Since their introduction in the early 1980s, CDSs have also generated considerable research work, especially for brain and eye targeting of various therapeutic agents, including those that cannot cross the blood–brain barrier or the blood–retinal barrier on their own.  Within this approach, three major general CDS classes have been identified:
:* Enzymatic physicochemical-based (e.g., brain-targeting) CDSs:  exploit site-specific traffic properties by sequential metabolic conversions that result in considerably altered properties
:* Site-specific enzyme-activated (e.g., eye-targeting) CDSs:  exploit specific enzymes found primarily, exclusively, or at higher activity at the site of action
:* Receptor-based transient anchor-type (e.g., lung-targeting) CDSs:  provide enhanced selectivity and activity through transient, reversible binding at the receptor
This concept has been extended to many drugs and peptides, its importance illustrated by the fact that its first applications and uses were published in Science  in 1975, 1981 and 1983.  Its extension to the targeted brain-delivery of neuropeptides was included by the Harvard Health Letter  as one of the top 10 medical advances of 1992.  Several compounds have reached advanced clinical development phase, such as
:* E-CDS (Estredox) for the brain-targeted delivery of estradiol  and
:* betaxoxime for the eye-targeted delivery of betaxolol
In the first example above, brain-targeted CDSs employ a sequential metabolic conversion of a redox-based targetor moiety, which is closely related to the ubiquitous NAD(P)H  ⇌ NAD(P) coenzyme system, to exploit the unique properties of the blood–brain barrier (BBB).  After enzymatic oxidation of the NADH type drug conjugate to its corresponding NAD- drug, the still inactive precursor, "locks-in" behind the BBB to provide targeted and sustained CNS-delivery of the compound of interest.
The second example involves eye-specific delivery of betaxoxime, the oxime derivative of betaxolol.  The administered, inactive β-amino-ketoxime is converted to the corresponding ketone via oxime hydrolase, an enzyme recently identified with preferential activity in the eye, and then stereospecifically reduced to its alcohol form.  IOP-lowering activity is demonstrated without producing the active β-blockers systemically, making them void of any cardiovascular activity, a major drawback of classical antiglaucoma agents.  Because of the advantages provided by this unique eye-targeting profile, oxime-based eye-targeting CDSs could replace the β-blockers currently used for ophthalmic applications.