■线粒体是lonidamine(LND)的重要靶标。然而,它有限的溶解度和不能特异性靶向线粒体,LND可导致肝毒性,并且仅显示出适度的抗癌活性。本研讨的目标是树立谷胱甘肽程控线粒体靶向递送LND,用于三阴性乳腺癌(TNBC)的有用医治。
■在这项研究中,LND被包裹在包裹有线粒体靶向短链三苯膦-生育酚聚乙二醇琥珀酸酯的聚(乳酸-乙醇酸)(PLGA)纳米颗粒(NP)中(TPP-TPGS,TPS)和肿瘤靶向长链1,2-二硬脂酰基-sn-甘油基-3-磷酸乙醇胺-S-S-聚乙二醇-R6RGD(DSPE-S-S-PEG2000-R6RGD,DSSR),被指定为LND-PLGA/TPS/DSSRNP。评估了释放行为,和细胞摄取,研究了纳米颗粒的体外和体内抗肿瘤活性。机制,包括肿瘤细胞凋亡、线粒体损伤和呼吸率检测,也被进一步调查。
■LND-PLGA/TPS/DSSRNP制备成功,和表征表明,它们是球形颗粒,表面光滑,平均直径约250nm。LND-PLGA/TPS/DSSRNP中的长链DSSR阻止带正电荷的LND-PLGA/TPSNP被网状内皮系统清除。此外,pH8.0时NPs的LND释放速率显着高于pH7.4和5.5时的LND释放速率,这表明线粒体中的LND特异性释放并防止LND在细胞质和溶酶体中的泄漏。NP可以位于线粒体中,释放的LND通过破坏线粒体和释放凋亡相关蛋白触发肿瘤细胞凋亡。此外,在TNBC小鼠模型中,程序性线粒体靶向NP提高了疗效并降低了LND毒性。
■LND-PLGA/TPS/DSSRNP可能是一种有用的系统,并为TNBC的治疗提供了有效的方法。
UNASSIGNED: 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).
UNASSIGNED: 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-PEG2000-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.
UNASSIGNED: 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.
UNASSIGNED: LND-PLGA/TPS/DSSR NPs may be a useful system and provide an effective approach for the treatment of TNBC.