Chitosan-g-TPGS nanoparticles for anticancer drug delivery and overcoming multidrug resistance.
To overcome the P-glycoprotein (P-gp)-induced multidrug resistance (MDR) of cancer cells, a novel copolymer, chitosan-graft-D-α-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 ∼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.
Tongji School of Pharmacy, §National Engineering Research Center for Nanomedicine, ⊥College of Life Science and Technology, Huazhong University of Science and Technology , Wuhan 430030, P.R. China.
Yuanyuan
Y
Guo
Min
M
Chu
Songwei
S
Tan
Shuang
S
Zhao
Hanxiao
H
Liu
Ben Oketch
BO
Otieno
Xiangliang
X
Yang
Chuanrui
C
Xu
Zhiping
Z
Zhang
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry*; D004317:Doxorubicin / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D011108:Polymers; D014810:Vitamin E; D011092:Polyethylene Glycols; D004317:Doxorubicin; D048271:Chitosan; C014225:tocophersolan