Targeted and controlled delivery of therapeutic agents using polymeric materials : hydrogels, nanofibers, nanogels and micelles

Abstract

Stimuli-responsive polymeric materials have emerged as attractive platforms for controlled drug delivery applications. In this thesis, photothermally active and pH-responsive nanofibers were fabricated for the triggered release of antibiotics and chemotherapeutic drugs, respectively. Alternatively, Redox- responsive hydrogels were designed for therapeutic protein delivery. Additionally, nanogels and micelles were synthesized for controlled and targeted delivery of chemotherapeutic agents. In the first part, reduced graphene-oxide-embedded poly(acrylic acid) nanofibers were prepared for the on-demand release of antibiotics for local infections. Ampicillin and cefepime were loaded to nanofibers, and E. coli K12 and S. epidermis bacterial strains were eradicated with photothermally released antibiotics. In the second part, pH-responsive nanofiber buttresses were fabricated using an acrylate-based copolymer containing acid-sensitive hydrolyzable hydrophobic side chains. Doxorubicin and docetaxel were loaded into the nanofiber buttresses, and selective drug release was observed in an acidic environment. In the third part, fast-forming dissolvable hydrogels were synthesized by crosslinking maleimide-terminated disulfide-containing PEG-based polymer. Various macromolecules were loaded into the hydrogels, and slow and on-demand release under a reductive environment was accomplished. In the fourth part, redox-responsive nanogels were fabricated using self-assembly and subsequent crosslinking of copolymers containing disulfide-linked maleimide side chains. Nanogels were loaded with docetaxel, and their surface was modified with a peptide-based targeting ligand. Enhanced cytotoxicity and internalization of targeted drug-loaded nanogels were observed. In the last part of the thesis, drug- loaded and targeted pH-responsive micellar structures were fabricated using a diblock copolymer composed of 5-fluorouracil and PEG-methacrylate-based blocks. Targeted dual-drug- containing micelles exhibited enhanced toxicity and cell internalization toward oral squamous carcinoma cells.