期刊
INTERNATIONAL JOURNAL OF PHARMACEUTICS
卷 557, 期 -, 页码 304-313出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2018.12.067
关键词
Nanocrystals; Multidrug resistance; Codelivery; Caveolar endocytosis; Antitumor efficacy
资金
- National Natural Science Foundation of China [81673377, 81473152, 81872823, 81871477]
- Ministry of Science and Technology of China [2017ZX09101001-004]
- Fostering Plan of University Scientific and Technological Innovation Team and Key Members of the Outstanding Young Teacher of Jiangsu Qing Lan Project
Multidrug resistance (MDR) is a common intractable barrier in success of clinical cancer chemotherapy. Codelivery of two drugs using nanocarriers is a commonly used approach to treat the MDR cancer. However, the drug payload in the conventional nanocarriers is low and thus compromises the treatment outcomes. Disulfiram (DSF) is promising to reverse MDR and increases the sensitivity of cancer cells to chemotherapy. While, paclitaxel (PTX) is one of the frequently used anticancer drug. Here, by using a drug-delivering-drug (DDD) strategy based on nanocrystals, hybrid PTX-DSF nanocrystals (PTX-DSF Ns) were developed for codelivery of PTX and DSF to reverse MDR in cancer. The 160-nm PTX-DSF Ns with rod-like morphology had drug-loading up to 43% at mass ratio of 5:1. Interestingly, the nanoparticles entered cells via caveolar endocytosis. By reducing intracellular ATP level and GST activity, PTX-DSF Ns killed the Taxol resistant A549 cells with higher efficiency than PTX alone, exhibiting as 6-fold increase of apoptosis in MDR tumor. The nanoparticles circulated in blood over time, accumulated in tumor efficiently and reduced the tumor volume by 12-fold in MDR tumor-bearing BALB/c nude mice and allowed 12-fold apoptosis in tumor. Additionally, the immunohistochemical examination demonstrated the safety of the nanoparticles. Overall, the DDD strategy-based PTX-DSF Ns have promising potential for the treatment of MDR cancer.
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