l-Amino Acid Based Phenol- and Catechol-Functionalized Poly(ester-urethane)s for Aromatic π-Interaction Driven Drug Stabilization and Their Enzyme-Responsive Delivery in Cancer Cells

Abstract

Exploiting aromatic π-interaction for the stabilization of polyaromatic anticancer drugs at the core of the polymer nanoassemblies is an elegant approach for drug delivery in cancer research. To demonstrate this concept, here we report one of the first attempts on enzyme-responsive polymers from aryl-unit containing amino acid bioresources such as l-tyrosine and 3,4-dihydroxy-l-phenylalanine (l-DOPA). A silyl ether protection strategy was adopted to make melt polymerizable monomers, which were subjected to solvent free melt polycondensation to produce silyl-protected poly(ester-urethane)s. Postpolymerization deprotection yielded phenol- and catechol-functionalized poly(ester-urethane)s with appropriate amphiphilicity and produced 100 ± 10 nm size nanoparticles in an aqueous solution. The aromatic π-core in the nanoparticle turns out to be the main driving force for the successful encapsulation of anticancer drugs such as doxorubicin (DOX) and topotecan (TPT). The electron-rich catechol aromatic unit in l-DOPA was found to be unique in stabilizing the DOX and TPT, whereas its l-tyrosine counterpart was found to exhibit limited success. Aromatic π-interactions between l-DOPA and anticancer drug molecules were established by probing the fluorescence characteristics of the drug–polymer chain interactions. Lysosomal enzymatic biodegradation of the poly(ester-urethane) backbone disassembled the nanoparticles and released the loaded drugs at the cellular level. The nascent polymer was nontoxic in breast cancer (MCF7) and WT-MEF cell lines, whereas its DOX and TPT loaded nanoparticles showed remarkable cell growth inhibition. A LysoTracker-assisted confocal microscopic imaging study directly evidenced the polymer nanoparticles’ biodegradation at the intracellular level. The present investigation gives an opportunity to design aromatic π-interaction driven drug stabilization in l-amino acid based polymer nanocarriers for drug delivery applications.