7. DOI:

[4] Bianco A, Kostarelos K, Prato M. Applications of carbon nanotubes in drug delivery. Current Opinion in Chemical Biology. 2005;**9**(6):674-679. DOI: 10.1016/j.cbpa.2005.10.005

[5] Ansorena MR, Marcovich NE, Pereda M. Food biopackaging based on chitosan. In: Torres Martínez L, Kharissova O, Kharisov B, editors. Handbook of Ecomaterials. Cham: Springer; 2017. pp. 1-27. DOI: 10.1007/978-3-319-48281-1\_68-1

[6] Zhang Q, Wu S, Zhang L, Lu J, Verproot F, Liu Y, et al. Fabrication of polymeric ionic liquid/graphene

oxidase immobilization and direct electrochemistry. Biosensors and Bioelectronics. 2011;**26**(5):2632-2637. DOI: 10.1016/j.bios.2010.11.024

[7] Shao Y, Wang J, Wu H, Liu J, Aksay I, Lin Y. Graphene based electrochemical sensors and biosensors: A Review. Electroanalysis. 2010;**22**(10):1027-1036.

nanocomposite for glucose

DOI: 10.1002/elan.200900571

[8] Dong H, Ding L, Yan F, Ji H, Ju H. The use of polyethylenimine-grafted

DOI: 10.1039/C5CS00869G

nn203862p

**References**

10.1155/2012/825060

*Functionalized Boron Nitride Applications in Biotechnology DOI: http://dx.doi.org/10.5772/intechopen.80849*

#### **References**

*Recent Advances in Boron-Containing Materials*

tion even in nanomedicine and nanobiology.

**Acknowledgements**

**Conflict of interest**

**36**

**Author details**

Milene Adriane Luciano1

Hélio Ribeiro1

Brazil

provided the original work is properly cited.

de Minas Gerais, Belo Horizonte, Brazil

\*, Paula von Cardoso Randow2

3 Centro Universitário Barão de Mauá, Ribeirão Preto, Brazil

\*Address all correspondence to<EMAIL_ADDRESS>
2 Fundação Ezequiel Dias, Belo Horizonte, Brazil

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

4 Nanobiomedical Research Group, Departamento de Física, Universidade Federal

and Lidia Maria de Andrade4

1 Departamento de Química Universidade Federal de Minas Gerais, Belo Horizonte,

and compatible with the environment of interest. Thus, it is also possible to produce nano-templates with advanced applications in biotechnology. Clearly, computational simulation is an important support tool in science that contributes to reduce time, costs, and risks. In the case of cancer, several types of drugs already exist; however, their delivery to their specific sites remains a big challenge and leads to undesirable consequences. Thus, the computational methods in conjunction with nanotechnology can optimize parameters and procedures maybe improving diagnosis and treatment, the chances of cure. Based on all what have had proposed and investigated, boron nitride arises as a promising nanomaterial for several applica-

The authors thank the researcher Wellington M. Silva (CDTN) and the Microscopy Center of the Federal University of Minas Gerais for the courtesy

The authors also declare that there is no conflict of interest in this work.

microscopy images. All images are produced exclusively for this work.

, Diego N. Vilela3

,

[1] Weng Q, Wang X, Wang X, Bando Y, Golberg D. Functionalized hexagonal boron nitride nanomaterials: Emerging properties and applications. Chemical Society Reviews. 2016;**45**(14):3989-4012. DOI: 10.1039/C5CS00869G

[2] Taha-Tijerina J, Narayanan T, Gao G, Rohde M, Tsentalovich D, Pasquali M, et al. Electrically insulating thermal nano-oils using 2D fillers. ACS Nano. 2012;**6**(2):1214-1220. DOI: 10.1021/ nn203862p

[3] Hong Y, Lee E, Choi J, Oh S, Haam S, Huh Y, et al. Gold nanorod-mediated photothermal modulation for localized ablation of cancer cells. Journal of Nanomaterials. 2012;**2012**:1-7. DOI: 10.1155/2012/825060

[4] Bianco A, Kostarelos K, Prato M. Applications of carbon nanotubes in drug delivery. Current Opinion in Chemical Biology. 2005;**9**(6):674-679. DOI: 10.1016/j.cbpa.2005.10.005

