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: Xinyi Jiang, Xianyi Sha, Hongliang Xin, Ximing Xu, Jijin Gu, Weiyi Xia, Shuo Chen, Yike Xie, Liangcen Chen, Yanzuo Chen, Xiaoling Fang
• Journal: Biomaterials (Biomaterials) Vol. 34 Issue 12 Pg. 2969-79 (Apr 2013) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 23380351 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Dioxanes
• Drug Carriers
• Integrins
• Polymers
• polytrimethylene carbonate
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage, pharmacokinetics, therapeutic use)
• Apoptosis
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Dioxanes (chemistry)
• Drug Carriers
• Glioma (drug therapy, metabolism, pathology)
• Humans
• Integrins (physiology)
• Mice
• Mice, Inbred BALB C
• Nanoparticles
• Paclitaxel (administration & dosage, pharmacokinetics, therapeutic use)
• Polymers (chemistry)
• Transcytosis (physiology)