Journal
THERANOSTICS
Volume 11, Issue 4, Pages 1953-1969Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.52997
Keywords
photodynamic therapy; hypoxia relief; mitochondrial respiration; adenosine triphosphate; nitric oxide
Categories
Funding
- National Natural Science Foundation of China [31630026]
- Chongqing Science & Technology Commission [cstc2019jscx-dxwtBX0004]
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The study introduces a nitric oxide-based nanoplatform that can inhibit the hyperactive oxygen metabolism in tumor cells and reduce oxygen depletion, thus enhancing the effectiveness of photodynamic therapy.
Photodynamic therapy (PDT) efficacy in cancer cells is affected by sub-physiological hypoxia caused by dysregulated and chaotic tumor microvasculature. However, current traditional O-2-replenishing strategies are undergoing their own intrinsic deficiencies. In addition, resistance mechanisms activated during PDT also lead the present situation far from satisfactory. Methods: We propose a nitric oxide (NO)-based theranostic nanoplatform by using biocompatible poly-lactic-co-glycolic acid nanoparticles (PLGA NPs) as carriers, in which the outer polymeric layer embeds chlorin e6 (Ce6) and incorporates L-Arginine (L-Arg). This nanoplatform (L-Arg@Ce6@P NPs) can reduce hyperactive O-2 metabolism of tumor cells by NO-mediated mitochondrial respiration inhibition, which should raise endogenous O-2 tension to counteract hypoxia. Furthermore, NO can also hinder oxidative phosphorylation (OXPHOS) which should cause intracellular adenosine triphosphate (ATP) depletion, inhibiting tumor cells proliferation and turning cells more sensitive to PDT. Results: When the L-Arg@Ce6@P NPs accumulate in solid tumors by the enhanced permeability and retention (EPR) effect, locally released L-Arg is oxidized by the abundant H2O2 to produce NO. In vitro experiments suggest that NO can retard hypoactive O-2 metabolism and save intracellular O-2 for enhancing PDT efficacy under NIR light irradiation. Also, lower intracellular ATP hinders proliferation of DNA, improving PDT sensitization. PDT phototherapeutic efficacy increased by combining these two complementary strategies in vitro/in vivo. Conclusion: We show that this NO-based nanoplatform can be potentially used to alleviate hypoxia and sensitize tumor cells to amplify the efficacy of phototherapy guided by photoacoustic (PA) imaging.
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