Employing the thiol-ene click reaction via metal-organic frameworks for integrated sonodynamic-starvation therapy as an oncology treatment

Abstract

Hypoxia in the tumor microenvironment (TME) greatly limits the tumor-killing therapeutic efficacy of sonodynamic therapy (SDT); this phenomenon is further exacerbated by increased glutathione (GSH) levels in cancer cells. Simultaneously, cancer starvation therapy is increasingly recognized nowadays as a promising clinical translation, but the efficacy of glucose oxidase (GOx)-based starvation therapy is also limited by the lack of oxygen in the tumor. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme and can therefore be a target for starvation therapy in the absence of oxygen engagement. Here, we proposed thiol-ene click reactions based on a two-dimensional metal-organic framework (MOF) modification for tumor treatments to enable the combination of SDT and starvation therapy. Experimental studies demonstrated that the prepared material could consume GSH and GAPDH free from oxygen in TME, which benefited from the thiol-ene click reactions between the MOFs and thiol substances in cancer cells. Further experiments in vitro and in vivo indicated the prepared MOF materials could kill cancer cells efficiently. This study is expected to create a promising avenue for thiol-ene click reactions in SDT and starvation therapy for cancer.

Understanding the role of metal–organic frameworks in cancer treatment

“…Tian et al constructed a Gd-TCPP-NC (NC = 5-norbornene-2-carbaldehyde) MOF as an SDT sensitizer. 45 Different from general sensitizers, the Gd-TCPP-NC causes no ROS generation. Instead, the NC moiety in the MOF can react with sulfhydryl groups.…”

Recent progress in metal–organic framework-based sonosensitizers for sonodynamic tumor therapy

“…Under pH 6.0 conditions, Cu-Fe-TCPP could induce 88% of cancer cell death with ultrasound irradiation (1.0 MHz, 1.5 W cm −2 , 1 min), while the cell death under pH 7.4 conditions was only 50%. More MOF-based sonosensitizers for SDT include Zr-TCPP, 44 Gd-TCPP, 45 and Fe-Zr-TCPP. 46…”

Facile synthesis of 2D Al-TCPP MOF nanosheets for efficient sonodynamic cancer therapy

“…Metal–organic frameworks (MOFs) are a class of porous ordered framework material that have been widely applied in various fields due to their remarkable physical and chemical properties, including high porosity, the possession of multiple active sites, high specific surface area, tunable morphology, and excellent biodegradability. 31–53 Recently, some porphyrin-based sonosensitizers ( e.g. , HMME: hematoporphyrin monomethyl ether, and TCPP: tetrakis(4-carboxyphenyl)porphyrin) have been used as organic ligands to assemble MOFs with various metal ions ( e.g.…”