Tpgs(2k)/Plga Nanoparticles For Overcoming Multidrug Resistance By Interfering Mitochondria Of Human Alveolar Adenocarcinoma Cells
ACS APPLIED MATERIALS & INTERFACES(2015)
Abstract
In this study, we successfully synthesized d-a-tocopheryl polyethylene glycol 2000 succinate (TPGS(2k)) and prepared TPGS(2k)-modified poly(lactic-co-glycolic acid) nanoparticles (TPGS(2k)/PLGA NPs) loaded with 7-ethyl-10-hydroxycamptothecin (SN-38), designated TPGS(2k)/PLGA/SN-38 NPs. Characterization measurements showed that TPGS(2k)/PLGA/SN-38 NPs displayed flat and spheroidal particles with diameters of 80-104 nm. SN-38 was encapsulated in TPGS(2k) emulsified PLGA NPs with the entrapment efficiency and loading rates of SN-38 83.6 and 7.85%, respectively. SN-38 could release constantly from TPGS(2k)/PLGA/SN-38 NPs in vitro. TPGS(2k)/PLGA/SN-38 NPs induced significantly higher cytotoxicity on A549 cells and the multidrug resistance (MDR) cell line (A549/DDP cells and A549/Taxol cells) compared with free SN-38. Further studies on the mechanism of the NPs in increasing the death of MDR cells showed that following the SN-38 releasing into cytoplasm the remaining TPGS(2k)/PLGA NPs could reverse the P-gp mediated MDR via interfering with the structure and function of mitochondria and rather than directly inhibiting the enzymatic activity of P-gp ATPase. Therefore, TPGS(2k)/PLGA NPs can reduce the generation of ATP and the release of energy for the requisite of P-gp efflux transporters. The results indicated that TPGS(2k)/PLGA NPs could become the nanopharmaceutical materials with the capability to reversal MDR and improve anticancer effects of some chemotherapy drugs as P-gp substrates.
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Key words
TPGS(2k), nanopharmaceutical materials, nanoparticles, multidrug resistance, P-glycoprotein, mitochondria, ATP
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