Intelligent Responsive Drug Delivery Capsule-Esterase-Responsive Peptide Nanomicelles

Directly using anticancer drugs are damage to normal tissues of human body,and the drugs themselves have many shortcomings such as poor water solubility.In order to overcome these problems,stimuli-responsive drug-loaded nanoparticles which could target cancer cells have attracted considerable attention.Due to the complexity of tumor microenvironment,non-specific anti-cancer drug delivery can stimulate cancer-associated fibroblasts.When they are stimulated,these Cancer-associated fibroblasts are known to secrete various growth factors involved in the process of angiogenesis in tumor.It could promote cancer cell survival and disease progression.Therefore,the specific delivery of anticancer drugs is important.Esterase is one of the overexpressed enzymes in tumor cells,which presents high expression level in cancer cells but low level in normal cell.Therefore,esterase-responsive nanocarriers can transport anti-cancer drugs specifically.The polyamino acid with unique secondary conformation has the characteristics of biocompatibility and biodegradability,which is an ideal nano-drug carrier.There are generally two methods to preparing stimuli-responsive polyamino acids.One is NCA ring-opening polymerization,and the other is post-modification method.The post-modification method could be more flexible to obtain stimuli-responsive polyamino acids.In this paper,polylysine was firstly prepared by NCA ring-opening method,and then esterase-responsive polypeptide was obtained by post-modification method,and finally its structure and properties were studied:1.Synthesis of polylysine based on 4-acetoxybenzyl carbamate and studied its enzyme responsibility:Esterase responsive polypeptide poly(ethylene glycol)-b-poly(N~?-(((4-acetoxybenzyl)oxy)carbonyl)-L-lysine)(PEG-b-PLLNA)was successfully synthesized.PEG-b-PLLNA was synthesized by PEG-b-PLL through amine-trans-esterification,which belonged to post-modification method.Polymers could self-assemble into micelles in water.Esterase catalyzed the hydrolysis of phenolic acetate moieties,followed by self-immolative decaging reactions to generate the primary amines.Simultaneously,the amidation reactions occurred to crosslink the membrane,which transited the membrane from hydrophobic to hydrophilic to accelerate the release of drug from vesicles without compromising the colloidal stability.2.The study of biological experiment of PEG-b-PLLNA drug-loaded micelles:In vitro cell experiments,our group used mouse fibroblast L929 and cancer cell Hela.Through experiment comparison,the cell viability of L929 was much higher than that of Hela,when micelles loaded with the same amount Dox.In cell confocal experiment,both L929 and Hela cells had a small amount of drug-loaded micelles entering the cytoplasm in 1 hour;in 4 hours,more drug-loaded micelles entered Hela and L929 cells,and a small amount of loaded Dox was released into the nuclei of Hela.In vivo experiment of mice,comparing the size of tumor tissues of three groups on 27th day,Dox-loaded PEG-b-PLLNA micelles had the best inhibitory effect on tumor growth.Therefore,the synthesis of esterase-responsive polypeptide PEG-b-PLLNA provides a new synthetic route for nano-drug carrying systems and a new ideas for application of biomedical materials.