Nanocrystal Formulation Improves Vaginal Delivery of CSIC for HIV Prevention
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5-Chloro-3-phenylsulfonylindole-2-carboxamide (CSIC) is a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI) with potential for use in topical prophylaxis against HIV transmission. However, the hydrophobic nature of CSIC limits its administration through vaginal route. In this study, we developed nanocrystals of CSIC to potentially improve the aqueous solubility and intracellular uptake of CSIC in vitro and in vivo. CSIC nanocrystals were manufactured and stabilized with Pluronic F98 and hydroxypropyl methylcellulose E5. Transmission electron microscopy showed CSIC nanocrystals to be needle-like. Dynamic light scattering measurements showed a hydrodynamic size of 243 nm (polydispersity index < 0.3) and near neutral surface charge (− 7.8 mV). Particle size was maintained for at least 7 days in the liquid state and for at least 5 months after lyophilization. Drug content in the CSIC nanocrystal formulation (nanosuspension) was 0.8 mg/mL, which is 1000 times higher than the aqueous solubility of CSIC. In vitro release study showed that over 90% of CSIC was released from the nanocrystal formulation in a linear fashion over a period of 4 days. Importantly, CSIC nanocrystals showed equivalent cell-based anti-HIV activity (EC50 ~ 1 nM) as that of non-formulated drug. In vitro studies demonstrated rapid macrophage uptake of CSIC nanocrystals via both energy-dependent (endocytosis) and independent processes. In vivo studies in Swiss Webster female mice showed that the nanocrystal formulation significantly improved CSIC delivery to mouse cervicovaginal tissues following intravaginal instillation. In summary, nanocrystals are a promising formulation approach for topical delivery of CSIC for protection against HIV sexual transmission.
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The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We would like to acknowledge Eva Nagy (University of Pittsburgh, School of Medicine) for her assistance with the bioactivity study and Ming Sun (University of Pittsburgh, Center for Biologic Imaging) for her support with the TEM work. In addition, special thanks go to Dr. Robert Powers, Dr. Ida Washing, Anthony Battelli, and Pamela Wintruba for their valuable suggestions on animal study experimental design and IACUC submission. We also would like to acknowledge Drs. Vinayak Sant, Junmei Zhang, and Himabindu Ruttala for help with editing/proofreading of this manuscript.
Work reported in the current publication was funded by Microbicide Innovation Program (grant number: U19 AI079801) of the National Institute of Allergy and Infectious Diseases, Division of AIDS.
Compliance with Ethical Standards
All animal protocols for evaluation of drug distribution in mice were approved by the University of Pittsburgh Institutional Animal Care and Use Committee (IACUC).
There was no involvement from any pharmaceutical companies. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflict of Interest
The authors declare that they have no conflict of interest.
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