In vitro/vivo antitumor study of modified-chitosan/carboxymethyl chitosan boosted charge-reversal nanoformulation

Major obstacles in the development of nanoformulations as efficient drug delivery systems are the rapid clearance from blood circulation and lysosomal entrapment. To overcome these problems, a polysaccharide-based core-shell type charge-switchable nanoformulation (CS-LA-DMMA/CMCS/PAMAM@DOX) is constructed to improve antitumor efficacy of DOX. By applying carboxymethyl chitosan (CMCS) as bridge polymer and negatively charged chitosan-derivative as outer shell, the stability and pH-sensitivity of this nanoformulation is promisingly enhanced. Furthermore, the positively charged PAMAM@DOX could escape from lysosomes via proton sponge effect and cationic-anionic interaction with lysosome membranes. Admirable cellular uptake and high apoptosis/necrosis rate were detected in this study. In vitro assays demonstrate that the CS-LA-DMMA/ CMCS/PAMAM@DOX was internalized into HepG2 cells predominantly via the clathrin-mediated endocytosis pathway. Excitingly, in vivo studies showed that high accumulation of CS-LA-DMMA/CMCS/PAMAM@DOX in tumor tissue led to enhanced tumor inhibition. Compared with free DOX, the tumor inhibition rate of nanoformulation was improved up to 226%.

Automated summary

This study developed a polysaccharide-based charge-switchable nanoformulation to enhance the efficacy of the anticancer drug DOX, showing promising stability and pH-sensitivity. The nanoformulation significantly improved cellular uptake, apoptosis/necrosis rates, and tumor inhibition in vivo, with a 226% enhancement compared to free DOX.