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

阴道内环（IVRs）是一种聚合环状装置，能够提供持续（约14天）的药物释放。目前还没有设计用于传递遗传物质（如小干扰RNA (siRNA)）的IVR设备。此外，ivr旨在提供连续不间断的药物输送，即使不再需要。由于微环境的变化，自动“打开/关闭”药物释放的能力非常有吸引力，因为这意味着降低药物成本和及时给药。材料科学领域的一个主要挑战是开发精确调谐的聚合物，这些聚合物可以对不同的刺激产生可预测的反应。因此，拟议的研究计划集中于开发先进的生物材料，用于制造刺激反应性ivr，以提供sirna封装纳米颗粒的受控递送。最初的重点将放在开发“一次性”IVRs上，该IVRs涂有一层ph响应膜，用于快速释放sirna封装的纳米颗粒。此外，新的ph响应聚合物将被合成，用于制造“多用途”的基于储层的ivr，这种ivr可以在14天内打开/关闭sirna封装的纳米颗粒的递送。这些ivr被设计为对女性生殖道的pH值变化做出反应，例如在正常生理阴道pH值（<4.5）时几乎没有药物释放，而当环境pH值升高（>6.0）时药物释放迅速。在全球范围内，这将是第一个为“单用途”和“多用途”模式开发和表征ph响应性ivr的研究项目。将对新合成的pH响应聚合物进行物理化学表征，以确定熔融温度、透水性、溶胀性、孔隙度和pH敏感性等特性。这些不同性质对制备的IVRs结构特征的影响及其对sirna包封纳米颗粒释放谱的影响也将被研究。IVR给药系统将在体外进行生物相容性和长期稳定性评估。

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. Overall, the proposed research program is innovative and will significantly contribute to the advancement of knowledge in the field of materials science, via the generation of novel stimuli-responsive polymers for the controlled delivery of siRNA. Most importantly, highly qualified personnel trained in this research program will acquire the necessary knowledge and skills to be leaders in the fields of biopolymers, engineering, and drug delivery.