title: Integrin-facilitated transcytosis for enhanced penetration of advanced gliomas by poly(trimethylene carbonate)-based nanoparticles encapsulating paclitaxel.
abstract: The treatment of cerebral tumor, especially advanced gliomas, represents one of the most formidable challenges in oncology. In this study, integrin-mediated poly(trimethylene carbonate)-based nanoparticulate system (c(RGDyK)-NP) was proposed as a delivery vehicle for enhancing drug penetration and chemotherapy of malignant gliomas. Following the recognition by integrin proteins on cell surface, c(RGDyK)-NP could be energy-dependently internalized by human U87MG glioma cells through a multiple endocytic pathway. The tumor penetration, homing specificity and anticancer efficacy of PTX-loaded c(RGDyK)-NP (c(RGDyK)-NP/PTX) were performed on the 3D glioma spheroids, the U87MG glioma cells and the intracranial glioma mice model, respectively. Compared with conventional nanoparticles (NP/PTX) and Taxol, c(RGDyK)-NP/PTX showed the strongest penetration and accumulation into 3D glioma spheroids, an obvious microtubule stabilization effect to U87MG glioma cells, a significant homing specificity to malignant glioma in vivo, and an extended median survival time in the intracranial glioma-bearing mice. Furthermore, preliminary in vivo subacute toxicity was also evaluated by measuring the histopathology, blood cell counts and clinical biochemistry parameters, and the results revealed no obvious subacute toxicity to hematological system, major organs or tissues were observed post successive intravenous injection of c(RGDyK)-NP. Therefore, our results suggested that cyclic RGD-conjugated PEG-PTMC nanoparticle could be a promising vehicle for enhancing the penetration and cxhemotherapy of high-grade malignant gliomas.
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors: Xinyi
authors: X
authors: Jiang
authors: Xianyi
authors: X
authors: Sha
authors: Hongliang
authors: H
authors: Xin
authors: Ximing
authors: X
authors: Xu
authors: Jijin
authors: J
authors: Gu
authors: Weiyi
authors: W
authors: Xia
authors: Shuo
authors: S
authors: Chen
authors: Yike
authors: Y
authors: Xie
authors: Liangcen
authors: L
authors: Chen
authors: Yanzuo
authors: Y
authors: Chen
authors: Xiaoling
authors: X
authors: Fang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004146:Dioxanes / Q000737:chemistry*; D004337:Drug Carriers; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016023:Integrins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011108:Polymers / Q000737:chemistry*; D057900:Transcytosis / Q000502:physiology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004146:Dioxanes; D004337:Drug Carriers; D016023:Integrins; D011108:Polymers; C059299:polytrimethylene carbonate; D017239:Paclitaxel