Nanoscale Metal-Organic Frameworks Generate Reactive Oxygen Species for Cancer Therapy

Abstract

In the past 15 years, enormous progress has been made in cancer nanotechnology, and a several nanoparticles have entered clinical testing for cancer treatment. Among these nanoparticles are nanoscale metal-organic frameworks (nMOFs), a class of organic-inorganic hybrid nanomaterials constructed from metal binding sites and bridging ligands, which have attracted significant attention for their ability to integrate porosity, crystallinity, compositional and structural tunability, multifunctionality, and biocompatibility into a singular nanomaterial for cancer therapies. This Outlook article summarizes the progress on the design of nMOFs as nanosensitizers for photodynamic therapy (PDT), radiotherapy (RT), radiotherapy-radiodynamic therapy (RT-RDT), and chemodynamic therapy (CDT) via nMOF-mediated reactive oxygen species (ROS) generated under external energy stimuli or in the presence of endogenous chemical triggers. Inflammatory responses induced by nMOF-mediated ROS generation activate tumor microenvironments to potentiate cancer immunotherapy, extending the local treatment effects of nMOF-based ROS therapy to distant tumors via abscopal effects. Future research directions in nMOF-mediated ROS therapies and the prospect of clinical applications of nMOFs as cancer therapeutics are also discussed.

Figure 1

Schematic showing local nMOF-mediated photodynamic therapy, radiotherapy, radiotherapy–radiodynamic therapy, and chemodynamic therapy promoting ROS generation to kill tumor cells and induce local inflammation, which augments innate and adaptive immunity to synergize with cancer immunotherapy.

Figure 2

(a) Scheme of nMOF-mediated PDT upon light irradiation. (b) Cytotoxicity of Hf-DBP, H₂DBP, and commercial PpIX. (c) Illustration of electron transfer from porphyrin excited state to Ti^IV in Ti-TBP for Type I PDT. [Reprinted with permission from ref (25). Copyright 2019, American Chemical Society, Washington, DC.]

Figure 3

(a) Structure models of Hf₆-oxo, Hf₁₂-oxo, Hf₆-DBA, and Hf₁₂-DBA. (b) ^•OH generated from HfO₂, Hf₆-DBA and Hf₁₂-DBA upon irradiation probed by APF. (c) Schematic showing the radiosensitization process by Hf₁₂-DBA. (d) Schematic illustration of radiosensitization by POM@Hf₁₂-DBB-Ir with three different high-Z components for multifarious ROS generation. (e) ^•OH generation by POM@Hf₁₂-DBB-Ir determined by APF assay. (f) O₂^– generation by POM@Hf₁₂-DBB-Ir, as detected by ESR. [Reprinted with permission from ref (32). Copyright 2019, American Chemical Society, Washington, DC.]

Figure 4

(a) Mitochondria-targeted RT-RDT by Hf-DBB-Ru. (b) Confocal images showing colocalization of Hf-DBB-Ru and mitochondria (scale bar = 50 μm). (c) Topographic profiles showing fluorescence intensities of straight white lines marked in panel (b). (d) Hf-DBB-Ru-mediated RT-RDT upon X-ray irradiation to generate both ^•OH via radiolysis and ¹O₂ via energy transfer to photosensitizing linkers. (e) DNA double strand breaks and ¹O₂ generation in vitro by Hf-DBB-Ru-mediated RT-RD, as probed by γ-H2AX and SOSG, respectively (scale bar = 10 μm).

Figure 5

Scheme (a) and efficacy curves (b, c) to show abscopal effect of TBC-Hf-mediated local PDT synergized with IDO inhibition to attenuate immunosuppression to reactivate systemic antitumor immunity. [Reprinted with permission from ref (36). Copyright 2016, American Chemical Society, Washington, DC.] (d) Scheme of local nMOF-mediated hypoxic PDT on bilateral colorectal tumor model potentiated anti-PD-L1 checkpoint blockade immunotherapy to afford abscopal effect. [Reprinted with permission from ref (24). Copyright 2018, American Chemical Society, Washington, DC.]