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

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

Untangling Mucosal Drug Delivery: Engineering, Designing, and Testing Nanoparticles to Overcome the Mucus Barrier

“…Similarly, PVA/γ-carregeenan films laden with PLGA–PEG-PEI nanoparticles showed significant improvements over aqueous nanoparticle formulations . Embedding nanoparticles within a matrix can also enable a stimulus-responsive release of nanoparticle payloads, as was demonstrated in the pH-responsive prophylactic delivery of mucopenetrating solid lipid nanoparticles (SLNs) laden with siRNA to prevent HIV infection . The selection of matrix form also impacts the delivery of embedded nanoparticle payload.…”

“…157 Embedding nanoparticles within a matrix can also enable a stimulus-responsive release of nanoparticle payloads, as was demonstrated in the pH-responsive prophylactic delivery of mucopenetrating solid lipid nanoparticles (SLNs) laden with siRNA to prevent HIV infection. 159 The selection of matrix form also impacts the delivery of embedded nanoparticle payload. A direct comparison of mucoadhesive gels and nanofibers, both laden with chitosan nanoparticles, demonstrated that, while gels possess superior mucoadhesive properties, fibers provided higher drug permeation through vaginal tissue.…”