Behl Akanksha, Solanki Subhash, Paswan Shravan K, Datta Tirtha K, Saini Adesh K, Saini Reena V, Parmar Virinder S, Thakur Vijay Kumar, Malhotra Shashwat, Chhillar Anil K
Centre for Biotechnology, M.D. University, Rohtak, Haryana 124 001 India.
Animal Biotechnology Centre, ICAR-National Dairy Research Institute, Karnal, Haryana 132 001 India.
J Polym Environ. 2023;31(3):999-1018. doi: 10.1007/s10924-022-02654-4. Epub 2022 Nov 11.
Combating triple-negative breast cancer (TNBC) is still a problem, despite the development of numerous drug delivery approaches. Mucin1 (MUC1), a glycoprotein linked to chemo-resistance and progressive malignancy, is unregulated in TNBC. GO-201, a MUC1 peptide inhibitor that impairs MUC1 activity, promotes necrotic cell death by binding to the MUC1-C unit. The current study deals with the synthesis and development of a novel nano-formulation (DM-PEG-PCL NPs) comprising of polyethylene glycol-polycaprolactone (PEG-PCL) polymer loaded with MUC1 inhibitor and an effective anticancer drug, doxorubicin (DOX). The DOX and MUC1 loaded nanoparticles were fully characterized, and their different physicochemical properties, viz size, shape, surface charge, entrapment efficiencies, release behavior, etc., were determined. With IC values of 5.8 and 2.4 nm on breast cancer cell lines, accordingly, and a combination index (CI) of < 1.0, DM-PEG-PCL NPs displayed enhanced toxicity towards breast cancer cells (MCF-7 and MDA-MB-231) than DOX-PEG-PCL and MUC1i-PEG-PCL nanoparticles. Fluorescence microscopy analysis revealed DOX localization in the nucleus and MUC1 inhibitor in the mitochondria. Further, DM-PEG-PCL NPs treated breast cancer cells showed increased mitochondrial damage with enhancement in caspase-3 expression and reduction in Bcl-2 expression.In vivo evaluation using Ehrlich Ascites Carcinoma bearing mice explicitly stated that DM-PEG-PCL NPs therapy minimized tumor growth relative to control treatment. Further, acute toxicity studies did not reveal any adverse effects on organs and their functions, as no mortalities were observed. The current research reports for the first time the synergistic approach of combination entrapment of a clinical chemotherapeutic (DOX) and an anticancer peptide (MUC1 inhibitor) encased in a diblock PEG-PCL copolymer. Incorporating both DOX and MUC1 inhibitors in PEG-PCL NPs in the designed nanoformulation has provided chances and insights for treating triple-negative breast tumors. Our controlled delivery technology is biodegradable, non-toxic, and anti-multidrug-resistant. In addition, this tailored smart nanoformulation has been particularly effective in the therapy of triple-negative breast cancer.
The online version contains supplementary material available at 10.1007/s10924-022-02654-4.
尽管已开发出多种药物递送方法，但对抗三阴性乳腺癌（TNBC）仍是一个难题。黏蛋白1（MUC1）是一种与化疗耐药性和恶性进展相关的糖蛋白，在TNBC中表达失调。GO-201是一种MUC1肽抑制剂，可损害MUC1活性，通过与MUC1-C单元结合促进坏死性细胞死亡。当前的研究涉及一种新型纳米制剂（DM-PEG-PCL NPs）的合成与开发，该制剂由负载MUC1抑制剂和有效抗癌药物阿霉素（DOX）的聚乙二醇-聚己内酯（PEG-PCL）聚合物组成。对负载DOX和MUC1的纳米颗粒进行了全面表征，并测定了它们不同的物理化学性质，即尺寸、形状、表面电荷、包封率、释放行为等。相应地，DM-PEG-PCL NPs对乳腺癌细胞系（MCF-7和MDA-MB-231）的半数抑制浓度（IC）值分别为5.8和2.4 nM，联合指数（CI）<1.0，显示出比DOX-PEG-PCL和MUC1i-PEG-PCL纳米颗粒对乳腺癌细胞具有更强的毒性。荧光显微镜分析显示DOX定位于细胞核，MUC1抑制剂定位于线粒体。此外，经DM-PEG-PCL NPs处理的乳腺癌细胞显示线粒体损伤增加，同时caspase-3表达增强，Bcl-2表达降低。使用携带艾氏腹水癌的小鼠进行的体内评估明确表明，与对照治疗相比，DM-PEG-PCL NPs疗法使肿瘤生长最小化。此外，急性毒性研究未发现对器官及其功能有任何不良影响，因为未观察到死亡情况。当前的研究首次报道了在二嵌段PEG-PCL共聚物中联合包封临床化疗药物（DOX）和抗癌肽（MUC1抑制剂）的协同方法。在设计的纳米制剂中将DOX和MUC1抑制剂都纳入PEG-PCL NPs中，为治疗三阴性乳腺肿瘤提供了机会和见解。我们的控释技术具有生物可降解性、无毒且抗多药耐药性。此外，这种定制的智能纳米制剂在三阴性乳腺癌的治疗中特别有效。
在线版本包含可在10.1007/s10924-022-02654-4获取的补充材料。
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