Enzyme and pH dual responsive l -amino acid based biodegradable polymer nanocarrier for multidrug delivery to cancer cells

Abstract

We report a new pH and enzyme dual responsive biodegradable polymer nanocarrier to deliver multiple anticancer drugs at the intracellular compartment in cancer cells. Natural L-aspartic acid was converted into multifunctional monomer and polymerized to yield new classes of biodegradable aliphatic polyester in-build with pH responsiveness. The transformation of side chain BOC urethanes into cationic NH 1 3 in the acidic endosomal environment disassembled the polymers nanoparticles (pH trigger-1). The biodegradation of aliphatic polyester backbone by esterase enzyme ruptured the nanoassemblies and released the drugs in the cytoplasm (trigger-2). The polymer scaffolds were capable of delivering multiple drugs such as doxorubicin, topotecan, and curcumin (CUR). The cytotoxicity of the nascent and drug-loaded nanoparticles were tested in cervical (HeLa) and breast (MCF-7) cancer cell lines. The nascent polymer nanoscaffolds were found to be nontoxic to cells whereas their drug-loaded nanoparticles exhibited excellent killing. Confocal microscopic images revealed that the drug-loaded polymer nanoparticles were taken up by the cells and the dual degradation process delivered the drugs to nucleus and established the proof-of-concept. The present investigation opens up new platform for L-amino acid based polyester scaffolds, for the first time, in the intracellular drug delivery in cancer treatment.their monomer constituents from un-natural resources. Hence, it would be more appropriate to design biodegradable polymer nanocarriers based on biological monomer resources for cancer treatment and biomedical applications. Among the natural resources, L-amino acids are particularly interesting since their sequence and structure control the three dimensional assemblies of proteins and their enzymatic action in biological system. 24,25 L-Amino acid based synthetic amphiphilic oligopeptides 26 and diblock polypeptides 27-30 were tailor-made and their supramolecular nanoscaffolds were employed for tissue engineering, 31,32 drug and gene delivery, 33,34 etc. Unfortunately, these synthetic peptides were known to encounter difficulty for biodegradation at the intracellular level. 35 Digestive enzymes such as a-chymotrypsin and trypsin (available in intestine) were found to be highly specific in action to cleave peptide sequences in proteins. For example, a-chymotrypsinenzyme selectively cleaves C-terminal of phenyl alanine, tyrosine and tryptophan peptide linkages 36-38 whereas trypsinenzyme cleaves the C-terminal of arginine and lysine in peptides. 7 Hence, it is very difficult to predict or programme the enzymatic biodegradation of synthetic polypeptides in drug Additional Supporting Information may be found in the online version of this article.

Strategies To Design and Synthesize Polymer‐Based Stimuli‐Responsive Drug‐Delivery Nanosystems

“…Saxena and Jayakannan reported a new pH‐responsive and enzyme‐degradable amphiphilic aliphatic polyester, which was synthesized from natural l ‐amino acid resources and could self‐assemble into NPs . In cancer cells, the acidic endosomal environment caused the disassembly of NPs due to the transformation of side‐chain of tert ‐butyl decarbonate‐protected urethanes into cationic NH 3 + , and the lysosomal esterase enzyme induced the cleavage of ester bonds in polymer backbones (Figure A).…”

Application and design of esterase-responsive nanoparticles for cancer therapy

“…Another disadvantage is that esterase activity in tumor cells is different from person to person (Niu et al., 2012). In that case, some nanoparticles can respond to multi-stimuli simultaneously, such as GSH/esterase (Lv et al., 2015), pH/esterase (Fernando et al., 2015; Saxena & Jayakannan, 2016), heat/esterase (Kashyap et al., 2016; Aluri et al., 2018), etc. A multi-stimulus responsive drug carrier can simultaneously respond to different stimulating factors in tumor tissues and cells, not only can promote the uptake of drug conjugates by cells, but also promote the releasing of drugs in tumors, allowing the drug to function better in target cells.…”

Stimuli-Responsive Polymers Providing New Opportunities for Various Applications

“…Degradation of polymeric structure can be achieved by breaking down the enzyme-responsive groups in the polymer chain (Figure 10a). These enzymeresponsive groups can be located in the end group of the polymer chain, along the main chain, and at the junction of two different blocks of block copolymers [376,[380][381][382]. In Figure 10b, changes occur in the hydrophilicity of the polymer chain by enzyme-responsive group separation or addition of the side groups in the polymer chain [383,384].…”