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基于谷胱甘肽的线粒体靶向载药传递系统用于递送洛尼达明治疗三阴性乳腺癌的研究

Glutathione Programmed Mitochondria Targeted Delivery of Lonidamine for Effective Against Triple Negative Breast Cancer.

机构信息

School of Food and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, 210023, People's Republic of China.

College of Life Science, Nanjing Normal University, Nanjing, 210023, People's Republic of China.

出版信息

Int J Nanomedicine. 2023 Jul 24;18:4023-4042. doi: 10.2147/IJN.S413217. eCollection 2023.

DOI:10.2147/IJN.S413217
PMID:37520302
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10378575/
Abstract

INTRODUCTION

Mitochondria are a significant target of lonidamine (LND). However, its limited solubility and inability to specifically target mitochondria, LND can lead to hepatic toxicity and has shown only modest anticancer activity. The objective of this study is to establish a glutathione programmed mitochondria targeted delivery of LND for the effective treatment of triple negative breast cancer (TNBC).

METHODS

In this study, LND was encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) wrapped with mitochondria-targeting short-chain triphenylphosphonium-tocopherol polyethylene glycol succinate (TPP-TPGS, TPS) and tumor-targeting long-chain 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-S-S-polyethylene glycol-R6RGD (DSPE-S-S-PEG-R6RGD, DSSR), which were designated as LND-PLGA/TPS/DSSR NPs. The release behavior was evaluated, and cellular uptake, in vitro and in vivo antitumor activity of nanoparticles were investigated. The mechanism, including apoptosis of tumor cells and mitochondrial damage and respiratory rate detection, was also further investigated.

RESULTS

LND-PLGA/TPS/DSSR NPs were successfully prepared, and characterization revealed that they are globular particles with smooth surfaces and an average diameter of about 250 nm. Long-chain DSSR in LND-PLGA/TPS/DSSR NPs prevented positively charged LND-PLGA/TPS NPs from being cleared by the reticuloendothelial system. Furthermore, LND release rate from NPs at pH 8.0 was significantly higher than that at pH 7.4 and 5.5, which demonstrated specific LND release in mitochondria and prevented LND leakage in cytoplasm and lysosome. NPs could locate in mitochondria, and the released LND triggered apoptosis of tumor cells by damaging mitochondria and releasing apoptosis-related proteins. In addition, in TNBC mice model, programmed mitochondria targeted NPs improved efficacy and reduced LND toxicity.

CONCLUSION

LND-PLGA/TPS/DSSR NPs may be a useful system and provide an effective approach for the treatment of TNBC.

摘要

简介

线粒体是 Lonidamine（LND）的重要靶点。然而，由于其有限的溶解度和不能特异性靶向线粒体，LND 可导致肝毒性，且仅显示出适度的抗癌活性。本研究的目的是建立谷胱甘肽程序性靶向线粒体的 LND 递送系统，以有效治疗三阴性乳腺癌（TNBC）。

方法

在这项研究中，LND 被包裹在聚（乳酸-共-乙醇酸）（PLGA）纳米颗粒（NPs）中，这些 NPs 被带有线粒体靶向的短链三苯基膦-生育酚聚乙二醇琥珀酸酯（TPP-TPGS，TPS）和肿瘤靶向的长链 1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-S-S-聚乙二醇-R6RGD（DSPE-S-S-PEG-R6RGD，DSSR）包裹，分别命名为 LND-PLGA/TPS/DSSR NPs。评估了其释放行为，并研究了纳米颗粒的细胞摄取、体外和体内抗肿瘤活性。还进一步研究了机制，包括肿瘤细胞凋亡和线粒体损伤以及呼吸速率检测。

结果

成功制备了 LND-PLGA/TPS/DSSR NPs，其特性表明它们是具有光滑表面的球形颗粒，平均直径约为 250nm。LND-PLGA/TPS/DSSR NPs 中的长链 DSSR 防止带正电荷的 LND-PLGA/TPS NPs 被网状内皮系统清除。此外，在 pH8.0 时，NPs 中 LND 的释放速率明显高于 pH7.4 和 pH5.5，这表明在线粒体中具有特异性 LND 释放，并防止 LND 在细胞质和溶酶体中的泄漏。NPs 可以定位在线粒体中，释放的 LND 通过损伤线粒体和释放凋亡相关蛋白来触发肿瘤细胞凋亡。此外，在 TNBC 小鼠模型中，程序性靶向线粒体的 NPs 提高了疗效并降低了 LND 的毒性。

结论

LND-PLGA/TPS/DSSR NPs 可能是一种有用的系统，为治疗 TNBC 提供了一种有效的方法。

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