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Eph A10-modified pH-sensitive liposomes loaded with novel triphenylphosphine-docetaxel conjugate possess hierarchical targetability and sufficient antitumor effect both in vitro and in vivo.

ABSTRACT: Mitochondrial-targeting therapy was considered to be a promising approach for the efficient treatment of cancer while positive charge induced nonspecific cytotoxicity severely limits its application. To overcome this drawback, a novel mitochondria targeted conjugate triphenylphosphine-docetaxel (TD) has been synthesized successfully and incorporated it into liposomes (EPSLP/TD), which possessed excellent pH-sensitive characteristic, EphA 10 mediated active targetability as well as mitochondria-targeting capability. EPSLP/TD was characterized to have a small particle size, high-encapsulation efficiency and excellent pH-sensitive characteristic. Compared with DTX-loaded liposomes (EPSLP/DTX), EPSLP/TD possessed higher cytotoxicity against MCF-7 cell line. Mitochondrial-targeting assay demonstrated mitochondria-targeting moiety triphenylphosphine (TPP) could efficiently deliver DTX to mitochondria. Western immunoblotting assay indicated that EPSLP/TD could efficiently deliver antitumor drug to mitochondria and induce cell apoptosis via mitochondria-mediated apoptosis pathway. In vivo antitumor study demonstrated EPSLP/TD owed excellent in vivo antitumor activity. Histological assay demonstrated EPSLP/TD showed strongly apoptosis inducing effect, anti-proliferation effect and anti-angiogenesis effect. This work investigated the potential of hierarchical targeting pH-sensitive liposomes is a suitable carrier to activate mitochondria-mediated apoptosis pathway for cancer therapy.

SUBMITTER: Zhang J

PROVIDER: S-EPMC6058733 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Eph A10-modified pH-sensitive liposomes loaded with novel triphenylphosphine-docetaxel conjugate possess hierarchical targetability and sufficient antitumor effect both in vitro and in vivo.

Zhang Jiulong J Yang Chunrong C Pan Shuang S Shi Menghao M Li Jie J Hu Haiyang H Qiao Mingxi M Chen Dawei D Zhao Xiuli X

Drug delivery 20181101 1

Mitochondrial-targeting therapy was considered to be a promising approach for the efficient treatment of cancer while positive charge induced nonspecific cytotoxicity severely limits its application. To overcome this drawback, a novel mitochondria targeted conjugate triphenylphosphine-docetaxel (TD) has been synthesized successfully and incorporated it into liposomes (EPSLP/TD), which possessed excellent pH-sensitive characteristic, EphA 10 mediated active targetability as well as mitochondria-t ...[more]

PMID: 29513049

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Project description:This study aimed at encapsulation of commonly administered, highly cytotoxic anticancer drug Docetaxel (DTX) in camel milk fat globule-derived liposomes for delivery in triple negative breast cancer cells. Prior to liposomal encapsulation of drug, in silico analysis of Docetaxel was done to predict off target binding associated toxicities in different organs. For this purpose, the ADMET Predictor (TM) Cloud version 10.4.0.5, 64-bit, was utilized to simulate Docetaxel's pharmacokinetic and physicochemical parameters. Freshly milked camel milk was bought from local market, from two breeds Brella and Marecha, in suburbs of Islamabad. After extraction of MFGM-derived liposomes from camel milk, docetaxel was loaded into liposomes by thin film hydration method. The physiochemical properties of liposomes were analyzed by SEM, FTIR and Zeta analysis. The results from SEM showed that empty liposomes (Lp-CM-ChT80) had spherical morphology while DTX loaded liposomes (Lp-CM-ChT80-DTX) exhibited rectangular shape, FTIR revealed the presence of characteristic functional groups which confirmed the successful encapsulation of DTX. Zeta analysis showed that Lp-CM-ChT80-DTX had size of 836.6 nm with PDI of 0.088 and zeta potential of - 18.7 mV. The encapsulation efficiency of Lp-CM-ChT80 turned out to be 25% while in vitro release assay showed slow release of DTX from liposomes as compared to pure DTX using dialysis membrane. The in vitro anticancer activity was analyzed by cell morphology analysis and MTT cytotoxicity assay using different concentrations 80 µg/ml, 120 µg/ml and 180 µg/ml of Lp-CM-ChT80-DTX on MDA-MB-231 cells. The results showed cytotoxic effects increased in time and dose dependent manner, marked by rounding, shrinkage and aggregation of cells. MTT cytotoxicity assay showed that empty liposomes Lp-CM-ChT80 did not have cytotoxic effect while Lp-CM-ChT80-DTX showed highest cytotoxic potential of 60.2% at 180 µg/ml. Stability analysis showed that liposomes were stable till 24 h in solution form at 4 °C.

Dataset Information

Eph A10-modified pH-sensitive liposomes loaded with novel triphenylphosphine-docetaxel conjugate possess hierarchical targetability and sufficient antitumor effect both in vitro and in vivo.

Publications

Eph A10-modified pH-sensitive liposomes loaded with novel triphenylphosphine-docetaxel conjugate possess hierarchical targetability and sufficient antitumor effect both in vitro and in vivo.

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