Melt Polycondensation Strategy for Amide-Functionalized l-Aspartic Acid Amphiphilic Polyester Nano-assemblies and Enzyme-Responsive Drug Delivery in Cancer Cells

Aliphatic polyesters are intrinsicallyenzymatic-biodegradable,and there is ever-increasing demand for safe and smart next-generationbiomaterials including drug delivery nano-vectors in cancer research.Using bioresource-based biodegradable polyesters is one of the elegantstrategies to meet this requirement; here, we report an l-amino acid-based amide-functionalized polyester platform and exploretheir lysosomal enzymatic biodegradation aspects to administrate anticancerdrugs in cancer cells. l-Aspartic acid was chosen and differentamide-side chain-functionalized di-ester monomers were tailor-madehaving aromatic, aliphatic, and bio-source pendant units. Under solvent-freemelt polycondensation methodology; these monomers underwent polymerizationto yield high molecular weight polyesters with tunable thermal properties.PEGylated l-asparticmonomer was designed to make thermo-responsive amphiphilic polyesters.This amphiphilic polyester was self-assembled into a 140 +/- 10nm-sized spherical nanoparticle in aqueous medium, which exhibitedlower critical solution temperature at 40-42 degrees C. The polyesternano-assemblies showed excellent encapsulation capabilities for anticancerdrug doxorubicin (DOX), anti-inflammatory drug curcumin, biomarkerssuch as rose bengal (RB), and 8-hydroxypyrene-1,3,6-trisulfonic acidtrisodium salt. The amphiphilic polyester NP was found to be verystable under extracellular conditions and underwent degradation uponexposure to horse liver esterase enzyme in phosphate-buffered salineat 37 degrees C to release 90% of the loaded cargoes. Cytotoxicity studiesin breast cancer MCF 7 and wild-type mouse embryonic fibroblasts celllines revealed that the amphiphilic polyester was non-toxic to celllines up to 100 mu g/mL, while their drug-loaded polyester nanoparticleswere able to inhibit the cancerous cell growth. Temperature-dependentcellular uptake studies further confirmed the energy-dependent endocytosisof polymer NPs across the cellular membranes. Confocal laser scanningmicroscopy assisted time-dependent cellular uptake analysis directlyevident for the endocytosis of DOX loaded polymer NP and their internalizationfor biodegradation. In a nutshell, the present investigation opensup an avenue for the l-amino acid-based biodegradable polyestersfrom l-aspartic acids, and the proof of concept is demonstratedfor drug delivery in the cancer cell line.