Overcoming Hypoxia by Multistage Nanoparticle Delivery System to Inhibit Mitochondrial Respiration for Photodynamic Therapy

Abstract

Hypoxia, as characterized by the low local oxygen, confers on cancer cells resistance to oxygen-consuming photodynamic therapy (PDT). The limited success reached by current approaches harnessing reoxygenation to enhance PDT outcome promotes the reconsideration of the design of the therapeutic approach. In this study, a multistage delivery system capable of reversing hypoxia is demonstrated. Unlike previous strategies that only expect to affect the peripheral tumor tissue, the size-shrinkable system allows those deeply located hypoxia regions to be treated. Specifically, therapeutics, including atovaquone and indocyanine green derivatives that are respectively responsible for oxidative phosphorylation blockage and PDT, are encapsulated in a gelatin nanoparticle, whose structure would rupture to promote deep penetration when facing matrix metallopeptidase 2 enzyme overexpression in tumor tissue. The antihypoxic performance of the platform has been evaluated using a variety of analyses including flow-cytometry assay, immunofluorescence, and micro-positron-emission tomography imaging. Tumor regression in animal models confirms the feasibility and effectiveness of conquering the PDT-resistance through abrogating the oxygen consumption. It is hopeful that such a strategy could shed light on the development of next-generation PDT-adjuvant treatment.

Mo2C‐Derived Polyoxometalate for NIR‐II Photoacoustic Imaging‐Guided Chemodynamic/Photothermal Synergistic Therapy

“…ROS and heat can cause mitochondria dysfunction and therefore profound cell damage. We investigated POM induced mitochondria dysfunction using JC‐1 probe to indicate mitochondria‐membrane potential (Δ Ψ m ) drop . Compared to the control group, cells treated with H 2 O 2 (100 μ m ), POM (100 μg mL −1 ) slightly caused dimming of red fluorescence and appearance of orange signal owing to overlap of red and green fluorescence (Figure c), indicating mitochondria were adversely affected by 1 O 2 generation and GSH depletion due to the reactions between POM and H 2 O 2 inside the cell.…”

Bypassing the Immunosuppression of Myeloid‐Derived Suppressor Cells by Reversing Tumor Hypoxia Using a Platelet‐Inspired Platform

“…Oxygen level of 4T1 cells before and after the treatment of Bi 2 WO 6 NPs was measured by using a JPB‐607A dissolved oxygen meter (Rex Electric Chemical, China) as previous report. [ 36 ] Briefly, 4T1 cells were seeded in dishes and cultured with DMEM for 24 h. Then, 4T1 cells were co‐cultured with Bi 2 WO 6 NPs (100 µg mL −1 tungsten) and irradiated with an 808 nm laser (5 min, 1 W cm −2 ). To avoid oxygen exchange, liquid paraffin was added onto the DMEM before the co‐incubation with Bi 2 WO 6 NPs and the laser irradiation to seal the culture.…”

Recent Progress in Mitochondria-Targeted Drug and Drug-Free Agents for Cancer Therapy

“…Inhibition of the mitochondrial respiratory pathway has been found to increase the production of intramitochondrial oxygen, which in turn enhances the efficiency of PDT. Thus, mitochondria-targeted PDT has attracted much attention compared with other cellular targets or subcellular targets [57]. PDT agents can be modified with metal complexes or porphyrins having lipophilic cations (TPP, pyridinium), cyanine, or IR-780-based PSs.…”