Department of Materials Science and Engineering, Southern University of Science and Technology, 1088 Xueyuan Blvd., Nanshan District, Shenzhen, Guangdong 518055, PR China.
Department of Materials Science and Engineering, Southern University of Science and Technology, 1088 Xueyuan Blvd., Nanshan District, Shenzhen, Guangdong 518055, PR China.
Acta Biomater. 2023 Oct 15;170:330-343. doi: 10.1016/j.actbio.2023.08.025. Epub 2023 Aug 20.
Metal-organic frameworks (MOFs) with periodically arranged porphyrinic linkers avoiding the self-quenching issue of porphyrins in photodynamic therapy (PDT) have been widely applied. However, the porphyrinic MOFs still face challenges of poor stability under physiological conditions and limited photodynamic efficiency by the hypoxia condition of tumors. Herein, we fabricate the MOF@MOF structure with a protective MOF shell to improve the stability and relieve the hypoxia condition of tumors for sensitized PDT. Under protection of the MOF shell, the MOF@MOF structure can keep intact for 96 h under physiological conditions. Consequently, the tumoral accumulation efficiency is two folds of the MOF core. Furthermore, the MOF shell decomposes under acidic environment, and the loaded inhibitor of mitochondria pyruvate carrier (7-amino carboxycoumarins-2, 7ACC2) will be released. 7ACC2 inhibits the mitochondrial pyruvate influx and simultaneously blocks glucose and lactate from fueling the mitochondrial respiration, thereupon relieving the hypoxia condition of tumors. Under a 5-min laser irradiation, the 7ACC2 carrying MOF@MOF nanoplatforms induced doubled cellular apoptosis and reduced 70% of the tumor growth compared with the cargo-free MOF@MOF. In summary, the design of this stable and hypoxia self-relievable MOF@MOF nanoplatform will enlighten the future development of MOF-based nanomedicines and PDT. STATEMENT OF SIGNIFICANCE: Though widely used for photodynamic therapy (PDT) in previous studies, porphyrinic metal-organic frameworks (MOFs) still face challenges in poor stability under physiological conditions and limited photodynamic efficiency due to the hypoxia condition of tumors. In order to solve these problems, (1) we develop the MOF@MOF strategy to improve the physiological stability; (2) an inhibitor of mitochondria pyruvate carrier, 7-amino carboxycoumarins-2 (7ACC2), is loaded to inhibit the mitochondrial pyruvate influx and simultaneously block glucose and lactate from fueling the mitochondrial respiration, thereupon relieving the hypoxia condition of tumors. In comparison with previous studies, our strategy simultaneously improves stability and overcomes the limited PDT efficiency in the hypoxia tumor tissue, which will enlighten the future development of MOF-based nanomedicines and PDT.
具有周期性卟啉连接体的金属有机骨架（MOFs）可避免卟啉在光动力疗法（PDT）中的自猝灭问题，因此被广泛应用。然而，卟啉 MOFs 仍然面临着在生理条件下稳定性差以及肿瘤缺氧条件下光动力效率有限的挑战。在此，我们构建了具有保护 MOF 壳的 MOF@MOF 结构，以提高稳定性并缓解肿瘤的缺氧状态，从而实现敏化 PDT。在 MOF 壳的保护下，MOF@MOF 结构在生理条件下可保持完整 96 小时。因此，肿瘤的积累效率是 MOF 核的两倍。此外，MOF 壳在酸性环境下分解，并且负载的线粒体丙酮酸载体抑制剂（7-氨基香豆素-2,7ACC2）将被释放。7ACC2 抑制线粒体丙酮酸内流，同时阻止葡萄糖和乳酸为线粒体呼吸提供燃料，从而缓解肿瘤的缺氧状态。在 5 分钟的激光照射下，与无载药 MOF@MOF 相比，负载 7ACC2 的 MOF@MOF 纳米平台诱导细胞凋亡增加了一倍，肿瘤生长减少了 70%。总之，这种稳定且可自我缓解缺氧的 MOF@MOF 纳米平台的设计将为基于 MOF 的纳米药物和 PDT 的未来发展提供启示。
