Spot - synthesis of pretargeted oncology theranostics
To overcome size-related drawbacks of intact antibodies (Ab) for active tumor targeting, small but multivalent Ab-fragments, which fall in the “ideal tumor targeting zone”, are gaining increasing interest. However, the achieved benefits of Ab-fragments are lost when conjugated to imaging probes or drug carriers. Therefore, the SPOT action is going to focus on the generation of small Ab-fragments with highly specific targeting capacities and deep tissue penetration that are able to subsequently undergo a bioorthogonal click reaction at the tumor site. As cancer model, pancreatic ductal adenocarcinoma (PDAC), which currently still has an extremely poor prognosis, is going to be targeted. Two different click reaction will be evaluated: The cycloaddition between tetrazine and trans-cyclooctene (TCO) as well as azide and dibenzocyclooctyne (DBCO), whereby the Ab-fragments are functionalized with the TCO and DBCO groups. The opponent moieties are attached to alginate and hyaluronic acid-based ligands, which are subsequently introduced to the nanoparticle’s (NP) surface, additionally providing shielding from the immunological system. After the accumulation of the clickable Ab-fragments at the tumor site and their clearance from healthy tissue, the imaging or drug-delivering NPs with the opponent clickable moieties are injected, allowing for their exclusive accumulation at the pretargeted tumor site. For effective visualization of PDAC tissue, state-of-the-art silver sulfide NPs, with a high contrast-to-noise ratio and deep tissue imaging, are applied. The use of these NPs can be a significant step towards early PDCA diagnosis and therefore providing better chances for a positive treatment outcome. For the pretargeted drug-delivery approach, poly(lactic acid)-based NPs with encapsulated gemcitabine or docetaxel generated via electrospraying are going to be tested as a potential chemotherapeutic approach for PDAC, preforming small animal in vivo studies with PDAC xenografts.