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

用于受控 siRNA 递送的刺激响应阴道环的合理设计

• 批准号: RGPIN-2015-06008
• 负责人: Ho, Emmanuel
• 金额: $ 1.82万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613879
• 关键词: Rational; Design; Stimuli; Responsive; Intravaginal

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.

阴道内环（IVRs）是能够提供持续（>14天）药物释放的聚合物环形装置。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，IVRs旨在提供连续不间断的药物输送，即使不再需要。由于微环境内的变化而自动“打开/关闭”药物释放的能力是非常有吸引力的，因为这转化为降低的药物成本和适时的药物递送。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，拟议的研究计划的重点是开发先进的生物材料，用于制造刺激响应的IVR，这将提供siRNA封装的纳米颗粒的受控递送。最初的重点将是开发“一次性”IVR，其涂覆有pH响应膜，用于快速释放siRNA封装的纳米颗粒。此外，将合成新型pH响应性聚合物，用于制造“多用途”基于siRNA的IVR，其可以在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特有的pH变化做出响应，例如，在正常生理阴道pH值（<4.5）下几乎没有药物释放，而在环境pH值升高（>6.0）时快速释放药物。在全球范围内，这将是第一个为“一次性”和“多次使用”模式开发和表征pH响应IVR的研究项目。将对新合成的pH响应性聚合物进行物理化学表征，以确定熔融温度、透水性、溶胀性、孔隙率和pH敏感性等特性。还将研究这些不同性质对所制造的IVR的结构特征的影响及其对siRNA封装的纳米颗粒的释放曲线的影响。将在体外评价IVR输送系统的生物相容性和长期稳定性。 总的来说，拟议的研究计划是创新的，将通过产生用于siRNA控制递送的新型刺激响应聚合物，为材料科学领域的知识进步做出重大贡献。最重要的是，在这项研究计划中培训的高素质人员将获得必要的知识和技能，成为生物聚合物，工程和药物输送领域的领导者。