Yufei Feng1, Guozhao Qin1, Shuyuan Chang1, Zhongxu Jing2, Yanyan Zhang1, Yanhong Wang1. 1. Key Laboratory of Chinese Materia Medica in Ministry of Education, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, People's Republic of China. 2. Heilongjiang Provincial Administration of Traditional Chinese Medicine, Harbin, Heilongjiang, People's Republic of China.
Abstract
INTRODUCTION: Hyperoside (HYP), a flavonol glycoside compound, has been shown to significantly inhibit the proliferation of malignant tumors. Mitochondria serve as both "energy factories" and "suicide weapon stores" of cells. Targeted delivery of cytotoxic drugs to the mitochondria of tumor cells and tumor vascular cells is a promising strategy to improve the efficacy of chemotherapy. OBJECTIVE: We report a novel dual-functional liposome system possessing both extracellular charge reversal and mitochondrial targeting properties to enhance drug accumulation in mitochondria and trigger apoptosis of cancer cells. METHODS: L-lysine was used as a linker to connect 2,3-dimethylmaleic anhydride (DMA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to yield a new compound, DSPE-Lys-DMA (DLD). Then, DLD was mixed with other commercially available lipids to form charge reversed and mitochondria-targeted liposomes (DLD-Lip). The size, morphology, zeta potential, serum stability, and protein adsorption of the HYP loaded DLD-Lip (HYP/DLD-Lip) were measured. The release profile, cellular uptake, in vitro and in vivo toxicity, and anticancer activity of HYP/DLD-Lip were investigated. RESULTS: The results showed that the mean diameter of the liposomes was less than 200 nm. The zeta potential of the liposomes was negative at pH 7.4. However, the zeta potential was positive at weak acidic pH values with the cleavage of the DMA amide. The charge reversion of HYP/DLD-Lip facilitated the cellular internalization and mitochondrial accumulation for enhanced antitumor effect. The strongest tumor growth inhibition (TGI 88.79%) without systemic toxicity was observed in DLD/HYP-Lips-treated CBRH-7919 tumor xenograft BALB/C mice. CONCLUSION: The charge reversed and mitochondria-targeted liposomes represented a promising anticancer drug delivery system for enhanced anticancer therapeutic efficacy.
INTRODUCTION: Hyperoside (HYP), a flavonol glycoside compound, has been shown to significantly inhibit the proliferation of malignant tumors. Mitochondria serve as both "energy factories" and "suicide weapon stores" of cells. Targeted delivery of cytotoxic drugs to the mitochondria of tumor cells and tumor vascular cells is a promising strategy to improve the efficacy of chemotherapy. OBJECTIVE: We report a novel dual-functional liposome system possessing both extracellular charge reversal and mitochondrial targeting properties to enhance drug accumulation in mitochondria and trigger apoptosis of cancer cells. METHODS: L-lysine was used as a linker to connect 2,3-dimethylmaleic anhydride (DMA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to yield a new compound, DSPE-Lys-DMA (DLD). Then, DLD was mixed with other commercially available lipids to form charge reversed and mitochondria-targeted liposomes (DLD-Lip). The size, morphology, zeta potential, serum stability, and protein adsorption of the HYP loaded DLD-Lip (HYP/DLD-Lip) were measured. The release profile, cellular uptake, in vitro and in vivo toxicity, and anticancer activity of HYP/DLD-Lip were investigated. RESULTS: The results showed that the mean diameter of the liposomes was less than 200 nm. The zeta potential of the liposomes was negative at pH 7.4. However, the zeta potential was positive at weak acidic pH values with the cleavage of the DMA amide. The charge reversion of HYP/DLD-Lip facilitated the cellular internalization and mitochondrial accumulation for enhanced antitumor effect. The strongest tumor growth inhibition (TGI 88.79%) without systemic toxicity was observed in DLD/HYP-Lips-treated CBRH-7919 tumor xenograft BALB/C mice. CONCLUSION: The charge reversed and mitochondria-targeted liposomes represented a promising anticancer drug delivery system for enhanced anticancer therapeutic efficacy.
Authors: Anne M Strohecker; Jessie Yanxiang Guo; Gizem Karsli-Uzunbas; Sandy M Price; Guanghua Jim Chen; Robin Mathew; Martin McMahon; Eileen White Journal: Cancer Discov Date: 2013-08-21 Impact factor: 39.397
Authors: Jiawei Sun; Lei Jiang; Yi Lin; Ethan Michael Gerhard; Xuehua Jiang; Li Li; Jian Yang; Zhongwei Gu Journal: Int J Nanomedicine Date: 2017-02-27