Molecular Engineering of Polymers and Hydrogels for Biomedical Applications

该研究项目的重点是设计、合成和剪裁用于生物医学应用的新型多组分刺激反应聚合物和水凝胶。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精心设计，包括碳水化合物残基，磷胆碱基团和生物相关肽。以碳水化合物和磷胆碱为基础的聚合物和水凝胶是众所周知的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具有独特物理、化学和生物特性的先进合成策略。这项工作的第一个目标是设计和合成明确的刺激反应聚合物-肽生物偶联物核酸递送。为此，我们计划利用芳基硼酯和张力顺式二醇之间的双正交键合反应，将阳离子肽偶联到聚合物上。与生物相关的是，细胞穿透阳离子肽将由一个末端芳基硼酯残基合成，与RAFT合成的聚合物上的顺式二醇进行简单而完全可逆的咔嗒反应。由此产生的聚合物-肽偶联物将是siRNA递送的理想载体。由于pH值、活性氧（ROS）和糖对动态共价相互作用的敏感性，我们预计一旦偶联物内化到细胞中，聚合物片段上的肽就会发生位点特异性切割，从而促进核酸有效载荷的释放。该系统将对其细胞毒性、选择性和基因敲除效率进行评估。

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.