State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China.
Department of Chemistry, Korea University, Seoul 02841, Korea.
J Am Chem Soc. 2020 Mar 18;142(11):5380-5388. doi: 10.1021/jacs.0c00734. Epub 2020 Mar 9.
Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O delivery approaches, here we describe an innovative binary photodynamic O-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O through type-I photochemistry, and the generated O can further trigger a biocascade to reduce the PDT's demand for O in an O-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.
肿瘤缺氧已被证明是光动力疗法（PDT）向临床转化的主要瓶颈。与传统的 O 输送方法不同，在这里我们描述了一种创新的二元光动力 O 节约器（PDOE）策略，通过设计一种靶向线粒体呼吸的超氧自由基（O）发生器，称为 SORgenTAM，来逆转缺氧驱动的耐药性。该 PDOE 系统能够阻断细胞内 O 的消耗并下调 HIF-1α 的表达，从而成功使癌细胞免于缺氧，并减轻肿瘤内在的缺氧负担，从而为 PDT 过程节省足够的内源性 O。光致敏机制研究表明，SORgenTAM 具有理想的系间穿越率和三重态激发态寿命，可通过 I 型光化学产生 O，产生的 O 可以进一步触发生物级联反应，以可回收 O 的方式降低 PDT 对 O 的需求。此外，SORgenTAM 还可激活 AMPK 代谢信号通路，抑制细胞修复并促进细胞死亡。因此，通过两步 O 节约策略，在相对较低的光剂量照射下，可实现对缺氧肿瘤的出色治疗反应。这项研究为克服光疗的缺陷提供了一个概念性但实用的范例。
