Molecular Engineering of Polymers and Hydrogels for Biomedical Applications

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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.