title: Development of a hypoxia-triggered and hypoxic radiosensitized liposome as a doxorubicin carrier to promote synergetic chemo-/radio-therapy for glioma.
abstract: The treatment of malignant primary brain tumors is challenging. Concomitant radiochemotherapy has become the standard clinical treatment for malignant glioma, but there are two critical challenges to overcome in order to increase efficacy. First, glioma is known to have increased resistant to radiation due to its intra-tumoral hypoxia. In addition, the blood-brain barrier (BBB) restricts the distribution of the chemotherapeutic agent to the brain. Therefore, we developed a hypoxic radiosensitizer-prodrug liposome (MLP), in order to deliver DOX to the tumor and to overcome the above challenges, achieving a synergistic chemo-/radiotherapy treatment of malignant glioma. In this study, hypoxic radiosensitizer nitroimidazoles were conjugated with lipid molecules with a hydrolysable ester bond to form MDH. MDH was mixed together with DSPE-PEG2000 and cholesterol to make MLP liposomes, which were found to have strong radiosensitivity and to promote cargo release under hypoxic conditions, due to the properties of nitroimidazoles under hypoxic conditions. MLP/DOX was found to have distinct advantages, including precise and stealthy pharmacokinetics and efficient passive uptake by the tumor. Furthermore, the combination of MLP/DOX and radiotherapy (RT) significantly inhibited glioma growth as assessed by in vivo bioluminescence imaging. These findings suggest that MLP is a promising candidate as a DOX delivery system to enhance the antitumor treatment effects on glioma, owing to synergistic chemo-/radiotherapy.
authors.affiliation: Brain Hospital, Affiliated Hospital of Xuzhou Medical University, Xuzhou, PR China; Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, PR China. Electronic address: liuhongmei816@sina.com.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Liu
authors.affiliation: Brain Hospital, Affiliated Hospital of Xuzhou Medical University, Xuzhou, PR China; Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, PR China.
authors.forename: Yandong
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Brain Hospital, Affiliated Hospital of Xuzhou Medical University, Xuzhou, PR China; Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, PR China.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Brain Hospital, Affiliated Hospital of Xuzhou Medical University, Xuzhou, PR China; Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, PR China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Brain Hospital, Affiliated Hospital of Xuzhou Medical University, Xuzhou, PR China; Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, PR China.
authors.forename: Baiyang
authors.initials: B
authors.lastname: Li
authors.affiliation: Brain Hospital, Affiliated Hospital of Xuzhou Medical University, Xuzhou, PR China; Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, PR China.
authors.forename: Honglin
authors.initials: H
authors.lastname: Mao
authors.affiliation: National Institute of Biological Sciences, Beijing, 102206, PR China.
authors.forename: Yingguo
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, 221116, Jiangsu Province, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Radiation Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, PR China; Cancer Institute of Xuzhou Medical University, Xuzhou, 221002, PR China.
authors.forename: Longzhen
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Brain Hospital, Affiliated Hospital of Xuzhou Medical University, Xuzhou, PR China; Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, PR China. Electronic address: yu.rutong@163.com.
authors.forename: Rutong
authors.initials: R
authors.lastname: Yu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D016896:Treatment Outcome; D000072258:Tumor Hypoxia
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D011838:Radiation-Sensitizing Agents; D004317:Doxorubicin
keywords: Glioma; Hypoxia-triggered; Hypoxic radiosensitization liposome; Synergetic chemo-/radio-therapy