Segmented intravaginal ring for the combination delivery of hydroxychloroquine and anti-CCR5 siRNA nanoparticles as a potential strategy for preventing HIV infection

Yannick L Traore,Emmanuel A Ho,Fernanda Padilla,Yufei Chen

doi:10.1007/s13346-021-00983-w

Abstract

Vaginal drug delivery has been shown to be a promising strategy for the prevention of sexually transmitted infections. Therapy delivered at the site of infection has many advantages including improved therapeutic efficacy, reduction in systemic toxicity, and reduced potential for development of drug resistance. We developed a “smart” combination intravaginal ring (IVR) that will (1) provide continuous release of hydroxychloroquine (HCQ) to induce T cell immune quiescence as the first-line of defense and (2) release nanoparticles containing anti-CCR5 siRNA only during sexual intercourse when triggered by the presence of seminal fluid as the second-line of defense. The IVR was capable of releasing HCQ over 25 days with a mean daily release of 31.17 ± 3.06 µg/mL. In the presence of vaginal fluid simulant plus seminal fluid simulant, over 12 × more nanoparticles (5.12 ± 0.9 mg) were released over a 4-h period in comparison to IVR segments that were incubated in the presence of vaginal fluid simulant alone (0.42 ± 0.19 mg). Anti-CCR5 siRNA nanoparticles were able to knockdown 83 ± 5.1% of CCR5 gene expression in vitro in the CD4+ T cell line Sup-T1. The IVR system also demonstrated to be non-cytotoxic to VK2/E6E7 vaginal epithelial cells.Graphical abstract

Highlights

Despite the efforts that have been made to date, HIV is still one of the leading causes of death in developing countries
A complete macaque-size intravaginal ring (IVR) has a diameter of 25 mm, and a cross-sectional diameter of 5 mm
The matrix IVR was coated with the modified pH-responsive polymer containing small interfering RNA (siRNA)-NP-Ab

Summary

Introduction

Despite the efforts that have been made to date, HIV is still one of the leading causes of death in developing countries. Women are not able to negotiate condom usage with their partners [4]. To reduce the development of multidrug resistance, therapy involving different classes of antiretrovirals is necessary [5]. This multidrug therapy can pose as a burden for patients especially when it must be taken daily. The necessity to develop an easy and effective therapy against HIV that does not require daily drug administration is required. A great strategy is to develop microbicides (self-administrated topical PrEP) that do not require much effort from the user [9]. An ideal microbicide would be one that is long-acting and is capable of delivering high dose of drug to the target site demonstrating therapeutic efficacy and low toxicity.

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