Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma.
Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma.
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DOI：
10.2147/ijn.s139507
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发表时间：
2017
影响因子：
8
通讯作者：
Zhen YS
中科院分区：
文献类型：
--
作者：
Liu XJ;Li L;Liu XJ;Li Y;Zhao CY;Wang RQ;Zhen YS
以往的研究表明，光神霉素A（mithramycin A，MIT）是一种通过抑制转录因子Sp1而治疗胰腺癌的有希望的药物。然而，全身毒性可能限制其临床应用。在这里，我们报告了一种合理设计的MIT-loaded纳米颗粒（MIT-NPs）的配方，具有小尺寸和持续释放，用于改善被动靶向和增强治疗效果。通过将MIT封装到甲氧基聚乙二醇-嵌段-聚（d，l-乳酸-羟基乙酸）（mPEG-PLGA）纳米粒（NPs）中，制备了平均粒径为25.0±4.6 nm的近球形MIT-NPs，载药量为2.11%± 0.51%。MIT-NP的体外释放持续>48 h，具有缓释模式。MIT-NP对人胰腺癌BxPC-3和MIA Paca-2细胞的细胞毒性与游离MIT相当。通过流式细胞仪和共聚焦显微镜检测，NPs快速有效地内化到细胞中，在1-2 h达到峰值水平。体内荧光成像显示，制备的NPs在BxPC-3和MIA Paca-2异种移植物中逐渐积累，并保留168 h。BxPC-3和MIA Paca-2肿瘤中的荧光强度比各种测试器官的荧光强度强得多。用渗透性差的BxPC-3胰腺癌异种移植模型评价治疗功效。在耐受性良好的2 mg/kg剂量下，MIT-NP抑制BxPC-3肿瘤生长96%。在同等剂量下，MIT-NPs的治疗效果明显高于游离MIT（86%比51%，P<0.01）。此外，MIT和MIT-NPs的处理降低了由Sp1调节的癌基因c-Myc的表达水平，并且显著地，它们都降低了CD 47的蛋白水平。总之，MIT-NP的新制剂对胰腺癌异种移植物显示出高度的治疗功效。此外，MIT-NPs可下调CD 47的表达，这意味着它可能在癌症免疫治疗中发挥积极作用。
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.