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 - MbetaCD and (2-hydroxy)propyl-beta-CD - HPbetaCD) 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 (pHPbetaCD and pMbetaCD) were prepared and fully characterized. The physicochemical characterization and in vitro drug release confirmed the successful synthesis of pHPbetaCD and pMbetaCD, the formation of sub-micron sized particles and a 12-14 fold increase in LPV solubility. Cytotoxicity assays indicated that both pHPbetaCD and pMbetaCD were able to improve the safety profile of LPV while the viral infectivity assay revealed a concentration independent anti-HIV-1 effect for both pHPbetaCD and pMbetaCD with a maximum percentage inhibition (MPI) of 79 and 91 % respectively. After LPV loading, the antiviral profile of pHPbetaCD to was reversed to the sigmoidal dose-response profile of LPV, while pMbetaCD's maintained its dose-independent profile followed by a LPV mediated increase in viral inhibition. Overall, both pHPbetaCD and pMbetaCD demonstrated anti-HIV-1 activity, while drug loaded pMbetaCD indicated its potential as functional sub-micron sized drug delivery polymers for achieving synergistic anti-HIV activity.