[5] Ansorena MR, Marcovich NE, Pereda M. Food biopackaging based on chitosan. In: Torres Martínez L, Kharissova O, Kharisov B, editors. Handbook of Ecomaterials. Cham: Springer; 2017. pp. 1-27. DOI: 10.1007/978-3-319-48281-1\_68-1

[6] Zhang Q, Wu S, Zhang L, Lu J, Verproot F, Liu Y, et al. Fabrication of polymeric ionic liquid/graphene nanocomposite for glucose oxidase immobilization and direct electrochemistry. Biosensors and Bioelectronics. 2011;**26**(5):2632-2637. DOI: 10.1016/j.bios.2010.11.024

[7] Shao Y, Wang J, Wu H, Liu J, Aksay I, Lin Y. Graphene based electrochemical sensors and biosensors: A Review. Electroanalysis. 2010;**22**(10):1027-1036. DOI: 10.1002/elan.200900571

[8] Dong H, Ding L, Yan F, Ji H, Ju H. The use of polyethylenimine-grafted graphene nanoribbon for cellular delivery of locked nucleic acid modified molecular beacon for recognition of microRNA. Biomaterials. 2011;**32**(15):3875-3882. DOI: 10.1016/j. biomaterials.2011.02.001

[9] Zhu M, Wang R, Nie G. Applications of nanomaterials as vaccine adjuvants. Human Vaccines & Immunotherapeutics. 2014;**10**(9):2761-2774. DOI: 10.4161/ hv.29589

[10] Ciofani G, Raffa V, Menciassi A, Dario P. Preparation of boron nitride nanotubes aqueous dispersions for biological pplications. Journal of Nanoscience and Nanotechnology. 2008;**8**(12):6223-6231. DOI: 10.1166/ jnn.2008.339

[11] Chen X, Wu P, Rousseas M, Okawa D, Gartner Z, Zettl A, et al. Boron nitride nanotubes are noncytotoxic and can be functionalized for interaction with proteins and cells. Journal of the American Chemical Society. 2009;**131**(3):890-891. DOI: 10.1021/ja807334b

[12] Ribeiro H, Trigueiro J, Silva W, Woellner C, Owuor P, Cristian Chipara A, et al. Hybrid MoS2/h-BN nanofillers as synergic heat dissipation and reinforcement additives in epoxy nanocomposites. ACS Applied Materials & Interfaces. 2017. DOI: 10.1021/ acsami.7b09945. https://pubs.acs.org/ doi/10.1021/acsami.7b09945

[13] Ribeiro H, Trigueiro J, Lopes M, Pedrotti J, Woellner C, Silva W, et al. Enhanced thermal conductivity and mechanical properties of hybrid MoS2/ h-BN polyurethane nanocomposites. Journal of Applied Polymer Science. 2018;**135**(30):46560. DOI: 10.1002/ app.46560

[14] Ribeiro H, Trigueiro J, Owuor P, Machado L, Woellner C, Pedrotti J, et al. Hybrid 2D nanostructures for

mechanical reinforcement and thermal conductivity enhancement in polymer composites. Composites Science and Technology. 2018;**159**:103-110. DOI: 10.1016/j.compscitech.2018.01.032

[15] Emanet M, Şen Ö, Çulha M. Evaluation of boron nitride nanotubes and hexagonal boron nitrides as nanocarriers for cancer drugs. Nanomedicine. 2017;**12**(7):797-810. DOI: 10.2217/nnm-2016-0322

[16] Kuila T, Bose S, Mishra A, Khanra P, Kim N, Lee J. Chemical functionalization of graphene and its applications. Progress in Materials Science. 2012;**57**(7):1061-1105. DOI: 10.1016/j.pmatsci.2012.03.002

[17] Tang P, Hu G, Gao Y, Li W, Yao S, Liu Z, et al. The microwave adsorption behavior and microwave-assisted heteroatoms doping of graphene-based nano-carbon materials. Scientific Reports. 2014;**4**(1). DOI: 10.1038/ srep05901

