Pro-oxidant drug-loaded porphyrinic zirconium metal-organic-frameworks for cancer-specific sonodynamic therapy
Pro-oxidant drug-loaded porphyrinic zirconium metal-organic-frameworks for cancer-specific sonodynamic therapy
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DOI：
10.1016/j.colsurfb.2021.112189
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发表时间：
2021-11-06
影响因子：
5.8
通讯作者：
Shim, Min Suk
中科院分区：
文献类型：
--
作者：
Hoang, Quan Truong;Kim, Miyeon;Shim, Min Suk
声动力疗法利用超声波（US）产生细胞毒性活性氧（ROS），可以克服光动力疗法的关键缺点，例如有限的组织穿透深度。然而，开发具有优异声动力效应和理想生物相容性的声敏剂仍然是一个重大挑战。在这项研究中，纳米级锆基卟啉金属有机骨架（MOF）（PCN222）被开发为安全有效的纳米声敏剂。聚乙二醇 (PEG) 涂层的 PCN-222 (PEGPCN) 负载有促氧化剂药物胡椒长明 (PL)，以实现肿瘤特异性化学光动力联合治疗。 PEG-PCN 和 PL 掺入的 PEG-PCN (PL-PEG-PCN) 在生物介质中均表现出较高的胶体稳定性。此外，纳米级 PL-PEG-PCN 可以被乳腺癌细胞有效内化，导致在美国暴露下大大增加 ROS 的产生。由于 PL 的促氧化活性，PEG-PCN 有效地在细胞内递送 PL，进一步提高了乳腺癌细胞中细胞内 ROS 的水平。因此，PL-PEG-PCN 的声毒性显着高于游离 PL 和 PEG-PCN。由于PL引发的癌症特异性细胞凋亡，与正常成纤维细胞相比，PL-PEG-PCN在乳腺癌细胞中表现出癌症选择性细胞死亡。这项研究表明，负载促氧化剂药物的卟啉 MOF 是用于癌症靶向化学-声动力学联合治疗的生物相容性且有效的声敏剂。
Sonodynamic therapy, which utilizes ultrasound (US) to produce cytotoxic reactive oxygen species (ROS), can overcome the critical drawbacks of photodynamic therapy, such as limited tissue penetration depth. However, the development of sonosensitizers having superior sonodynamic effects and desirable biocompatibility remains a major challenge. In this study, nanoscale zirconium-based porphyrinic metal organic frameworks (MOFs) (PCN222) were developed as safe and effective nanosonosensitizers. Polyethylene glycol (PEG)-coated PCN-222 (PEGPCN) was loaded with a pro-oxidant drug, piperlongumine (PL), to enable tumor-specific chemo-photodynamic combination therapy. Both PEG-PCN and PL-incorporated PEG-PCN (PL-PEG-PCN) showed high colloidal stability in biological media. In addition, nanoscale PL-PEG-PCN was efficiently internalized by breast cancer cells, leading to substantially increased ROS generation under US exposure. The effective intracellular delivery of PL by PEG-PCN further elevated the level of intracellular ROS in breast cancer cells owing to the pro-oxidative activity of PL. Therefore, PL-PEG-PCN revealed significantly higher sonotoxicity than free PL and PEG-PCN. Owing to the cancer-specific apoptosis triggered by PL, PL-PEG-PCN showed cancer-selective cell death in breast cancer cells compared with normal fibroblast cells. This study demonstrates that pro-oxidant drug-loaded porphyrinic MOFs are biocompatible and effective sonosensitizers for cancer-targeted chemo-sonodynamic combination therapy.