Polymeric nanocarriers have been extensively used to improve the delivery of hydrophobic drugs, but often provide low encapsulation efficiency and percent loading for hydrophilic compounds. In particular, insufficient loading has limited the development of sustained-release therapeutics against HIV, where many of the most promising drug combinations include a hydrophilic member. To address the low encapsulation observed for the HIV integrase inhibitor raltegravir (RAL) we developed a prodrug strategy where the loading, release and subsequent hydrolysis can be tuned by promoiety selection. Prodrugs with large partition coefficients increased the encapsulation efficiency by as much as 25-fold relative to RAL, leading to significant dose reductions in antiviral activity assays. The differential hydrolysis rates of these prodrugs also led to distinct patterns of RAL availability and observed antiviral activity, likely reflecting changes in the temporal distribution of both prodrug and RAL in cellular compartments. Our results suggest that the design of prodrugs for specific polymeric nanocarrier systems could provide a more generalized strategy to formulate physicochemically diverse hydrophilic drugs with a number of biomedical applications.

Enhanced delivery of HIV integrase inhibitors with prodrugs designed for polymeric nanocarriers

253rd National Meeting (2017)

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