The Fifth Affiliated Hospital, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, P. R. China.
Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, 510515, P. R. China.
Adv Healthc Mater. 2021 Jun;10(12):e2100198. doi: 10.1002/adhm.202100198. Epub 2021 May 3.
Photodynamic therapy (PDT) often suffers from the exacerbated tumor hypoxia and the heterogeneous distribution of photosensitizers, leading to an inefficient ROS productivity and availability. In this work, a mitochondria targeted O economizer (designated as Mito-OxE) is developed to improve PDT efficiency by alleviating tumor hypoxia and enhancing the subcellular localization of photosensitizers. Specifically, the photosensitizer of protoporphyrin IX (PpIX) is modified with the hydrophilic polyethylene glycol and the lipophilic cation of triphenylphosphine (TPP) to fabricate the biocompatible mitochondria targeted photosensitizers (designated as Mito-PSs). And Mito-OxE is prepared by using Mito-PSs to load the mitochondrial oxidative phosphorylation inhibitors of atovaquone (ATO). Benefiting from the targeting capability of TPP, Mito-OxE can selectively accumulate in mitochondria after cellular uptake. Subsequently, the mitochondrial respiration would be suppressed to with the participation of ATO, resulting in a local hypoxia mitigation for enhanced PDT. Compared with Mito-PSs, Mito-OxE maximizes the therapeutic effect against hypoxic tumors under light irradiation. This design of mitochondria targeted O economizer would advance the development of targeted drug delivery system for effective PDT regardless of hypoxic microenvironment.
光动力疗法（PDT）常受到肿瘤乏氧和光敏剂分布不均的影响，导致活性氧（ROS）的产生和利用率降低。在本工作中，设计了一种靶向线粒体的 O 节约剂（命名为 Mito-OxE），通过缓解肿瘤乏氧和增强光敏剂的亚细胞定位来提高 PDT 效率。具体而言，亲水性聚乙二醇和三苯基膦（TPP）的疏脂阳离子对原卟啉 IX（PpIX）进行修饰，制备了具有生物相容性的靶向线粒体的光敏剂（命名为 Mito-PSs）。Mito-OxE 通过用 Mito-PSs 装载线粒体氧化磷酸化抑制剂阿托伐醌（ATO）制备得到。受益于 TPP 的靶向能力，Mito-OxE 在细胞摄取后可以选择性地积聚在线粒体中。随后，ATO 的参与会抑制线粒体呼吸，从而减轻局部缺氧，增强 PDT。与 Mito-PSs 相比，Mito-OxE 在光照下最大限度地提高了对缺氧肿瘤的治疗效果。这种靶向线粒体的 O 节约剂的设计将推进针对有效 PDT 的靶向药物输送系统的发展，而不受缺氧微环境的影响。
