Parkinson's disease (PD) is a devastating neurodegenerative disease affecting a large proportion of older adults. Exposure to pesticides like rotenone is a leading cause for PD. To reduce disease progression and prolong life expectancy, it is important to target disease mechanisms that contribute to dopaminergic neuronal atrophy, including mitochondrial dysfunction. Achieving targeted mitochondrial delivery is difficult for many therapeutics by themselves, necessitating higher therapeutic doses that could lead to toxicity. To minimize this adverse effect, targeted nano-carriers such as polyanhydride nanoparticles (NPs) can protect therapeutics from degradation and provide sustained release, enabling fewer administrations and lower therapeutic dose. This work expands upon the use of the polyanhydride NP platform for targeted drug delivery by functionalizing the polymer with a derivative of triphenylphosphonium called (3-carboxypropyl) triphenylphosphonium (CPTP) using a novel method that enables longer CPTP persistence on the NPs. The extent to which neurons internalized both nonfunctionalized and functionalized NPs was tested. Next, the efficacy of these nanoformulations in treating rotenone-induced mitochondrial dysfunction in the same cell line was evaluated using a novel neuroprotective drug, mito-metformin. CPTP functionalization significantly improved NP internalization by neuronal cells. This was correlated with significant protection by CPTP-functionalized, mito-metformin encapsulated NPs against rotenone-induced mitochondrial dysfunction. However, nonfunctionalized, mito-metformin encapsulated NPs and soluble mito-metformin administered at the same dose did not significantly protect cells from rotenone-induced toxicity. These results indicate that the targeted NP platform can provide enhanced dose-sparing and potentially reduce the occurrence of systemic side-effects for PD therapeutics.

中文翻译：

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用于改善线粒体功能障碍治疗的功能化聚酐纳米颗粒

帕金森病 (PD) 是一种破坏性神经退行性疾病，影响大部分老年人。接触鱼藤酮等杀虫剂是导致 PD 的主要原因。为了减少疾病进展和延长预期寿命，重要的是针对导致多巴胺能神经元萎缩的疾病机制，包括线粒体功能障碍。许多疗法本身很难实现靶向线粒体递送，因此需要更高的治疗剂量，这可能会导致毒性。为了最大限度地减少这种不利影响，靶向纳米载体（如聚酐纳米颗粒 (NPs)）可以保护治疗剂免于降解并提供持续释放，从而减少给药次数和降低治疗剂量。这项工作扩展了聚酐 NP 平台用于靶向药物递送的用途，通过使用一种新方法使聚合物功能化，使用一种称为（3-羧丙基）三苯基鏻 (CPTP) 的衍生物对聚合物进行功能化，该方法能够在 NPs 上实现更长的 CPTP 持久性。测试了神经元内化非功能化和功能化 NP 的程度。接下来，使用新型神经保护药物mito-metformin评估了这些纳米制剂治疗同一细胞系中鱼藤酮诱导的线粒体功能障碍的功效。CPTP 功能化显着改善了神经元细胞的 NP 内化。这与 CPTP 功能化、mito-metformin 封装的 NPs 对鱼藤酮诱导的线粒体功能障碍的显着保护相关。然而，非功能化，以相同剂量施用的丝裂二甲双胍包裹的纳米颗粒和可溶性丝裂二甲双胍并不能显着保护细胞免受鱼藤酮诱导的毒性。这些结果表明，靶向 NP 平台可以提供增强的剂量节省，并可能减少 PD 治疗的全身副作用的发生。