Preclinical effects of CRLX101, an investigational camptothecin-containing nanoparticle drug conjugate, on treating glioblastoma multiforme via apoptosis and antiangiogenesis.
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.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Chien-Ju
CJ
Lin
Brain Disease Research Center, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
Yi-Ling
YL
Lin
Sino-American Cancer Foundation, Temple City, California, USA.
Frank
F
Luh
Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan.|Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Yun
Y
Yen
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Brain Disease Research Center, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.|Comprehensive Cancer Center, Taipei Medical University, Taipei, Taiwan.|Anesthetics and Toxicology Research Center and Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan.
Ruei-Ming
RM
Chen
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy; D002166:Camptothecin / Q000494:pharmacology*; D000071231:Carbonic Anhydrase IX / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D003505:Cyclodextrins / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D005910:Glioma / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D058726:Nanoconjugates / Q000737:chemistry; D050997:Nanomedicine; D009389:Neovascularization, Pathologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D019108:Tight Junctions; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D003505:Cyclodextrins; C542292:IT-101; D058726:Nanoconjugates; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011092:Polyethylene Glycols; D000071231:Carbonic Anhydrase IX; D002166:Camptothecin
angiogenesis; apoptosis; malignant glioma; nanoparticle