A Metal‐Organic Framework (MOF) Fenton Nanoagent‐Enabled Nanocatalytic Cancer Therapy in Synergy with Autophagy Inhibition

Abstract

Nanocatalytic medicine has been developed recently to trigger intratumoral generation of highly toxic reactive oxygen species (ROS) for cancer therapy, which, unfortunately, suffers from compromised therapeutic efficacy due to a self‐protective mechanism, autophagy, of cancer cells to mitigate oxidative damage. In this work, during the efforts of ROS generation by nanocatalytic medicine, a pharmacological autophagy inhibition strategy is implemented for augmenting ROS‐induced oxidative damage for synergetic cancer therapy. An iron‐containing metal‐organic framework [MOF(Fe)] nanocatalyst as a peroxidase mimic is used to catalyze the generation of highly oxidizing •OH radicals specifically within cancer cells, while chloroquine is applied to deacidify lysosomes and inhibit autophagy, cutting off the self‐protection pathway under severe oxidative stress. Cancer cells fail to extract their components to detoxicate and strengthen themselves, finally succumbing to the ROS‐induced oxidative damage during nanocatalytic therapy. Both in vitro and in vivo results demonstrate the synergy between nanocatalytic therapy and autophagy inhibition, suggesting that such a combined strategy is applicable to amplify tumor‐specific oxidative damage and may be informative to future design of therapeutic regimen.

Developing New Cancer Nanomedicines by Repurposing Old Drugs

“…Phase I/II virus infection alycolysis inhibition for reduction of energy production [10,18] disulfiram approved alcohol abuse chelating with Cu 2+ to generate toxic CuET [26,29] artemisinin approved malaria reacting with Fe 3+ to generate toxic free radicals [35] chloroquine approved malaria autophagy blockage for inhibiting self-detoxication [42] metformin approved Type II diabetes OXPHOS inhibition to modulate hypoxia and lower energy production [50] aspirin approved pain, fever, and inflammation cyclooxygenase inhibition for enhancing Tcell infiltration [55] Angewandte Chemie…”

“…Very recently, we have successfully used CQ to enhance MOF nanoparticle‐enabled nanocatalytic cancer therapy (Figure 6). [42] The MOF nanoparticle NH 2 ‐MIL‐88B (Fe) presents peroxidase‐like activity in the acidic tumor microenvironment, which can catalyze the decomposition of intratumoral H 2 O 2 into highly toxic . OH for initiating oxidative damage, while CQ blocks the autophagic pathway of cancer cells and thus inhibits the self‐protecting mechanism, finally enhancing the efficacy of nanocatalytic medicine.…”

“…Autophagy inhibition by CQ for enhancing nanocatalytic therapy.CQise fficient to block lysosomald egradation and subsequent selfdetoxification during autophagic process, finally potentiating the oxidatived amage of cancer cells. Reproducedwith permission from ref [42]…”

Review of the Biomolecular Modification of the Metal-Organ-Framework

“…This kind of therapeutic effect is slight, but the effects will be different when we make use of all linked and correlated nodes in entire reaction chains, such as the chain of ROS-induced oxidation. In the latest research, MOF(Fe) is used to promote ROS-induced oxidative damage in cancer cells, and chloroquine modification will inhibit lysosome autophagy, so that this nanodrug can cut off the self-protection node under the oxidative stress chain and improve the anti-cancer effect (Yang et al, 2020 ). As we can see, the regulation of multiple reactive nodes in a biological chain can be achieved by setting the reaction times of substances loaded onto MOFs.…”

Developing New Cancer Nanomedicines by Repurposing Old Drugs

“…Phase I/II virus infection alycolysis inhibition for reduction of energy production [10,18] disulfiram approved alcohol abuse chelating with Cu 2+ to generate toxic CuET [26,29] artemisinin approved malaria reacting with Fe 3+ to generate toxic free radicals [35] chloroquine approved malaria autophagy blockage for inhibiting self-detoxication [42] metformin approved Type II diabetes OXPHOS inhibition to modulate hypoxia and lower energy production [50] aspirin approved pain, fever, and inflammation cyclooxygenase inhibition for enhancing Tcell infiltration [55] Angewandte Chemie Kurzaufsätze 22020 www.angewandte.de…”