Journal
MOLECULAR PHARMACEUTICS
Volume 11, Issue 1, Pages 59-70Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp400514t
Keywords
nanoparticles; chitosan; TPGS; doxorubicin; multidrug resistance
Funding
- National Basic Research Program of China (973 Program) [2012CB932500]
- NSFC [21204024, 81373360]
- Ministry of Education of China [20120142120093]
- China Postdoctoral Science Foundation [2013T60722]
- Chutian Scholar of Hubei province
- Innovative Research Fund
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To overcome the P-glycoprotein (P-gp)-induced multidrug resistance (MDR) of cancer cells, a novel copolymer, chitosan-graft-D-alpha-tocopheryl polyethylene glycol 1000 (TPGS) (CT) was synthesized for doxorubicin (DOX) delivery by the P-gp inhibiting virtue of TPGS. DOX-loaded CT nanoparticles (NPs) were fabricated by a modified solvent extraction/evaporation method combined with ionic cross-linking to form a uniform particle size of 140-180 nm with similar to 40% DOX loading efficiency. These drug-loaded CT NPs demonstrated a pH-responsive release behavior, and DOX was released more quickly Under low pH values. Significant cell cytotoxicity was observed on the human hepatocarcinoma cells (HepG2 and BEL-7402) and human breast adenocarcinoma cells (MCF-7). The cell cytotoxicity and apoptosis of drug-resistant cells (MCF-7/DOX and BEL-7402/5-Fu), was greatly enhanced as compared to Adriamycin. The IC50 value showed that DOX-loaded CT NPs could be 1.5-199-fold more effective than Adriamycin. This can be attributed to the P-gp blocking and down-regulation of ATP levels by the CT NPs. The potential of these NPs to act as an oral delivery system was also investigated. Both the pharmacokinetic properties and in vivo antitumor activity of DOX-loaded CT NPs were improved compared with Adriamycin.
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