Preclinical effects of CRLX101, an investigational camptothecin-containing nanoparticle drug conjugate, on treating glioblastoma multiforme via apoptosis and antiangiogenesis
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Chien-Ju Lin1, Yi-Ling Lin2, Frank Luh3, Yun Yen4,5, Ruei-Ming Chen1,2,4,6
1Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
2Brain Disease Research Center, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan
3Sino-American Cancer Foundation, Temple City, California, USA
4Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan
5Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
6Anesthetics and Toxicology Research Center and Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan
Ruei-Ming Chen, email: firstname.lastname@example.org
Yun Yen, email: email@example.com
Keywords: nanoparticle, malignant glioma, apoptosis, angiogenesis
Received: March 01, 2016 Accepted: May 23, 2016 Published: June 7, 2016
Malignant gliomas are difficult to treat in clinical practice. This study was aimed to investigate the preclinical efficacy of CRLX101, an investigational nanoparticle-drug conjugate developed by conjugating camptothecin (CPT) with cyclodextrin-polyethylene glycol, against gliomas. CPT fluorescence was detected across tight-junction barriers and in mouse plasma and brain. Following CRLX101 treatment, CPT was distributed in the cytoplasm of human U87 MG glioma cells. U87 MG cell viability was decreased by CRLX101 and CPT. Moreover, CRLX101 induced less cytotoxicity to human astrocytes compared to CPT. Exposure of U87 MG cells to CRLX101 induced G2/M cell cycle arrest and apoptosis. Administration of CRLX101 induced apoptosis in mice brain tumor tissues and prolonged the survival rate of mice. In addition, CRLX101 inhibited hypoxia and angiogenesis by suppressing the expression of carbonic anhydrase IX, vascular endothelial growth factor, and CD31 in tumor sections. Taken together, this preclinical study showed that CRLX101 possesses antitumor abilities by inducing cell cycle arrest and apoptosis in glioma cells and inhibiting tumor angiogenesis, thereby prolonging the lifespan of mice bearing intracranial gliomas. These data support further research of CRLX101 in patients with brain tumors.
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