Open AccessSustained Intracellular Raltegravir Depots Generated with Prodrugs Designed for Nanoparticle Delivery
Author(s) -
Rachel Creighton,
Ian T. Suydam,
Mikaela E Ebner,
Wilma E Afunugo,
Alaina M. Bever,
Shijie Cao,
Yuanchun Jiang,
Kim A. Woodrow
Publication year - 2019
Publication title -
acs biomaterials science and engineering
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.082
H-Index - 50
ISSN - 2373-9878
DOI - 10.1021/acsbiomaterials.9b00658
Subject(s) - prodrug , raltegravir , nanocarriers , drug delivery , pharmacology , drug , intracellular , chemistry , lipophilicity , combinatorial chemistry , human immunodeficiency virus (hiv) , biochemistry , antiretroviral therapy , medicine , organic chemistry , virology , viral load
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 of hydrophilic antiretroviral drugs such as the integrase inhibitor raltegravir (RAL) has limited the development of sustained-release therapeutics or prevention strategies against HIV. To address this, we developed a generalizable prodrug strategy using RAL as a model where loading, release and subsequent hydrolysis can be tuned by promoiety selection. Prodrugs with large partition coefficients increased the encapsulation efficiency up to 25-fold relative to RAL, leading to significant dose reductions in antiviral activity assays. The differential hydrolysis rates of these prodrugs led to distinct patterns of RAL availability and observed antiviral activity. We also developed a method to monitor the temporal distribution of both prodrug and RAL in cells treated with free prodrug or prodrug-NPs. Results of these studies indicated that prodrug-NPs create an intracellular drug reservoir capable of sustained intracellular drug release. Overall, 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.