1-MT grafted carboxymethyl chitosan and its nanoparticles: Preparation, characterization and evaluation

This work aims to synthesize two novel 1-MT (1-Methyl-DL-tryptophan) grafted CMCS (carboxymethyl chitosan) polymer prodrugs CMCS-amido-1-MT and CMCS-ester-1-MT, and to further manufacture their nanoparticles for potential biomedical applications. The polymeric prodrugs are prepared by three-step chemical synthesis. The chemical structure of drugs is confirmed by FTIR and 1H-NMR. The drug loadings of the CMCS-amido-1-MT NPs and CMCS-ester-1-MT NPs are 11.43% and 10.18%, respectively. The surface morphology of the nanoparticles is spherical or nearly spherical, while the surface is smooth and the size distribution is uniform. The average particle size is both about 200 nm, while the polydispersity index is both about 0.15. The nanoparticles have a negative charge on the surface. The particle size and its distribution change little, when the two nanoparticles are tested in the simulated blood pH environment for 7 days. However, only the CMCS-ester-1-MT nanoparticles are pH-sensitive. The cell toxicity of the CMCS-ester-1-MT nanoparticles and the original drug are both in a dose- and time-dependent manner, while the nanoparticles enter cells by endocytosis. In ECA109 cells, the CMCS-ester-1-MT nanoparticles and the original drug both induce the apoptosis. CMCS-ester-1-MT NPs can activate the ATF4/CHOP pathway in endoplasmic reticulum stress, and achieve cancer suppression through mitochondrial-related apoptosis.