MP01-15 MODULATION OF HYPOXIC AND ACIDIC TUMOR MICROENVIRONMENT TO REVITALIZE AUTOPHAGY INHIBITOR FOR COMBINATION WITH RADIATION THERAPY

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I (MP01)1 Apr 2020MP01-15 MODULATION OF HYPOXIC AND ACIDIC TUMOR MICROENVIRONMENT TO REVITALIZE AUTOPHAGY INHIBITOR FOR COMBINATION WITH RADIATION THERAPY Tingsheng Lin* Tingsheng Lin*Tingsheng Lin* More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000815.015AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Tumor hypoxia and acidosis are main characteristics of the bladder cancer microenvironment, and the abnormal tumor microenvironment (TME) lead to autophagy activation to support cancer cells survival in metabolic stress. Autophagy inhibition therapy plays an important role in tumor treatment. Since the tumor autophagy activity is largely driven by the hypoxia and acid microenvironment, tumor autophagy activity could be inhibited by the modulation of abnormal TME. Moreover, the therapeutic efficacy of autophagy inhibitors may be also impeded by the abnormal TME. Herein, we proposed a new strategy using manganese dioxide (MnO2) to modify the abnormal TME to revitalize autophagy inhibitor, and combined with radiation therapy to treat bladder cancer. METHODS: The nanoparticles were fabricated by MnO2 with an autophagy inhibitor (chloroquine, CQ) in human serum albumin (HSA) based nanoplatform (HSA-MnO2-CQ NPs). RESULTS: The NPs had an excellent performance in generating O2 and increasing pH in vitro upon reaction with H+/H2O2 at endogenous levels, and the encapsulated CQ released in a H+/H2O2 dependent manner. In vitro study showed HSA-MnO2-CQ NPs restored the autophagy-inhibiting activity of chloroquine in acidic conditions via increased cellular uptake of chloroquine, and enhanced the autophagy-inhibiting effect and radiation effect by ameliorating hypoxia. In vivo study showed the NPs was able to improve tumor hypoxic and acidic microenvironment to enhance autophagy inhibition effect. Furthermore, the HSA-MnO2-CQ NPs suppressed tumor growth via regulating TME and restoring autophagy-inhibiting activity of CQ, and the NPs effectively inhibited bladder tumors when combined with radiation therapy. CONCLUSIONS: The HSA-MnO2-CQ nanoparticles modulated tumor hypoxic and acidic microenvironment to revitalize autophagy inhibitor, and the NPs exhibited a very strong anti-tumor effect when combined with radiation therapy. Source of Funding: none © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e7-e8 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tingsheng Lin* More articles by this author Expand All Advertisement PDF downloadLoading ...