- Neuro Oncol. 2008 Apr;10(2):112-20. Epub 2008 Feb 20.
New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163.
Hashizume R, Ozawa T, Gryaznov SM, Bollen AW, Lamborn KR, Frey WH 2nd, Deen DF.
Tumor Research Center, Department of Neurological Surgery, University
of California San Francisco, San Francisco, CA 94143-0520, USA.
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 microl 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.