[18] Ribeiro H, da Silva W, Neves J, Calado H, Paniago R, Seara L, et al. Multifunctional nanocomposites based on tetraethylenepentamine-modified graphene oxide/epoxy. Polymer Testing. 2015;**43**:182-192. DOI: 10.1016/j. polymertesting.2015.03.010

[19] Sharma P, Tuteja S, Bhalla V, Shekhawat G, Dravid V, Suri C. Biofunctionalized graphene–graphene oxide nanocomposite based electrochemical immunosensing. Biosensors and Bioelectronics. 2013;**39**(1):99-105. DOI: 10.1016/j.bios.2012.06.061

[20] Kuila T, Khanra P, Mishra A, Kim N, Lee J. Functionalized-graphene/ethylene vinyl acetate co-polymer composites for improved mechanical and thermal properties. Polymer Testing. 2012;**31**(2):282-289. DOI: 10.1016/j. polymertesting.2011.12.003

[21] Valentini L, Cardinali M, Fortunati E, Torre L, Kenny J. A novel method

to prepare conductive nanocrystalline cellulose/graphene oxide composite films. Materials Letters. 2013;**105**:4-7. DOI: 10.1016/j.matlet.2013.04.034

[22] Gao K, Shao Z, Wu X, Wang X, Li J, Zhang Y, et al. Cellulose nanofibers/ reduced graphene oxide flexible transparent conductive paper. Carbohydrate Polymers. 2013;**97**(1):243- 251. DOI: 10.1016/j.carbpol.2013.03.067

[23] Ke G, Guan W, Tang C, Guan W, Zeng D, Deng F. Covalent functionalization of multiwalled carbon nanotubes with a low molecular weight chitosan. Biomacromolecules. 2007;**8**(2):322-326. DOI: 10.1021/ bm0604146

[24] Jiang Y, Zhang Q, Li F, Niu L. Glucose oxidase and graphene bionanocomposite bridged by ionic liquid unit for glucose biosensing application. Sensors and Actuators B: Chemical. 2012;**161**(1):728-733. DOI: 10.1016/j.snb.2011.11.023

[25] Liu Z, Robinson J, Sun X, Dai H. PEGylated nanographene oxide for delivery of water-insoluble cancer drugs. Journal of the American Chemical Society. 2008;**130**(33):10876-10877. DOI: 10.1021/ja803688x

[26] Zheng M, Jagota A, Semke E, Diner B, Mclean R, Lustig S, et al. DNAassisted dispersion and separation of carbon nanotubes. Nature Materials. 2003;**2**(5):338-342. DOI: 10.1038/ nmat877

[27] Ciofani G, Raffa V, Menciassi A, Dario P. Preparation of boron nitride nanotubes aqueous dispersions for biological applications. Journal of Nanoscience and Nanotechnology. 2008;**8**(12):6223-6231. DOI: 10.1166/ jnn.2008.339

[28] Ciofani G, Danti S, Genchi G, Mazzolai B, Mattoli V. Boron nitride nanotubes: Biocompatibility and

**39**

*Functionalized Boron Nitride Applications in Biotechnology*

in human endothelial cells. Colloids and Surfaces B: Biointerfaces. 2013;**111**:142- 149. DOI: 10.1016/j.colsurfb.2013.05.031

[36] Hanagata N, Zhang H, Chen S, Zhi C, Yamazaki T. Chitosan-coated boron nitride nanospheres enhance delivery of CpG oligodeoxynucleotides and induction of cytokines. International Journal of Nanomedicine. 2013:1783.

[37] Ciofani G, Raffa V, Menciassi A, Cuschieri A. Cytocompatibility, interactions, and uptake of

polyethyleneimine-coated boron nitride nanotubes by living cells: Confirmation of their potential for biomedical applications. Biotechnology and Bioengineering. 2008;**101**(4):850-858.

[38] Kıvanç M, Barutca B, Koparal A, Göncü Y, Bostancı S, Ay N. Effects

nanoparticles on antimicrobial and antibiofilm activities, cell viability. Materials Science and Engineering C. 2018;**91**:115-124. DOI: 10.1016/j.

[39] Ciofani G, Danti S, Nitti S, Mazzolai B, Mattoli V, Giorgi M. Biocompatibility of boron nitride nanotubes: An up-date of in vivo toxicological investigation. International Journal of Pharmaceutics. 2013;**444**(1-2):85-88. DOI: 10.1016/j.

