title: An Implantable Depot That Can Generate Oxygen in Situ for Overcoming Hypoxia-Induced Resistance to Anticancer Drugs in Chemotherapy.
abstract: In the absence of adequate oxygen, cancer cells that are grown in hypoxic solid tumors resist treatment using antitumor drugs (such as doxorubicin, DOX), owing to their attenuated intracellular production of reactive oxygen species (ROS). Hyperbaric oxygen (HBO) therapy favorably improves oxygen transport to the hypoxic tumor tissues, thereby increasing the sensitivity of tumor cells to DOX. However, the use of HBO with DOX potentiates the ROS-mediated cytotoxicity of the drug toward normal tissues. In this work, we hypothesize that regional oxygen treatment by an implanted oxygen-generating depot may enhance the cytotoxicity of DOX against malignant tissues in a highly site-specific manner, without raising systemic oxygen levels. Upon implantation close to the tumor, the oxygen-generating depot reacts with the interstitial medium to produce oxygen in situ, effectively shrinking the hypoxic regions in the tumor tissues. Increasing the local availability of oxygen causes the cytotoxicity of DOX that is accumulated in the tumors to be significantly enhanced by the elevated production of ROS, ultimately allaying the hypoxia-induced DOX resistance in solid malignancies. Importantly, this enhancement of cytotoxicity is limited to the site of the tumors, and this feature of the system that is proposed herein is unique.
authors.forename: Chieh-Cheng
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Orthopaedics, National Taiwan University Hospital, Hsinchu Branch , Hsinchu 30013, Taiwan, ROC.
authors.forename: Wei-Tso
authors.initials: WT
authors.lastname: Chia
authors.forename: Ming-Fan
authors.initials: MF
authors.lastname: Chung
authors.forename: Kun-Ju
authors.initials: KJ
authors.lastname: Lin
authors.forename: Chun-Wen
authors.initials: CW
authors.lastname: Hsiao
authors.forename: Chuan
authors.initials: C
authors.lastname: Jin
authors.forename: Woon-Hui
authors.initials: WH
authors.lastname: Lim
authors.forename: Chun-Chieh
authors.initials: CC
authors.lastname: Chen
authors.forename: Hsing-Wen
authors.initials: HW
authors.lastname: Sung
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002122:Calcium Chloride / Q000737:chemistry; D000071231:Carbonic Anhydrase IX / Q000378:metabolism; D002374:Catalase / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004343:Drug Implants / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D006931:Hyperbaric Oxygenation / Q000379:methods*; D008819:Mice, Nude; D010100:Oxygen; D010545:Peroxides / Q000737:chemistry; D049268:Positron-Emission Tomography; D000072258:Tumor Hypoxia / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004343:Drug Implants; D010545:Peroxides; C403632:calcium peroxide; D004317:Doxorubicin; D002374:Catalase; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002122:Calcium Chloride; D010100:Oxygen