Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma

International Journal of Nanomedicine, Jul 2017

Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma Xu-Jie Liu, Liang Li, Xiu-Jun Liu, Yi Li, Chun-Yan Zhao, Rui-Qi Wang, Yong-Su Zhen Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China Abstract: Previous studies have shown that mithramycin A (MIT) is a promising candidate for the treatment of pancreatic carcinoma through inhibiting transcription factor Sp1. However, systemic toxicities may limit its clinical application. Here, we report a rationally designed formulation of MIT-loaded nanoparticles (MIT-NPs) with a small size and sustained release for improved passive targeting and enhanced therapeutic efficacy. Nearly spherical MIT-NPs with a mean particle size of 25.0±4.6 nm were prepared by encapsulating MIT into methoxy poly(ethylene glycol)-block-poly(d,l-lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPs) with drug loading of 2.11%±0.51%. The in vitro release of the MIT-NPs lasted for >48 h with a sustained-release pattern. The cytotoxicity of MIT-NPs to human pancreatic cancer BxPC-3 and MIA Paca-2 cells was comparable to that of free MIT. Determined by flow cytometry and confocal microscopy, the NPs internalized into the cells quickly and efficiently, reaching the peak level at 1–2 h. In vivo fluorescence imaging showed that the prepared NPs were gradually accumulated in BxPC-3 and MIA Paca-2 xenografts and retained for 168 h. The fluorescence intensity in both BxPC-3 and MIA Paca-2 tumors was much stronger than that of various tested organs. Therapeutic efficacy was evaluated with the poorly permeable BxPC-3 pancreatic carcinoma xenograft model. At a well-tolerated dose of 2 mg/kg, MIT-NPs suppressed BxPC-3 tumor growth by 96%. Compared at an equivalent dose, MIT-NPs exerted significantly higher therapeutic effect than free MIT (86% versus 51%, P

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Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma

International Journal of Nanomedicine Mithramycin-loaded mPeg-Plga nanoparticles exert potent antitumor efficacy against pancreatic carcinoma 0 Institute of Medicinal Biotechnology, c hinese a cademy of Medical s ciences and Peking Union Medical College , Beijing , People's Republic of China Previous studies have shown that mithramycin A (MIT) is a promising candidate for the treatment of pancreatic carcinoma through inhibiting transcription factor Sp1. However, systemic toxicities may limit its clinical application. Here, we report a rationally designed formulation of MIT-loaded nanoparticles (MIT-NPs) with a small size and sustained release for improved passive targeting and enhanced therapeutic efficacy. Nearly spherical MIT-NPs with a mean particle size of 25.0±4.6 nm were prepared by encapsulating MIT into methoxy poly(ethylene glycol)-block-poly(d ,l -lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPs) with drug loading of 2.11%±0.51%. The in vitro release of the MIT-NPs lasted for .48 h with a sustained-release pattern. The cytotoxicity of MIT-NPs to human pancreatic cancer BxPC-3 and MIA Paca-2 cells was comparable to that of free MIT. Determined by flow cytometry and confocal microscopy, the NPs internalized into the cells quickly and efficiently, reaching the peak level at 1-2 h. In vivo fluorescence imaging showed that the prepared NPs were gradually accumulated in BxPC-3 and MIA Paca-2 xenografts and retained for 168 h. The fluorescence intensity in both BxPC-3 and MIA Paca-2 tumors was much stronger than that of various tested organs. Therapeutic efficacy was evaluated with the poorly permeable BxPC-3 pancreatic carcinoma xenograft model. At a well-tolerated dose of 2 mg/kg, MIT-NPs suppressed BxPC-3 tumor growth by 96%. Compared at an equivalent dose, MIT-NPs exerted significantly higher therapeutic effect than free MIT (86% versus 51%, P,0.01). Moreover, the treatment of MIT and MIT-NPs reduced the expression level of oncogene c-Myc regulated by Sp1, and notably, both of them decreased the protein level of CD47. In summary, the novel formulation of MIT-NPs shows highly therapeutic efficacy against pancreatic carcinoma xenograft. In addition, MIT-NPs can downregulate CD47 expression, implying that it might play a positive role in cancer immunotherapy. - Owing to perineural and vascular local growth and early distant metastases, pancreatic cancer is usually unresectable in most patients diagnosed at first. Effective chemotherapy is needed for patients who undergo surgical resection or are unable to have a curative surgery. However, pancreatic cancer is generally associated with a remarkable resistance to most conventional therapies.1 Thus, novel chemotherapeutic methods are urgently needed to treat pancreatic cancer. Mithramycin A (MIT), also called plicamycin, is a natural aureolic acid-type polyketide isolated from various strains of streptomyces.3 MIT has been used clinically as a chemotherapeutic agent to treat several cancer types, including testicular embryonal carcinoma and glioblastoma, although systemic toxicities limited its clinical use. In recent years, there has been renewed interest in the capability of MIT to bind to the minor groove of guanine and cytosine-rich DNA regions, since pharmacologically mediated modulation of DNA/protein complex formation represents a promising submit your manuscript | www.dovepress.com Dovepress aggressive clinical behavior and Sp1 overexpression increased the probability of cancer metastasis.17 MIT can exhibit an inhibitory effect on pancreatic cancer growth through distinct mechanisms of Sp1 inhibition. Treatment with MIT resulted in the inhibition of Sp1 recruitment onto vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β type II receptor (TGF-β RII) promoters, leading to downregulation of VEGF and TGF-β RII protein expression in pancreatic cancer cells.15,18,19 Meanwhile, MIT can sensitize pancreatic cancer cells to TRAIL-induced apoptosis.20 In spite of promising preclinical findings, the clinical use of MIT, especially as an anticancer drug requiring higher doses, has been hampered by its systemic toxicity. In order to enhance its safety and efficacy, one of the feasible strategies is to develop efficient formulations of drug delivery systems. Nanotechnology has attracted growing interest in cancer therapies due to its uniquely appealing features for drug delivery. The nanoparticle (NP) platforms for the targeted delivery of therapeutic drugs to solid tumors hold great promise for improving drug bioavailability and minimizing systemic toxicity. NPs are widely used as drug carriers because large molecules can avoid renal clearance and circulate in the body for prolonged time in comparison to small molecules. NPs accumulate in the tumor through the enhanced permeability and retention (EPR) effect, which enter the tumor interstitial space by enhanced permeability of the abnormal tumor microvasculature and re (...truncated)


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Xu-Jie Liu, Liang Li, Xiu-Jun Liu, Yi Li, Chun-Yan Zhao, Rui-Qi Wang, Yong-Su Zhen. Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma, International Journal of Nanomedicine, 2017, pp. 5255-5269, DOI: 10.2147/IJN.S139507