Nano Therapeutics Research Laboratory, Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16288-93. doi: 10.1073/pnas.1210096109. Epub 2012 Sep 18.
Mitochondrial dysfunctions cause numerous human disorders. A platform technology based on biodegradable polymers for carrying bioactive molecules to the mitochondrial matrix could be of enormous potential benefit in treating mitochondrial diseases. Here we report a rationally designed mitochondria-targeted polymeric nanoparticle (NP) system and its optimization for efficient delivery of various mitochondria-acting therapeutics by blending a targeted poly(d,l-lactic-co-glycolic acid)-block (PLGA-b)-poly(ethylene glycol) (PEG)-triphenylphosphonium (TPP) polymer (PLGA-b-PEG-TPP) with either nontargeted PLGA-b-PEG-OH or PLGA-COOH. An optimized formulation was identified through in vitro screening of a library of charge- and size-varied NPs, and mitochondrial uptake was studied by qualitative and quantitative investigations of cytosolic and mitochondrial fractions of cells treated with blended NPs composed of PLGA-b-PEG-TPP and a triblock copolymer containing a fluorescent quantum dot, PLGA-b-PEG-QD. The versatility of this platform was demonstrated by studying various mitochondria-acting therapeutics for different applications, including the mitochondria-targeting chemotherapeutics lonidamine and α-tocopheryl succinate for cancer, the mitochondrial antioxidant curcumin for Alzheimer's disease, and the mitochondrial uncoupler 2,4-dinitrophenol for obesity. These biomolecules were loaded into blended NPs with high loading efficiencies. Considering efficacy, the targeted PLGA-b-PEG-TPP NP provides a remarkable improvement in the drug therapeutic index for cancer, Alzheimer's disease, and obesity compared with the nontargeted construct or the therapeutics in their free form. This work represents the potential of a single, programmable NP platform for the diagnosis and targeted delivery of therapeutics for mitochondrial dysfunction-related diseases.
线粒体功能障碍会导致许多人类疾病。一种基于可生物降解聚合物的平台技术，可将生物活性分子递送到线粒体基质中，对于治疗线粒体疾病可能具有巨大的潜在益处。在这里，我们报告了一种经过合理设计的靶向聚合物纳米颗粒（NP）系统，并通过将靶向聚（D，L-乳酸-共-乙醇酸）嵌段（PLGA-b）-聚乙二醇（PEG）-三苯基膦（TPP）聚合物（PLGA-b-PEG-TPP）与非靶向的 PLGA-b-PEG-OH 或 PLGA-COOH 混合，对其进行了优化，以实现各种线粒体作用治疗剂的有效传递。通过对具有不同电荷和粒径的 NP 文库进行体外筛选，确定了一种优化的配方，并通过对用由 PLGA-b-PEG-TPP 和含有荧光量子点的三嵌段共聚物组成的混合 NP 处理的细胞的细胞质和线粒体部分进行定性和定量研究，研究了线粒体摄取情况。通过研究不同应用的各种线粒体作用治疗剂，证明了该平台的多功能性，包括用于癌症的线粒体靶向化疗药 lonidamine 和 α-生育酚琥珀酸酯、用于阿尔茨海默病的线粒体抗氧化剂姜黄素以及用于肥胖症的线粒体解偶联剂 2,4-二硝基苯酚。这些生物分子被装入混合 NP 中，具有较高的载药效率。考虑到疗效，与非靶向构建体或游离形式的治疗剂相比，靶向 PLGA-b-PEG-TPP NP 显著提高了癌症、阿尔茨海默病和肥胖症的药物治疗指数。这项工作代表了单一可编程 NP 平台在诊断和靶向传递与线粒体功能障碍相关疾病的治疗剂方面的潜力。