[40] Salvetti A, Rossi L, Iacopetti P, Li X, Nitti S, Pellegrino T, et al. In vivo biocompatibility of boron nitride nanotubes: Effects on stem cell biology and tissue regeneration in planarians. Nanomedicine. 2015;**10**(12):1911-1922.

[41] Ferreira T, Hollanda L, Lancellotti M, de Sousa E. Boron nitride nanotubes

chemically functionalized with glycol chitosan for gene transfection in eukaryotic cell lines. Journal of Biomedical Materials Research Part A.

DOI: 10.2147/ijn.s43251

DOI: 10.1002/bit.21952

of hexagonal boron nitride

msec.2018.05.028

ijpharm.2013.01.037

DOI: 10.2217/nnm.15.46

*DOI: http://dx.doi.org/10.5772/intechopen.80849*

potential spill-over in nanomedicine. Small. 2013;**9**(9-10):1672-1685. DOI:

Biomaterials and Nanobiotechnology. 2011;**02**(04):426-434. DOI: 10.4236/

[30] da Silva W, Hilário Ferreira T, de Morais C, Soares Leal A, Barros Sousa E.

[31] Dorato M, Buckley L. Toxicology

Samarium doped boron nitride nanotubes. Applied Radiation and Isotopes. 2018;**131**:30-35. DOI: 10.1016/j.

testing in drug discovery and development. Current Protocols in Toxicology. 2007. DOI: 10.1002/0471141755.tx1901s31

[32] Fellows M, O'Donovan M. Cytotoxicity in cultured mammalian cells is a function of the method used to estimate it. Mutagenesis. 2007;**22**(4):275-280. DOI: 10.1093/

[33] Rocca A, Marino A, Del Turco S, Cappello V, Parlanti P, Pellegrino M, et al. Pectin-coated boron nitride nanotubes: In vitro cyto−/immunecompatibility on RAW 264.7

macrophages. Biochimica et Biophysica Acta. 2016;**1860**(4):775-784. DOI: 10.1016/j.bbagen.2016.01.020. General

[34] Horváth L, Magrez A, Golberg D, Zhi C, Bando Y, Smajda R, et al. In vitro investigation of the cellular toxicity of boron nitride nanotubes. ACS Nano. 2011;**5**(5):3800-3810. DOI: 10.1021/

[35] Del Turco S, Ciofani G, Cappello V, Gemmi M, Cervelli T, Saponaro C, et al. Cytocompatibility evaluation of glycolchitosan coated boron nitride nanotubes

[29] Ferreira T, Silva P, Santos R, Sousa E. A novel synthesis route to produce boron nitride nanotubes for bioapplications. Journal of

10.1002/smll.201201315

jbnb.2011.24052

apradiso.2017.10.045

mutage/gem013

Subjects

nn200139h

*Functionalized Boron Nitride Applications in Biotechnology DOI: http://dx.doi.org/10.5772/intechopen.80849*

potential spill-over in nanomedicine. Small. 2013;**9**(9-10):1672-1685. DOI: 10.1002/smll.201201315

*Recent Advances in Boron-Containing Materials*

mechanical reinforcement and thermal conductivity enhancement in polymer composites. Composites Science and Technology. 2018;**159**:103-110. DOI: 10.1016/j.compscitech.2018.01.032

to prepare conductive nanocrystalline cellulose/graphene oxide composite films. Materials Letters. 2013;**105**:4-7. DOI: 10.1016/j.matlet.2013.04.034

[22] Gao K, Shao Z, Wu X, Wang X, Li J, Zhang Y, et al. Cellulose nanofibers/ reduced graphene oxide flexible transparent conductive paper.

Carbohydrate Polymers. 2013;**97**(1):243- 251. DOI: 10.1016/j.carbpol.2013.03.067

[23] Ke G, Guan W, Tang C, Guan W,

[24] Jiang Y, Zhang Q, Li F, Niu L. Glucose oxidase and graphene bionanocomposite bridged by ionic liquid unit for glucose biosensing application. Sensors and Actuators B: Chemical. 2012;**161**(1):728-733. DOI: