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

Abstract

Aliphatic polyesters are intrinsically enzymatic-biodegradable, and there is ever-increasing demand for safe and smart nextgeneration biomaterials including drug delivery nano-vectors in cancer research. Using bioresource-based biodegradable polyesters is one of the elegant strategies to meet this requirement; here, we report an Lamino acid-based amide-functionalized polyester platform and explore their lysosomal enzymatic biodegradation aspects to administrate anticancer drugs in cancer cells. L-Aspartic acid was chosen and different amide-side chain-functionalized di-ester monomers were tailor-made having aromatic, aliphatic, and bio-source pendant units. Under solvent-free melt polycondensation methodology; these monomers underwent polymerization to yield high molecular weight polyesters with tunable thermal properties. PEGylated L-aspartic monomer was designed to make thermo-responsive amphiphilic polyesters. This amphiphilic polyester was self-assembled into a 140 ± 10 nm-sized spherical nanoparticle in aqueous medium, which exhibited lower critical solution temperature at 40−42 °C. The polyester nano-assemblies showed excellent encapsulation capabilities for anticancer drug doxorubicin (DOX), anti-inflammatory drug curcumin, biomarkers such as rose bengal (RB), and 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt. The amphiphilic polyester NP was found to be very stable under extracellular conditions and underwent degradation upon exposure to horse liver esterase enzyme in phosphate-buffered saline at 37 °C to release 90% of the loaded cargoes. Cytotoxicity studies in breast cancer MCF 7 and wild-type mouse embryonic fibroblasts cell lines revealed that the amphiphilic polyester was non-toxic to cell lines up to 100 μg/mL, while their drug-loaded polyester nanoparticles were able to inhibit the cancerous cell growth. Temperature-dependent cellular uptake studies further confirmed the energy-dependent endocytosis of polymer NPs across the cellular membranes. Confocal laser scanning microscopy assisted time-dependent cellular uptake analysis directly evident for the endocytosis of DOX loaded polymer NP and their internalization for biodegradation. In a nutshell, the present investigation opens up an avenue for the L-amino acid-based biodegradable polyesters from L-aspartic acids, and the proof of concept is demonstrated for drug delivery in the cancer cell line.

Experimental and Molecular Docking Studies on Enzyme-Driven Biohybrid-Inspired Micromotors Based on Amylose-b-(PEG-co-PBA) Inclusion Complexes

“…Since the main in vivo degradation mechanism in the polyester family is hydrolytic degradation, 38 we proposed the Candida Antarctica lipase B (CALB) enzyme, a subclass of the esterases, as the fuel for the IC nanomotors. Moreover, more than half of the current prodrug market is based on enzymatically biodegradable aliphatic ester chemical linkages; 39 thus, any work on enzymatic fuels and enzymatically degraded polymers is of great importance. Although in our previous works, CALB has been very well-known to degrade polyester polymers 40 and act as the fuel for powering the nanomotors; 41 in this work, one of our aims is to get a comprehensive understanding of the interaction of the enzyme and the polymer by molecular docking.…”

Biotinylated Theranostic Amphiphilic Polyurethane for Targeted Drug Delivery

“…1 H NMR (400 MHz, CDCl 3 , δ ppm, Figure S4): 8.05 (ArOH, 1H, s), 6.92 (ArH, 2H, s), 4.84 (ArCH 2 −, 4H, s), 2.27 (ArCH 3 , 3H, s), 0.96 (−SiC(CH 3 ) 3 , 18H, s), 0.14 (−S(CH 3 ) 2 , 12H, s). 13…”

“…Esterase is one of the most abundant classes of enzymes which is highly overexpressed in the tumor microenvironment. 13 Hence, based on the contrast of esterase concentration in tumor cells and normal cells, several drug delivery vehicles have been developed in recent times. 14 Drug release from the vehicles is mainly stimulated by esterase-triggered side chain degradation or main chain (polymer backbone) degradation.…”

Manganese-Doped Mesoporous Magnetic Nanocarriers for Cancer Treatment

“…To make drug release controllable, “intelligent” nanoparticles provide new possibilities for cancer treatment, − but it remains difficult to build delivery systems that are responsive to the body’s shifting metabolic conditions. Designing sensitive nanosystems for drug delivery in cancer therapy most commonly involves a pH-responsive system. , Pullulan oxide (oxPL) is an excellent pH-responsive gatekeeper because it is an inexpensive and nontoxic material that can be easily produced, remains stable in neutral environments, and disintegrates easily in acidic conditions. , A synergistic treatment approach combining photothermal therapy with drug therapy has been pursued to enhance the therapeutic efficacy.…”