Targeted drug delivery to the brain via phosphonate derivatives II. Anionic chemical delivery system for zidovudine (AZT)

Gabor Somogyi, Peter Buchwald, Daishuke Nomi, Laszlo Prokai, Nicholas Bodor

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The previously described anionic chemical delivery system (aCDS) approach (Somogyi, G., Nishitani, S., Nomi, D., Buchwald, P., Prokai, L., Bodor, N., 1997. Targeted drug delivery to the brain via phosphonate derivatives. I. Design, synthesis and evaluation of an anionic chemical delivery system for testosterone. Int. J. Pharm. (166, 15-26) was applied for brain-targeted delivery of AZT. For this system, the whole designed metabolic sequence, ending with release of the active drug at the targeted organ, was completed. As a less hindered ester function was built into this aCDS, cleavage by esterases, the first metabolic step in the decomposition process, was fairly rapid. The negatively charged decomposition product (AZT-P-) could be detected for about 48 h in different organs. In vitro experiments proved that AZT is released from this phosphonate derivative after phosphorolytic attack, the second metabolic step of the designed sequence, but only at a slow rate. While the phosphonate derivative of a secondary hydroxyl group proved completely resistant to such phosphorolytic attacks, alkaline phosphatase, but not phosphodiesterase, was able to cleave the P-O bond of the phosphonate derivative at the primary hydroxyl group in this system. After i.v. administration of AZT-aCDS in rabbits, AZT could be detected in the brain, albeit only at very low concentrations. Even if sufficiently high drug levels could not be delivered with the present aCDSs, the sequence was completed, the rate of metabolism was controllable, and the approach is flexible enough; therefore, further, adequate manipulations might render such anionic chemical delivery systems into a useful addition of the drug targeting arsenal.

Original languageEnglish
Pages (from-to)27-35
Number of pages9
JournalInternational Journal of Pharmaceutics
Issue number1
StatePublished - 11 May 1998


  • Alkyl phosphatase and phosphodiesterase
  • Anionic chemical delivery system (aCDS)
  • Azidothymidine (AZT)
  • Brain-targeted delivery


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