Targeted drug delivery to the central nervous system via phosphonate derivatives (anionic delivery system for...

An anionic chemical delivery system (aCDS) has been developed and applied to deliver testosterone (T) to the central nervous system (CNS). The delivery of a target compound is achieved through the use of a specific targetor moiety which is an (acyloxy)alkyl-phosphonate-type functional group. The T-aCDS readily penetrates biological membranes by passive transport due to its increased lipophilicity and enters the target organ. Hydrolytic cleavage by esterases provides a negatively charged, hydrophilic intermediate phosphonate compound (TP-), which is "locked in" the CNS and should provide sustained, site-specific release of the drug. In vitro and in vivo investigations in rats showed that methyl-pivaloyloxymethyl-17-testosterylphosphonate (T-aCDS) might function as an anionic chemical delivery system of testosterone. The concentration of T-aCDS decreased fairly rapidly in vitro. The half-lives (t1/2) in different organs are as follows: blood 4.48 min (r = 0.9388), lung 5.53 min (r = 0.9661), liver 2.82 min (r = 0.9498), and brain 7.37 min (r = 0.9972). Simultaneously with the disappearance of T-aCDS, testosterone-phosphonate (TP-) appeared as a main metabolite in increasing concentration. In vivo evaluations (tail vein 11.3 mg/kg in DMSO) found maximum T-aCDS brain levels 5-10 min after administration; they fell under the borderline of detectability (< 0.1 microgram/g) after 60 min. Maximum concentration of the decomposition product (TP-) was obtained at 30 min after administration; it did not decrease significantly during the study. Even if the phosphonate derivative of the secondary, hindered hydroxyl group in this product was fairly resistant to phosphorolytic attack, the design principle can work for other compounds.