School of Material Science and Engineering, Tiangong University, No. 399 BinShuiXi Road, Tianjin 300387, China.
State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China.
J Mater Chem B. 2022 Jun 22;10(24):4623-4631. doi: 10.1039/d2tb00309k.
The development of photodynamic nanomedicines that can alleviate intratumoral oxygen deficiency during photodynamic therapy (PDT) is of great significance for improving the therapeutic outcome of solid tumors characterized by severe hypoxia. Massive oxygen consumption due to vigorous cellular respiration, , mitochondrial-associated oxidative phosphorylation (OXPHOS), is another major cause of severe tumor hypoxia in addition to insufficient oxygen supply. Moreover, oxygen depletion during PDT further exacerbates the shortage of intratumoral oxygen. In this work, we engineered a novel oxygen-economical nano-photosensitizer co-encapsulation of an OXPHOS inhibitor (ATO) and a newly developed type-I photosensitizer (IPS) into a polymeric micelle of PEG--PCL. By controlling the length of hydrophobic PCL segments, we successfully optimized the micelle size to around 30 nm for enhanced tumor penetration. The orchestration of the two functional components, ATO and IPS, can simultaneously hinder the two major tumor oxygen-consuming pathways, where ATO targets mitochondrial complex III to inhibit cellular respiration, while IPS generates ROS through a low oxygen-consuming type-I photochemical pathway, enabling remarkable PDT efficacies in both hypoxic cells and a 4T1 tumor-bearing BALB/c mouse model. This work sheds new light on the construction of nano-photosensitizers to rejuvenate PDT against hypoxic solid tumors.
开发可缓解光动力疗法（PDT）期间肿瘤内缺氧的光动力纳米药物，对于改善严重缺氧的实体瘤的治疗效果具有重要意义。除了供氧不足外，由于细胞呼吸剧烈，线粒体相关氧化磷酸化（OXPHOS）所导致的大量氧气消耗也是严重肿瘤缺氧的另一个主要原因。此外，PDT 过程中氧气的消耗进一步加剧了肿瘤内氧气的短缺。在本工作中，我们设计了一种新型的经济型氧纳米光敏剂，将 OXPHOS 抑制剂（ATO）和一种新开发的 I 型光敏剂（IPS）共包封于 PEG-PCL 的聚合物胶束中。通过控制疏水性 PCL 段的长度，我们成功地将胶束尺寸优化至约 30nm，以增强肿瘤穿透性。两种功能成分 ATO 和 IPS 的协同作用可以同时阻断两个主要的肿瘤耗氧途径，其中 ATO 靶向线粒体复合物 III 以抑制细胞呼吸，而 IPS 通过低耗氧的 I 型光化学途径产生 ROS，从而在缺氧细胞和 4T1 荷瘤 BALB/c 小鼠模型中实现显著的 PDT 疗效。本工作为构建纳米光敏剂以恢复 PDT 治疗缺氧实体瘤提供了新的思路。
