In vitro/vivo antitumor study of modified-chitosan/carboxymethyl chitosan "boosted" charge-reversal nanoformulation
Lin Li1, Peng Zhang1, Congcong Li1
1School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China.
Abstract:
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%.
