Alpha-tocopheryl polyethylene glycol succinate-emulsified poly(lactic-co-glycolic acid) nanoparticles for reversal of multidrug resistance in vitro

• Published in: Nanotechnology 2012-12, Vol.23 (49), p.495103-495103
• Main Authors: Wang, Ying, Guo, Miao, Lu, Yu, Ding, Li-Ying, Ron, Wen-Ting, Liu, Ya-Qing, Song, Fei-Fei, Yu, Shu-Qin
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - chemistry; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - chemistry; Carriers; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drugs; Efflux; Emulsions - chemistry; Humans; Inhibitors; Lactic Acid - chemistry; Materials Testing; Modulators; Nanocapsules - administration & dosage; Nanocapsules - chemistry; Nanoparticles; Nanostructure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - pathology; Polyethylene glycol; Polyethylene Glycols - chemistry; Polyglycolic Acid - chemistry; Pumps; Vitamin E - analogs & derivatives; Vitamin E - chemistry
• ISSN: 0957-4484; 1361-6528
• DOI: 10.1088/0957-4484/23/49/495103

Multidrug resistance (MDR) is one of the factors in the failure of anticancer chemotherapy. In order to enhance the anticancer effect of P-glycoprotein (P-gp) substrates, inhibition of the P-gp efflux pump on MDR cells is a good tactic. We designed novel multifunctional drug-loaded alpha-tocopheryl polyethylene glycol succinate (TPGS)/poly(lactic-co-glycolic acid) (PLGA) nanoparticles (TPGS/PLGA/SN-38 NPs; SN-38 is 7-ethyl-10-hydroxy-camptothecin), with TPGS-emulsified PLGA NPs as the carrier and modulator of the P-gp efflux pump and SN-38 as the model drug. TPGS/PLGA/SN-38 NPs were prepared using a modified solvent extraction/evaporation method. Physicochemical characterizations of TPGS/PLGA/SN-38 NPs were in conformity with the principle of nano-drug delivery systems (nDDSs), including a diameter of about 200 nm, excellent spherical particles with a smooth surface, narrow size distribution, appropriate surface charge, and successful drug-loading into the NPs. The cytotoxicity of TPGS/PLGA/SN-38 NPs to MDR cells was increased by 3.56 times compared with that of free SN-38. Based on an intracellular accumulation study relative to the time-dependent uptake and efflux inhibition, we suggest novel mechanisms of MDR reversal of TPGS/PLGA NPs. Firstly, TPGS/PLGA/SN-38 NPs improved the uptake of the loaded drug by clathrin-mediated endocytosis in the form of unbroken NPs. Simultaneously, intracellular NPs escaped the recognition of P-gp by MDR cells. After SN-38 was released from TPGS/PLGA/SN-38 NPs in MDR cells, TPGS or/and PLGA may modulate the efflux microenvironment of the P-gp pump, such as mitochondria and the P-gp domain with an ATP-binding site. Finally, the controlled-release drug entered the nucleus of the MDR cell to induce cytotoxicity. The present study showed that TPGS-emulsified PLGA NPs could be functional carriers in nDDS for anticancer drugs that are also P-gp substrates. More importantly, to enhance the therapeutic effect of P-gp substrates, this work might provide a new insight into the design of pharmacologically inactive excipients that can serve as P-gp modulators instead of drugs that are P-gp inhibitors.