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.
Highlights
Cervical cancer caused by high-risk human papillomavirus (HPV) persistent infection is the second most common cancer in women worldwide [1,2]
These results showed that pShuttle2-endostatin was successfully constructed and expressed in HeLa cells
dynamic light scattering (DLS) assay showed that the hydrodynamic diameter of the polyplexed blank TPGS-b(PCL-ran-PGA) NPs (ANPs) was approximately 215 nm, while the diameters of the docetaxel-loaded TPGS-b(PCL-ran-PGA) and docetaxel-loaded TPGS-b-(PCLran-PGA) PEI-coated without pDNA NPs were approximately 242 and approximately 270 nm, respectively (Figure 2A)
Summary
Cervical cancer caused by high-risk human papillomavirus (HPV) persistent infection is the second most common cancer in women worldwide [1,2]. Two HPV vaccines (Gardasil (Merck Sharp & Dohme Corp., NJ, USA) and Cervarix (GlaxoSmithKline, TW, UK)) have been approved for use in many countries that would effectively reduce the incidence of cervical cancer genesis. These two vaccines have not shown any therapeutic effect against current cervical cancer, HPV infections or associated lesions [3]. Endostatin, a 20 kDa C-terminal proteolytic fragment of collagen XVIII, has received the greatest attention for its broad-spectrum and low-toxic anti-angiogenesis ability [6,9,10] These advantages accelerate the investigation process of endostatin into the clinical trial [11,12]. The main vectors for DNA delivery are viral vectors and non-viral vectors having great advantages in safety, convenient large-scale production, physiological stability, and no immunogenicity
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