Pyromellitic Dianhydride Crosslinked Soluble Cyclodextrin Polymers: Synthesis, Lopinavir Release from Sub-Micron Sized Particles and Anti-Hiv-1 Activity.

We report the synthesis of water soluble cyclodextrin (CD) polymers prepared by crosslinking pyromellitic dianhydride (PMDA) with two CD derivatives (methyl-beta-CD - M beta CD and (2-hydroxy)propyl-beta-CD - HP beta CD) and their evaluation as functional sub-micron sized carriers in the development of antiretroviral drug delivery systems. Using the protease inhibitor lopinavir (LPV) as model drug, LPV loaded CD polymers (pHP beta CD and pM beta CD) were prepared and fully characterized. The physicochemical characterization and in vitro drug release confirmed the successful synthesis of pHP beta CD and pM beta CD, the formation of sub-micron sized particles and a 12-14 fold increase in LPV solubility. Cytotoxicity assays indicated that both pHP beta CD and pM beta CD were able to improve the safety profile of LPV while the viral infectivity assay revealed a concentration independent anti-HIV1 effect for both pHP beta CD and pM beta CD with a maximum percentage inhibition (MPI) of 79 and 91% respectively. After LPV loading, the antiviral profile of pHP beta CD was reversed to the sigmoidal dose-response profile of LPV, while pM beta CD maintained its dose-independent profile followed by a LPV mediated increase in viral inhibition. Overall, both pHP beta CD and pM beta CD demonstrated anti-HIV-1 activity, while drug loaded pM beta CD indicated its potential as functional sub-micron sized drug delivery polymers for achieving synergistic anti-HIV activity.