Nanotechnology has the potential to provide formulations of antitumor agents with increased selectivity towards cancer tissue thereby decreasing systemic toxicity. This in vivo study evaluated the potential of novel nanoformulation based on poly(lactic-co-glycolic acid) (PLGA) to reduce the cardiotoxic potential of doxorubicin (DOX). In vivo toxicity of PLGADOX was compared with clinically approved non-PEGylated, liposomal nanoformulation of DOX (LipoDOX) and conventional DOX form (ConvDOX). The study was performed using Wistar Han rats of both sexes that were treated intravenously for 28 days with 5 doses of tested substances at intervals of 5 days. Histopathological analyses of heart tissues showed the presence of myofiber necrosis, degeneration processes, myocytolysis, and hemorrhage after treatment with ConvDOX, whereas only myofiber degeneration and hemorrhage were present after the treatment with nanoformulations. All DOX formulations caused an increase in the troponin T with the greatest increase caused by convDOX. qPCR analyses revealed an increase in the expression of inflammatory markers IL-6 and IL-8 after ConvDOX and an increase in IL-8 expression after lipoDOX treatments. The mass spectra imaging (MSI) of heart tissue indicates numerous metabolic and lipidomic changes caused by ConvDOX, while less severe cardiac damages were found after treatment with nanoformulations. In the case of LipoDOX, autophagy and apoptosis were still detectable, whereas PLGADOX induced only detectable mitochondrial toxicity. Cardiotoxic effects were frequently sex-related with the greater risk of cardiotoxicity observed mostly in male rats.

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基于 PLGA 的新型纳米制剂可降低阿霉素诱导的心脏毒性

纳米技术有潜力提供抗肿瘤药物制剂，提高对癌组织的选择性，从而降低全身毒性。这项体内研究评估了基于聚乳酸乙醇酸(PLGA) 的新型纳米制剂降低阿霉素 (DOX) 心脏毒性潜力的潜力。将 PLGADOX 的体内毒性与临床批准的非聚乙二醇化 DOX 脂质体纳米制剂 (LipoDOX) 和传统 DOX 形式 (ConvDOX) 进行比较。该研究使用雌雄 Wistar Han 大鼠进行，每 5 天注射 5 剂受试物质，进行静脉注射治疗 28 天。心脏组织的组织病理学分析显示，ConvDOX 治疗后出现肌纤维坏死、变性过程、肌细胞溶解和出血，而纳米制剂治疗后仅出现肌纤维变性和出血。所有 DOX 制剂都会引起肌钙蛋白 T 的增加，其中 convDOX 引起的增加最大。 qPCR 分析显示，ConvDOX 治疗后炎症标志物 IL-6 和 IL-8 的表达增加，lipoDOX 治疗后 IL-8 的表达增加。心脏组织的质谱成像 (MSI) 显示 ConvDOX 引起的许多代谢和脂质组学变化，而在纳米制剂治疗后发现心脏损伤较轻。在 LipoDOX 的情况下，自噬和细胞凋亡仍然是可检测到的，而 PLGADOX 只诱导可检测到的线粒体毒性。心脏毒性作用通常与性别相关，主要在雄性大鼠中观察到心脏毒性的风险更大。