L-Amino acid Based Amphiphilic Polymers for Drug Delivery Application

Abstract

L-Amino acids are biologically active molecules and play vital role in many biological processes. Synthetic polymers based on L-amino acids have attracted much attention because of their excellent biocompatibility and diverse functionality which provides them improved hydrophilicity and an opportunity for further modifications with bioactive molecules. Development of synthetic strategy for synthesis of amino acid-based polymers has great research opportunity in biomedical field. The aim of this thesis work is development of a green synthetic route for the synthesis of L-amino acid-based polyurethanes and poly ester-urethanes for drug delivery applications in cancer cells. L-Lysine was employed to synthesise new class of thermo-responsive polyurethane nanocarriers to deliver anticancer drugs by exploiting slightly elevated cancer tissue temperature (42 deg. C) compared to physiological conditions (37 deg. C). L-Tyrosine and L-DOPA resources were suitably modified with masked-monomer approach and subjected for melt polymerization to make new classes of enzyme-responsive phenol-functionalized poly(ester-urethanes)s. The aromatic pi-stacking secondary interactions between the polymer chains and polyaromatic anticancer drugs were explored for drug stabilization at the nano-confinement. Further, new class of completely bio-based polymers were developed using sugar-based diols and L-amino acids monomers for futuristic completely biodegradable polymers in the biomedical field. The dual ester-urethane condensation was successfully demonstrated for variety of amino acids including glycine, L-alanine, L-valine, L-leucine, L-isoleucine and L-phenylalanine. The occurrence of melt polymerisation and structure of polymers was confirmed by NMR technique. The end group analysis by MALDI-TOF-MS confirmed the stability of both the monomers under melt condition. The amino acid sugar hybrid polyester(urethane)s were showing relatively high glass transition temperature (Tg ≥ 80 0C) compare to their aliphatic diol-based polyester(urethane)s counterparts. These amphiphilic polymers self-assembled in 180 ±10 nm nanoparticles in aqueous medium and were capable of encapsulating anticancer drugs such as doxorubicin (DOX) and topotecan (TPT). Electron rich Aromatic amino acids were exploited for molecular interactions with electron deficient anticancer drugs for high drug loading. In vitro drug release studies revealed that the polymer nanoparticles were very stable at physiological conditions and undergoes biodegradation-assisted disassembly in the presence of lysosomal esterase enzyme and released the loaded drug in a controlled manner. Cytotoxic effects of these polymers were investigated in human breast cancer MCF-7 cells, and normal cell lines (WT-MEFs) demonstrating the biocompatible nature of the polymers however, drug loaded polymer nanoparticles were showing excellent cell killing in cancer cells. Finally, the thesis work is summarized with future perspectives.