Molecular Engineering of Polymers and Hydrogels for Biomedical Applications

用于生物医学应用的聚合物和水凝胶的分子工程

• 批准号: RGPIN-2020-04394
• 负责人: Narain, Ravin
• 金额: $ 2.11万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717010
• 关键词: Molecular; Engineering; Polymers; Hydrogels; Biomedical

This research program is focused towards the design, synthesis and tailoring of novel multi-component stimuli-responsive polymers and hydrogels for biomedical applications. Our focus is to develop biologically relevant materials and, as the molecular structure and compositions are critical, our polymeric materials will be carefully designed to include carbohydrate residues, phosphorylcholine groups and biologically relevant peptides. Carbohydrate and phosphorylcholine based polymers and hydrogels are well-known to be safe biomaterials for the therapeutic delivery. We have made significant contributions in this area and the next phase of our research program will focus on developing advanced synthetic strategies for unique physical, chemical and biological properties. The first objective of this work is to design and synthesize well-defined stimuli-responsive polymer-peptide bioconjugates for nucleic acid delivery. For this, we plan to exploit the biorthogonal click reaction between arylboronic ester and strained cis-diol for the cationic peptide conjugation to the polymer. Biologically relevant, cell penetrating cationic peptides will be synthesized with one terminal arylboronic ester residue for the facile and fully reversible click reaction with the pendent cis-diol on the RAFT synthesized polymers. The resulting polymer-peptide conjugates will be ideal vectors for siRNA delivery. Due to the pH, reactive oxygen species (ROS) and sugar sensitivity of the dynamic covalent interaction, we expect site specific cleavage of the peptide from the polymer segment once the conjugates are internalized in cells and hence promoting the release of the nucleic acid payload. This system will be evaluated for its cytotoxicity, selectivity and gene knockdown efficiency. The second objective of this research program will focus on temperature responsive polymer nanoparticles for the encapsulation and sustained delivery of the radiosensitizers, iodoazomycin arabinoside (IAZA) and a derivative of tirapazamine (I-TPZ). Those two compounds are highly potent for the sensitization of hypoxic tumors, however, due to their toxicity, a nanoformulation is required for the safe and targeted delivery. The hydrodynamic size, composition of the core, hydrophobicity, surface/core charge and crosslinker content will be evaluated and optimized for high drug-loading capacity and sustained release. We have recently reported a dual-cure network system for the fabrication of a self-healing, in situ forming and biorthogonal hydrogel that is hydrolytically stable and resistant to acid degradation. Such advanced hydrogels design showed remarkable self-healing, mechanical as well as biological properties. Therefore, the next goal of this research will build on further engineering of this dual-cure network for improved properties of the hydrogels. In particular, we plan to have better control on hydrogels for more controlled and on-demand release of encapsulated cells or drugs.

该研究计划的重点是设计，合成和定制新型多组分刺激响应聚合物和水凝胶用于生物医学应用。我们的重点是开发生物相关材料，由于分子结构和组成至关重要，我们的聚合物材料将经过精心设计，包括碳水化合物残基，磷酸胆碱基团和生物相关肽。众所周知，碳水化合物和磷酸胆碱基聚合物和水凝胶是用于治疗递送的安全生物材料。我们在这一领域做出了重大贡献，我们的研究计划的下一阶段将专注于开发独特的物理，化学和生物特性的先进合成策略。本工作的第一个目标是设计和合成定义明确的刺激响应性聚合物-肽生物缀合物用于核酸递送。为此，我们计划利用芳基硼酸酯和应变顺式二醇之间的双正交点击反应，用于阳离子肽缀合到聚合物上。将合成生物学相关的细胞穿透阳离子肽，其具有一个末端芳基硼酸酯残基，用于与RAFT合成的聚合物上的侧链顺式二醇进行容易且完全可逆的点击反应。所得的聚合物-肽缀合物将是用于siRNA递送的理想载体。由于动态共价相互作用的pH、活性氧物质（ROS）和糖敏感性，我们预期一旦缀合物在细胞中内化，肽就从聚合物片段位点特异性裂解，从而促进核酸有效载荷的释放。将评价该系统的细胞毒性、选择性和基因敲低效率。 本研究计划的第二个目标将集中在温度响应性聚合物纳米颗粒的放射增敏剂，碘唑霉素阿拉伯糖苷（IAZA）和替拉扎明（I-TPZ）的衍生物的封装和持续交付。这两种化合物对缺氧肿瘤的致敏作用非常有效，然而，由于它们的毒性，需要纳米制剂进行安全和靶向递送。将评价流体动力学尺寸、核心组成、疏水性、表面/核心电荷和交联剂含量，并优化高载药量和缓释。 我们最近报道了一种双固化网络系统，用于制造自修复、原位形成和双正交水凝胶，该水凝胶水解稳定且耐酸降解。这种先进的水凝胶设计显示出显着的自我修复，机械以及生物性能。因此，本研究的下一个目标将建立在这种双固化网络的进一步工程上，以改善水凝胶的性能。特别是，我们计划对水凝胶进行更好的控制，以更好地控制和按需释放封装的细胞或药物。