Metal–Organic Framework for Hypoxia/ROS/pH Triple‐Responsive Cargo Release

Abstract

Nanoparticulate antitumor photodynamic therapy (PDT) has been suffering from very short lifetime, limited diffusion distance of reactive oxygen species (ROS). Herein, we designed a hypoxia/ROS/pH triple‐responsive metal‐organic framework (MOF) to facilitate the on‐demand release of photosensitizers and hence enhanced PDT efficacy. Tailored azo‐containing imidazole ligand was coordinated with zinc to form MOF where photosensitizer (Chlorin e6/Ce6) was encapsulated. Azo could be reduced by overexpressed azoreductase in hypoxic tumor cells, resulting in depletion of glutathione (GSH) and thioredoxin (Trx) which are major antioxidants against ROS oxidative damage in PDT, resulting in rapid cargo release and additional efficacy amplification. The imidazole ionization caused proton sponge effect ensured the disintegration of the nanocarriers in acidic organelles, allowing the rapid release of Ce6 through lysosome escape. Under light irradiation, ROS produced by Ce6 would oxidize imidazole to urea, resulting in rapid cargo release. All of the triggers were expected to show interactive synergism. The pH‐ and hypoxia‐responsiveness could improve the release rate of Ce6 for enhanced PDT therapy, whereas the consumption of the oxygen by PDT will induce elevated hypoxia and hence in turn enhanced cargo release. This work highlights the role of triple‐responsive nanocarriers for triggered photosensitizer release and improved antitumor PDT efficacy.This article is protected by copyright. All rights reserved

Hypoxia and Singlet Oxygen Dual-Responsive Micelles for Photodynamic and Chemotherapy Therapy Featured with Enhanced Cellular Uptake and Triggered Cargo Delivery

“… 7 The intracellular reduction of the nitroimidazole group under hypoxic conditions requires the catalysis of nitroreductase with the presence of nicotinamide adenine dinucleotide phosphate (NADPH) that donates electrons and aids as the reducing agent. 17 , 25 To mimic such a reaction in vitro, a reducing agent, sodium dithionite sodium dithionite (Na 2 S 2 O 4 ), was mixed with DHM-Ce6@TPZ micelles to simulate the drug release under hypoxic conditions. The release experiments under normoxic conditions were presented with the concentration of Na 2 S 2 O 4 at 0 mM.…”

“…The supplement of a single nitroreductase plus NADPH in buffers could not mimic the intracellular conditions, so an inorganic reducing agent sodium dithionite was used for proof-of-concept in vitro. 17,[25][26][27][28] The presence of sodium dithionite significantly sped up the cargo release, this was because sodium dithionite donates electrons to azobenzene and nitroimidazole groups, leading to polymer degradation and micelle disintegration (Figure 1G and H). As shown in Figure 1I, the release rate and degree of TPZ after laser treatment is significantly higher than that without laser irradiation, this phenomenon was attributed to the imidazole moiety could oxidize to hydrophilic oxamic aldehyde, resulting in micelle disassembly.…”

Stimulus-Responsive Nanodelivery and Release Systems for Cancer Gene Therapy: Efficacy Improvement Strategies

“…The human body has a complex environment, and slight differences between internal microenvironments often render the single-response NDRS insufficiently sensitive. Therefore, researchers have begun to design dual- or triple-responsive NDRS (eg, pH/ROS, 98 pH/GSH, 95 , 96 GSH/enzyme, 97 hypoxia/ROS/pH, 113 , 124 and pH/ROS/enzyme 125 ) to further enhance the responsiveness of NDRS, increase their targeting to diseased sites, and reduce toxic side effects during treatment ( Figure 8 ). These multi-responsive NDRS utilize the synergistic effects between different stimuli to achieve highly sensitive nucleic acid delivery/release and can intelligently regulate gene transfer processes, overcoming intractable obstacles, such as low gene loading capacity, weak intracellular/lysosomal escape capability, slow gene release, high toxicity, and difficult nuclear transport.…”