© Copyright 2008 by the Society for Neuro-Oncology
Received December 20, 2006
Accepted August 17, 2007
Basic and Translational Investigations
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New therapeutic approach for brain tumors: Intranasal delivery of telomerase
inhibitor GRN163
Rintaro Hashizume 1*,
Tomoko Ozawa 1,
Sergei M. Gryaznov 2,
Andrew W. Bollen 3,
Kathleen R. Lamborn 1,
William H. Frey II 4,
Dennis F. Deen 1
1 Brain Tumor Research Center of the Department of Neurological Surgery,
University of California San Francisco, San Francisco, CA, USA
2 Geron Corporation, Menlo Park, CA, USA
3 Department of Pathology, University of California San Francisco, San Francisco,
CA, USA
4 Alzheimer's Research Center, HealthPartners Research Foundation at Regions
Hospital, St. Paul, MN, USA
* To whom correspondence should be addressed. E-mail: rintaro.hashizume{at}ucsf.edu.
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Abstract |
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The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain
tumors, and new strategies for bypassing it are greatly needed for brain-tumor therapy.
Intranasal delivery provides a practical, noninvasive method for delivering therapeutic
agents to the brain and could provide an alternative to intravenous injection and
convection-enhanced delivery. We treated rats bearing intracerebral human tumor xenografts
intranasally with GRN163, an oligonucleotide N3'
P5'thio-phosphoramidate telomerase
inhibitor. 3'-Fuorescein isothiocyanate (FITC)--labeled GRN163 was administered
intranasally every 2 min as 6 µl drops into alternating sides of the nasal cavity over 22
min. FITC-labeled GRN163 was present in tumor cells at all time points studied, and
accumulation of GRN163 peaked at 4 h after delivery. Moreover, GRN163 delivered
intranasally, daily for 12 days, significantly prolonged the median survival from 35 days in
the control group to 75.5 days in the GRN163-treated group. Thus, intranasal delivery of
GRN163 readily bypassed the blood-brain barrier, exhibited favorable tumor uptake, and
inhibited tumor growth, leading to a prolonged lifespan for treated rats compared to
controls. This delivery approach appears to kill tumor cells selectively, and no toxic
effects were noted in normal brain tissue. These data support further development of
intranasal delivery of tumor-specific therapeutic agents for brain tumor patients.
Key Words:
brain tumors, GRN163, intranasal delivery, telomerase inhibitor, xenografts
