Engineered triphenylphosphonium-based, mitochondrial-targeted liposomal drug delivery system facilitates cancer cell killing actions of chemotherapeutics†

IF 4.2 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY RSC Chemical Biology Pub Date : 2023-12-21 DOI:10.1039/D3CB00219E
Subramaniyam Sivagnanam, Kiran Das, Ieshita Pan, Adele Stewart, Atanu Barik, Biswanath Maity and Priyadip Das
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Abstract

In addition to their classical role in ATP generation, mitochondria also contribute to Ca2+ buffering, free radical production, and initiation of programmed cell death. Mitochondrial dysfunction has been linked to several leading causes of morbidity and mortality worldwide including neurodegenerative, metabolic, and cardiovascular diseases as well as several cancer subtypes. Thus, there is growing interest in developing drug-delivery vehicles capable of shuttling therapeutics directly to the mitochondria. Here, we functionalized the conventional 10,12-pentacosadiynoic acid/1,2-dimyristoyl-sn-glycero-3-phosphocholine (PCDA/DMPC)-based liposome with a mitochondria-targeting triphenylphosphonium (TPP) cationic group. A fluorescent dansyl dye (DAN) group was also included for tracking mitochondrial drug uptake. The resultant PCDA-TPP and PCDA-DAN conjugates were incorporated into a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-based lipid bilayer, and these modified liposomes (Lip-DT) were studied for their cellular toxicity, mitochondrial targeting ability, and efficacy in delivering the drug Doxorubicin (Dox) to human colorectal carcinoma (HCT116) and human breast (MCF7) cancer cells in vitro. This Lip-DT-Dox exhibited the ability to shuttle the encapsulated drug to the mitochondria of cancer cells and triggered oxidative stress, mitochondrial dysfunction, and apoptosis. The ability of Lip-DT-Dox to trigger cellular toxicity in both HCT116 and MCF7 cancer cells was comparable to the known cell-killing actions of the unencapsulated drug (Dox). The findings in this study reveal a promising approach where conventional liposome-based drug delivery systems can be rendered mitochondria-specific by incorporating well-known mitochondriotropic moieties onto the surface of the liposome.

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基于三苯基膦的线粒体靶向脂质体给药系统促进了化疗药物对癌细胞的杀伤作用
线粒体除了在产生 ATP 方面发挥传统作用外,还在 Ca2+ 缓冲、自由基生成和启动细胞程序性死亡方面做出了贡献。线粒体功能障碍与全球发病率和死亡率的几个主要原因有关,包括神经退行性疾病、代谢性疾病、心血管疾病以及几种癌症亚型。因此,人们对开发能够将治疗药物直接输送到线粒体的药物输送载体越来越感兴趣。在这里,我们在传统的 10,12-五碳二炔酸/1,2-二肉豆蔻基-sn-甘油-3-磷酸胆碱(PCDA/DMPC)脂质体上添加了线粒体靶向三苯基膦(TPP)阳离子基团。此外,还加入了荧光丹酰染料(DAN)基团,用于跟踪线粒体对药物的吸收。研究人员将 PCDA-TPP 和 PCDA-DAN 共轭物加入到基于 1,2-二肉豆蔻基-sn-甘油-3-磷酸胆碱(DMPC)的脂质双分子层中,并研究了这些修饰脂质体(Lip-DT)的细胞毒性、线粒体靶向能力以及在体外向人类结直肠癌细胞(HCT116)和人类乳腺癌细胞(MCF7)输送药物多柔比星(Dox)的功效。这种 Lip-DT-Dox 能够将封装的药物穿梭到癌细胞的线粒体,并引发氧化应激、线粒体功能障碍和细胞凋亡。Lip-DT-Dox 在 HCT116 和 MCF7 癌细胞中引发细胞毒性的能力与已知的未封装药物(Dox)的细胞杀伤作用相当。这项研究的结果揭示了一种很有前景的方法,即通过在脂质体表面加入众所周知的线粒体定向分子,可以使传统的脂质体药物递送系统具有线粒体特异性。
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6.10
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0.00%
发文量
128
审稿时长
10 weeks
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