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Co-delivery of docetaxel and endostatin by a biodegradable nanoparticle for the synergistic treatment of cervical cancer

Bo Qiu13, Minghui Ji2, Xiaosong Song34, Yongqiang Zhu34, Zhongyuan Wang34, Xudong Zhang34, Shu Wu34, Hongbo Chen34, Lin Mei345* and Yi Zheng345*

Author Affiliations

1 Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China

2 Southern Medical University, Guangzhou, 510515, People’s Republic of China

3 The Shenzhen Key Lab of Gene and Antibody Therapy, Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, People’s Republic of China

4 School of Life Sciences, Tsinghua University, Beijing, 100084, People’s Republic of China

5 L401, Tsinghua Campus, Xili University Town, Shenzhen, Guangdong Province, 518055, China

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Nanoscale Research Letters 2012, 7:666  doi:10.1186/1556-276X-7-666

Published: 6 December 2012

Abstract

Cervical cancer remains a major problem in women's health worldwide. In this research, a novel biodegradable d-α-tocopheryl polyethylene glycol 1000 succinate-b-poly(ε-caprolactone-ran-glycolide) (TPGS-b-(PCL-ran-PGA)) nanoparticle (NP) was developed as a co-delivery system of docetaxel and endostatin for the synergistic treatment of cervical cancer. Docetaxel-loaded TPGS-b-(PCL-ran-PGA) NPs were prepared and further modified by polyethyleneimine for coating plasmid pShuttle2-endostatin. All NPs were characterized in size, surface charge, morphology, and in vitro release of docetaxel and pDNA. The uptake of coumarin 6-loaded TPGS-b-(PCL-ran-PGA)/PEI-pDsRED by HeLa cells was observed via fluorescent microscopy and confocal laser scanning microscopy. Endostatin expression in HeLa cells transfected by TPGS-b-(PCL-ran-PGA)/PEI-pShuttle2-endostatin NPs was detected using Western blot analysis, and the cell viability of different NP-treated HeLa cells was determined by MTT assay. The HeLa cells from the tumor model, nude mice, were treated with various NPs including docetaxel-loaded-TPGS-b-(PCL-ran-PGA)/PEI-endostatin NPs, and their survival time, tumor volume and body weight were monitored during regimen process. The tumor tissue histopathology was analyzed using hematoxylin and eosin staining, and microvessel density in tumor tissue was evaluated immunohistochemically. The results showed that the TPGS-b-(PCL-ran-PGA)/PEI NPs can efficiently and simultaneously deliver both coumarin-6 and plasmids into HeLa cells, and the expression of endostatin was verified via Western blot analysis. Compared with control groups, the TPGS-b-(PCL-ran-PGA)/PEI-pShuttle2-endostatin NPs significantly decreased the cell viability of HeLa cells (p < 0.01), inhibited the growth of tumors, and even eradicated the tumors. The underlying mechanism is attributed to synergistic anti-tumor effects by the combined use of docetaxel, endostatin, and TPGS released from NPs. The TPGS-b-(PCL-ran-PGA) NPs could function as multifunctional carrier for chemotherapeutic drugs and genetic material delivery, and offer considerable potential as an ideal candidate for in vivo cancer therapy.

Keywords:
TPGS-b-(PCL-ran-PGA); nanoparticles; cervical cancer; endostatin; docetaxel