Bufalin-loaded vitamin E succinate-grafted-chitosan oligosaccharide/RGD conjugated TPGS mixed micelles demonstrated improved antitumor activity against drug-resistant colon cancer
Zeting Yuan,1,* Yuxia Yuan,1,* Lin Han,2 Yanyan Qiu,1 Xiaqin Huang,3 Feng Gao,3 Guohua Fan,1 Yixi Zhang,1 Xueyao Tang,1 Xue He,1 Ke Xu,1 Peihao Yin1,4,5 1Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 20...
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| Autores principales: | , , , , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
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Dove Medical Press
2018
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/98e2371c37eb45d395053545968447b4 |
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| Sumario: | Zeting Yuan,1,* Yuxia Yuan,1,* Lin Han,2 Yanyan Qiu,1 Xiaqin Huang,3 Feng Gao,3 Guohua Fan,1 Yixi Zhang,1 Xueyao Tang,1 Xue He,1 Ke Xu,1 Peihao Yin1,4,5 1Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, People’s Republic of China; 2Experimental Research Center, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, People’s Republic of China; 3Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, People’s Republic of China; 4Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, People’s Republic of China; 5Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Anhui 230022, People’s Republic of China *These authors contributed equally to this work Background: Multidrug resistance (MDR) is the major reason for the failure of chemotherapy in colon cancer. Bufalin (BU) is one of the most effective antitumor active constituents in Chansu. Our previous study found that BU can effectively reverse P-glycoprotein (P-gp)-mediated MDR in colon cancer. However, the clinical application of BU is limited due to its low solubility in water and high toxicity. In the present study, a multifunctional delivery system based on vitamin-E-succinate grafted chitosan oligosaccharide (VES-CSO) and cyclic (arginine-glycine-aspartic acid peptide) (RGD)-modified d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared by emulsion solvent evaporation method for targeted delivery of BU to improve the efficacy of drug-resistant colon cancer therapy.Methods: The cytotoxicity of BU-loaded micelles against drug-resistant colon cancer LoVo/ADR and HCT116/LOHP cells was measured by CCK-8 assay. The cellular uptake, Rho123 accumulation, and cell apoptosis were determined by flow cytometry. The expression of apoptosis-related protein and P-gp was measured by Western blot assay. The antitumor activity of BU-loaded micelles was evaluated in LoVo/ADR-bearing nude mice.Results: BU-loaded VES-CSO/TPGS-RGD mixed micelles (BU@VeC/T-RGD MM) were 140.3 nm in diameter with zeta potential of 8.66 mV. The BU@VeC/T-RGD MM exhibited good stability, sustained-release pattern, higher intracellular uptake, and greater cytotoxicity in LoVo/ADR cells. Furthermore, the mechanisms of the BU@VeC/T-RGD MM to overcome MDR might be due to enhanced apoptosis rate and P-gp efflux inhibition. Subsequently, in vivo studies confirmed an enhanced therapeutic efficiency and reduced side effects associated with BU@VeC/T-RGD MM compared with free BU, owing to the enhanced permeation and retention effect, improved pharmacokinetic behavior, and tumor targeting, which lead to MDR-inhibiting effect in LoVo/ADR-bearing nude mice.Conclusion: Our results demonstrated that VeC/T-RGD MM could be developed as a potential delivery system for BU to improve its antitumor activity against drug-resistant colon cancer. Keywords: bufalin, colon cancer, multidrug resistance, mixed micelle, tumor targeting, P-gp |
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