Journal
ACTA PHARMACOLOGICA SINICA
Volume 38, Issue 6, Pages 885-896Publisher
ACTA PHARMACOLOGICA SINICA
DOI: 10.1038/aps.2017.10
Keywords
human colon cancer; multidrug resistance; doxorubicin; dihydroartemisinin; combination therapy; tumor-targeted delivery; mannosylated liposome; mannose receptor
Funding
- 973 Program, China [2014CB931900, 2013CB932503]
- National Natural Science Foundation of China [81373357, 81422048, 81402883, 81521005, 81673382]
- Scientific Research and Equipment Development Project, Chinese Academy of Sciences [YZ201437]
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Multidrug resistance (MDR) is a major hurdle in cancer chemotherapy and makes the treatment benefits unsustainable. Combination therapy is a commonly used method for overcoming MDR. In this study we investigated the anti-MDR effect of dihydroartemisinin (DHA), a derivative of artemisinin, in combination with doxorubicin (Dox) in drug-resistant human colon tumor HCT8/ADR cells. We developed a tumor-targeting codelivery system, in which the two drugs were co-encapsulated into the mannosylated liposomes (Manliposomes). The Man-liposomes had a mean diameter of 158.8 nm and zeta potential of -15.8 mV. In the HCT8/ADR cells that overexpress the mannose receptors, the Man-liposomes altered the intracellular distribution of Dox, resulting in a high accumulation of Dox in the nuclei and thus displaying the highest cytotoxicity (IC50=0.073 mu g/mL) among all the groups. In a subcutaneous HCT8/ADR tumor xenograft model, administration of the Man-liposomes resulted in a tumor inhibition rate of 88.59%, compared to that of 47.46% or 70.54%, respectively, for the treatment with free Dox or free Dox+ DHA. The mechanisms underlying the anti-MDR effect of the Manliposomes involved preferential nuclear accumulation of the therapeutic agents, enhanced cancer cell apoptosis, downregulation of Bcl-xl, and the induction of autophagy.
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