TARGETED DRUG-DELIVERY TO THE BRAIN VIA PHOSPHONATE DERIVATIVES - I -DESIGN, SYNTHESIS AND EVALUATION OF AN ANIONIC CHEMICAL DELIVERY SYSTEM FOR TESTOSTERONE

An anionic chemical delivery system (aCDS) was designed and evaluated for brain-targeted delivery of testosterone (T). In this system, targe ting is achieved through the use of a specific, (acyloxy)alkyl-phospho nate-type, targetor moiety. The systemically administered T-aCDS can e nter the brain by passive transport due to its increased lipophilicity . Hydrolytic cleavage by esterases releases, via a chemically unstable , short-lived intermediate, a negatively charged, hydrophilic phosphon ate compound (TP-). This is locked in the brain and should provide sus tained, site-specific release of the active drug following a phosphoro lytic attack by alkaline phosphatase or by phosphodiesterase. In vivo evaluations found maximum T-aCDS brain levels 5-10 min after administr ation; they fell under the detection-limit (<0.1 mu g/g) after 60 min. With the employed (pivaloyloxy)methyl phosphonate ester, cleavage by esterases, the first metabolic step in the decomposition process, was not very fast. Maximum concentration of the decomposition product (TP- ) was obtained at 30 min after administration; it did not decrease sig nificantly during the study proving that this negatively charged inter mediate is 'locked in' the brain. However, the phosphonate derivative of the secondary, hindered hydroxyl group in this product was fairly r esistant to phosphorolytic attack, the second metabolic step. The rele ased drug could not be detected indicating that testosterone release, if any, is slower than metabolism and/or elimination. (C) 1998 Elsevie r Science B.V. All rights reserved.