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-β-CD - MβCD and (2-hydroxy)propyl-β-CD - HPβCD) 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 (pHPβCD and pMβCD) were prepared and fully characterized. The physicochemical characterization and in vitro drug release confirmed the successful synthesis of pHPβCD and pMβCD, the formation of sub-micron sized particles and a 12–14 fold increase in LPV solubility. Cytotoxicity assays indicated that both pHPβCD and pMβCD were able to improve the safety profile of LPV while the viral infectivity assay revealed a concentration independent anti-HIV-1 effect for both pHPβCD and pMβCD with a maximum percentage inhibition (MPI) of 79 and 91% respectively. After LPV loading, the antiviral profile of pHPβCD was reversed to the sigmoidal dose–response profile of LPV, while pMβCD maintained its dose-independent profile followed by a LPV mediated increase in viral inhibition. Overall, both pHPβCD and pMβCD demonstrated anti-HIV-1 activity, while drug loaded pMβCD indicated its potential as functional sub-micron sized drug delivery polymers for achieving synergistic anti-HIV activity.This work was supported by iMed.ULisboa, financed by national funds from FCT/MCTES (UID/DTP/04138/2019) and by the Portuguese Mass Spectrometry Network (Rede Nacional de Espectrometria de Massa - RNEM; LISBOA-01-0145-FEDER-402-022125). O.A. acknowledges the partial scholarship funding from the Tertiary Education Fund (TETFUND), Nigeria. J.C. is grateful to Fundação para a Ciência e a Tecnologia (FCT, Portugal) and PhD Programme in Medicines and Pharmaceutical Innovation (i3DU) for the grant [PD/BD/127813/2016]. I.B. is financed by national funds via FCT through Norma Transitória - DL57/2016/CP1376/CT0012.