Xu Jiangsheng, Zeng Fang, Wu Hao, Hu Caiping, Wu Shuizhu
College of Materials Science and Engineering, State Key Laboratory of Luminescent Materials and Devices, South China University of Technology , Guangzhou 510640, China.
Biomacromolecules. 2014 Nov 10;15(11):4249-59. doi: 10.1021/bm501270e. Epub 2014 Oct 29.
The applications of photodynamic therapy (PDT) are usually limited by photosensitizer's side effect and the singlet oxygen's short half-life. Herein, we demonstrate a dual-targeting (both cellular and subcellular targeting) strategy to enhance the PDT efficacy. A cationic porphyrin derivative (MitoTPP) was synthesized as the mitochondrion-targeting photosensitizer, and the dual-targeting PDT system was then fabricated by encapsulating MitoTPP into the acid-responsive and folic acid (FA)-modified polymer micelles. Under acidic pH, the micelles swell as a result of protonation of tertiary amines and disruption of the nucleobase pairing, thereby causing the release of the photosensitizer. Confocal microscope observation shows that the dual-targeting and micelle-based PDT system can preferably enter folate receptor (FR)-positive cancer cells, and upon cellular internalization, the MitoTPP molecules are released from the micelles and selectively accumulate in mitochondria. Under light irradiation, the singlet oxygen generated by the photosensitizer causes the oxidant damage to the mitochondrial and subsequently the apoptosis of the cells, as evidenced by the loss of mitochondrial membrane potential. Cell viability assays indicate that dual-targeting micelle-based systems exhibit enhanced cytotoxicity toward FR-positive cells. This study may provide a new approach for effectively enhancing the action of PDT systems.
光动力疗法（PDT）的应用通常受限于光敏剂的副作用和单线态氧的短半衰期。在此，我们展示了一种双靶向（细胞和亚细胞靶向）策略以提高PDT疗效。合成了一种阳离子卟啉衍生物（MitoTPP）作为线粒体靶向光敏剂，然后通过将MitoTPP封装到酸响应性和叶酸（FA）修饰的聚合物胶束中来构建双靶向PDT系统。在酸性pH下，由于叔胺质子化和碱基配对破坏，胶束膨胀，从而导致光敏剂释放。共聚焦显微镜观察表明，基于双靶向和胶束的PDT系统可优先进入叶酸受体（FR）阳性癌细胞，并且在细胞内化后，MitoTPP分子从胶束中释放并选择性地积聚在线粒体中。在光照下，光敏剂产生的单线态氧导致线粒体的氧化损伤并随后导致细胞凋亡，线粒体膜电位丧失证明了这一点。细胞活力测定表明，基于双靶向胶束的系统对FR阳性细胞表现出增强的细胞毒性。该研究可能为有效增强PDT系统的作用提供一种新方法。
