Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials, Ministry of Education Key Laboratory for the Green Preparation and Application of Functional Materials, Hubei University, Wuhan, Hubei, 430062, China.
Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
Biomaterials. 2019 Apr;199:52-62. doi: 10.1016/j.biomaterials.2019.01.044. Epub 2019 Feb 2.
Mitochondria, which are a major source of adenosine triphosphate (ATP) and apoptosis regulators, are the key organelles that promote tumor cell proliferation, and their dysfunction affects tumor cell behavior. Additionally, mitochondria have been shown to play a central role in the biosynthesis of protoporphyrin IX (PpIX), which is a widely used photosensitizer that has been used for tumor detection, monitoring and photodynamic therapy. Nevertheless, photosensitizers administrated exogenously are often restricted by limited bioavailability.δ-Aminolevulinic acid (δ-ALA) is a naturally occurring delta amino acid that can be converted in situ to PpIX via the heme biosynthetic pathway in mitochondria. Because δ-ALA is the precursor for PpIX, δ-ALA-based photodynamic therapy (PDT) shows promise in treating cancer. However, the accumulation of δ-ALA within endosomal system limits the production of PpIX and eventually impedes its effectiveness. Theranostic nanoparticles (NPs) capable of endosomal escape are expected to optimize the endogenous biosynthetic yield. In this study, δ-ALA was improved with triphenylphosphoniumcation (TPP), a high net position cation that functions in endosomal escape and as a mitochondria-targeting ligand, and was further modified with bovine serum albumin stabilized manganese dioxide (MnO). The tumor microenvironment (TME) responsive MnO in this system can elevate oxygen content to relieve hypoxia. Both enhanced photosensitizer yield and elevated oxygen contributing to the final therapeutic effect. Moreover, the enhancement of magnetic resonance imaging (MRI) (r = 5.410 smM) stemming from the degradation of MnO by the TME could serve as a guide prior to treatment for accurate location, while in situ hysteretic photoluminescence imaging derived from PpIX can be utilize as a supervisor for prognosis evaluation. This systematic design could broaden the biomedical application and highlight the considerable therapeutic promise of PDT.
线粒体是三磷酸腺苷（ATP）和凋亡调节剂的主要来源，是促进肿瘤细胞增殖的关键细胞器，其功能障碍会影响肿瘤细胞的行为。此外，线粒体在原卟啉 IX（PpIX）的生物合成中发挥核心作用，PpIX 是一种广泛应用于肿瘤检测、监测和光动力治疗的光敏剂。然而，外源性给予的光敏剂往往受到有限的生物利用度的限制。δ-氨基酮戊酸（δ-ALA）是一种天然存在的δ-氨基酸，可以通过线粒体中的血红素生物合成途径原位转化为 PpIX。由于 δ-ALA 是 PpIX 的前体，基于 δ-ALA 的光动力疗法（PDT）在治疗癌症方面显示出前景。然而，内体系统中 δ-ALA 的积累限制了 PpIX 的产生，最终阻碍了其疗效。能够逃避内体的治疗性纳米颗粒（NPs）有望优化内源性生物合成产量。在这项研究中，δ-ALA 与三苯基膦阳离子（TPP）进行了改进，TPP 是一种带正电荷的化合物，可用于内体逃逸，并作为线粒体靶向配体，进一步用牛血清白蛋白稳定的二氧化锰（MnO）进行了修饰。该系统中的肿瘤微环境（TME）响应性 MnO 可以提高氧含量以缓解缺氧。增强的光敏剂产量和升高的氧含量共同促成最终的治疗效果。此外，MnO 被 TME 降解所引起的磁共振成像（MRI）增强（r=5.410 smM）可以作为治疗前的指导，用于准确定位，而源自 PpIX 的原位磁滞光致发光成像可以用作预后评估的监测器。这种系统设计可以拓宽生物医学应用，并突出光动力治疗的巨大治疗潜力。
