TPGS2k/PLGA Nanoparticles for Overcoming Multidrug Resistance by Interfering Mitochondria of Human Alveolar Adenocarcinoma Cells

• Published in: ACS applied materials & interfaces 2015-02, Vol.7 (7), p.3888-3901
• Main Authors: Wang, Dong-Fang, Rong, Wen-Ting, Lu, Yu, Hou, Jie, Qi, Shan-Shan, Xiao, Qing, Zhang, Jue, You, Jin, Yu, Shu-Qin, Xu, Qian
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Camptothecin - analogs & derivatives; Camptothecin - chemistry; Camptothecin - pharmacology; Cell Line, Tumor; Drug Carriers - chemical synthesis; Drug Carriers - chemistry; Drug Delivery Systems - instrumentation; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Lactic Acid - chemistry; Mitochondria - drug effects; Mitochondria - metabolism; Nanoparticles - chemistry; Polyethylene Glycols - chemistry; Polyglycolic Acid - chemistry; Vitamin E - analogs & derivatives; Vitamin E - chemistry
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/am508340m

In this study, we successfully synthesized d-α-tocopheryl polyethylene glycol 2000 succinate (TPGS2k) and prepared TPGS2k-modified poly­(lactic-co-glycolic acid) nanoparticles (TPGS2k/PLGA NPs) loaded with 7-ethyl-10-hydroxycamptothecin (SN-38), designated TPGS2k/PLGA/SN-38 NPs. Characterization measurements showed that TPGS2k/PLGA/SN-38 NPs displayed flat and spheroidal particles with diameters of 80–104 nm. SN-38 was encapsulated in TPGS2k 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 TPGS2k/PLGA/SN-38 NPs in vitro. TPGS2k/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 TPGS2k/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, TPGS2k/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 TPGS2k/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.