Molecular Engineering of Polymers and Hydrogels for Biomedical Applications

这项研究计划致力于设计、合成和定制用于生物医学应用的新型多组分刺激响应性聚合物和水凝胶。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、磷酰胆碱基和生物相关多肽。众所周知，基于碳水化合物和磷胆碱的聚合物和水凝胶是安全的生物材料，用于治疗。我们在这一领域做出了重大贡献，我们下一阶段的研究计划将专注于开发先进的合成策略，以获得独特的物理、化学和生物特性。这项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-肽生物偶联物用于核酸递送。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将阳离子多肽连接到聚合物上。与生物学相关的是，穿透细胞的阳离子多肽将用一端的芳基硼酸酯残基与RAFT合成的聚合物上的侧链顺式二醇进行简单且完全可逆的点击反应来合成。由此得到的聚合物-多肽结合物将是理想的siRNA载体。由于动态共价相互作用的pH、活性氧物种(ROS)和糖的敏感性，我们预计一旦偶联物内化到细胞内，多肽就会从聚合物片段上特异性切割，从而促进核酸有效载荷的释放。该系统将评估其细胞毒性、选择性和基因敲除效率。 这项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，用于放射增敏剂阿拉伯碘佐霉素(IAZA)和替拉扎明衍生物(I-TPZ)的包裹和持续释放。这两种化合物对缺氧肿瘤有很强的增敏作用，但由于它们的毒性，需要一种纳米制剂来安全和靶向地传递。将对流体力学尺寸、核的组成、疏水性、表面/核电荷和交联剂含量进行评估和优化，以实现高载药量和缓释。 我们最近报道了一种双固化网络体系，用于制备一种自愈合、原位形成和双正交的水凝胶，该水凝胶具有水解性稳定和抗酸降解能力。这种先进的水凝胶设计显示出显著的自愈、机械和生物性能。因此，这项研究的下一个目标将建立在这种双重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，以便更好地控制和按需释放微囊化的细胞或药物。

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.