Development of targeted sunitinib plus vinorelbine liposomes modified with DSPE-PEG2000-pemetrexed conjugate and the inhibitory effect toresistant breast cancer in vitro

doi:10.5246/jcps.2014.05.039

Journal of Chinese Pharmaceutical Sciences ›› 2014, Vol. 23 ›› Issue (5): 287-294.DOI: 10.5246/jcps.2014.05.039

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Development of targeted sunitinib plus vinorelbine liposomes modified with DSPE-PEG2000-pemetrexed conjugate and the inhibitory effect toresistant breast cancer in vitro

Jifeng Shi, Ruijun Ju, Mengge Sun, Xiuying Li, Yao Zhao, Fan Zeng, Wanliang Lu^*

State Key Laboratory of Natural and Biomimetic Drugs; Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China

Received:2014-03-03 Revised:2014-03-31 Online:2014-05-23 Published:2014-04-06
Contact: Tel.: 86-10-82802683; E-mail: luwl@bjmu.edu.cn
Supported by:
Beijing Natural Science Foundation (Grant No. 7131009), the National Basic Research Program of China (Grant No. 973 program, 2013CB932501), the National Natural Science Foundation of China (Grant No. 81373343), and the Innovation Team of Ministry of Education (Grant No. BMU20110263).

Abstract

Abstract:

Multidrug resistance (MDR) of breast cancer is a major cause of failure in chemotherapy. In the present study,a distearoylphosphatidyl ethanolamine-polyethylene glycol-pemetrexed (DSPE-PEG₂₀₀₀-PMT) conjugate was synthesized from DSPE-PEG₂₀₀₀-NH₂ and pemetrexed, and targeted sunitinib plus vinorelbine liposomes were developed by modifying DSPE-PEG₂₀₀₀-PMT onto the surface of liposomes to overcome the MDR of breast cancer. The synthesized DSPE-PEG₂₀₀₀-PMT was confirmed to be consistent with the target product by matrix-assisted laser desorption/ionization time of flight massspectrometry (MALDI-TOF-MS). The concentrations of sunitinib and vinorelbine were measured simultaneously by highperformance liquid chromatography (HPLC). The analysis was performed on an ODS column at 30 °C at a wavelength of 215 nm with the mobile phase consisting of acetonitrile, 0.05 M KH₂PO₄ (pH 3.5) and triethylamine (35:65:0.3, v/v/v). The limits of detection for sunitinib and vinorelbine were 25 ng/mL and 5 ng/mL, respectively, and the limits of quantification for both drugs were 0.25 µg/mL. Two drugs were linearly correlated in the range of 0.5–25.0 µg/mL. For varying types of liposomes, the encapsulation efficiencies were >90%; the particle sizes were approximately 90 nm, and zeta potentials were slightly negative. The inhibitory effects were evaluated in the resistant breast cancer MCF-7/Adr cells. The results revealed that targeted sunitinib plus vinorelbine liposomes exhibited the strongest inhibitory effect to the resistant MCF-7/Adr cells among the varying formulations. Targeted coumarin liposomes were used as a fluorescent probe to evaluate the targeting effect to resistant breast cancer MCF-7/Adrcells. The results demonstrated that the targeted coumarin liposomes displayed the highest cellular uptake compared tonon-targeted formulations. In conclusion, the targeted sunitinib plus vinorelbine liposomes represented a novel type of nano-formulations, which could accumulate in the resistant breast cancer cells, thereby inhibiting proliferation of the resistant cancer cells. Accordingly, the targeted sunitinib plus vinorelbine liposomes may provide a new strategy for circumventing the drug resistance in the resistant breast cancer.

Key words: DSPE-PEG2000-pemetrexed, Sunitinib, Vinorelbine, Targeted liposomes, Resistant breast cancer

CLC Number:

R943

Supporting:

Jifeng Shi, Ruijun Ju, Mengge Sun, Xiuying Li, Yao Zhao, Fan Zeng, Wanliang Lu. Development of targeted sunitinib plus vinorelbine liposomes modified with DSPE-PEG2000-pemetrexed conjugate and the inhibitory effect toresistant breast cancer in vitro[J]. Journal of Chinese Pharmaceutical Sciences, 2014, 23(5): 287-294.

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Development of targeted sunitinib plus vinorelbine liposomes modified with DSPE-PEG2000-pemetrexed conjugate and the inhibitory effect toresistant breast cancer in vitro

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