Rational Design of Stimuli-Responsive Intravaginal Rings for Controlled siRNA Delivery

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Intravaginal rings (IVRs) are polymeric torus-shaped devices capable of providing sustained (>14 days) drug release. There are currently no IVR devices designed for the delivery of genetic material such as small interfering RNA (siRNA). Furthermore, IVRs are intended to provide continuous non-stop delivery of drugs even when it is no longer required. The ability to automatically “switch on/off” drug release due to changes within the microenvironment is very appealing as this translates to decreased drug cost and well-timed drug delivery. A major challenge in the materials science field is the development of precisely-tuned polymers that can produce predictable responses to different stimuli. As a result, the proposed research program is focused on the development of advanced biomaterials for the fabrication of stimuli-responsive IVRs that will provide controlled delivery of siRNA-encapsulated nanoparticles. Initial focus will be on the development of “single-use” IVRs coated with a pH-responsive film for the rapid release of siRNA-encapsulated nanoparticles. In addition, novel pH-responsive polymers will be synthesized for the purpose of fabricating “multi-use” reservoir-based IVRs that can switch on/off the delivery of siRNA-encapsulated nanoparticles over a 14-day period. These IVRs are designed to respond to pH changes specific to the female genital tract e.g. little to no drug release at normal physiological vaginal pH (<4.5) and rapid drug release when the environmental pH is elevated (>6.0). Globally, this will be the first research program to develop and characterize pH-responsive IVRs for both “single-use” and “multi-use” modalities. Physical-chemical characterization of the newly synthesized pH-responsive polymers will be performed to determine properties such as melting temperature, water permeability, swellability, porosity, and pH sensitivity. The influence of these various properties on the structural features of the fabricated IVRs and its impact on the release profile of siRNA-encapsulated nanoparticles will also be investigated. The IVR delivery system will be evaluated in vitro for biocompatibility and long-term stability.