New therapeutic approach for brain tumors: intranasal delivery of telomerase inhibitor GRN163. Neuro Oncol

Brain Tumor Research Center, Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143-0520, USA.
Neuro-Oncology (Impact Factor: 5.56). 05/2008; 10(2):112-20. DOI: 10.1215/15228517-2007-052
Source: PubMed


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 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.

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    • "The administration of [ 125 I]-labeled insulin-like growth factor-I ( 125 I-IGF-I) has been reported to increase levels of radioactivity in both the olfactory bulb and trigemininal ganglion of the rat brain, with the highest concentrations observed in the latter site (Thorne et al., 2004). In addition, the IN administration of various other products such as lidocaine, stem cells, and telomerase inhibitors have all been shown to reach the brainstem via trigeminal nerve fibers in rodents (Danielyan et al., 2011; Hashizume et al., 2008; Johnson et al., 2010), although it is possible that these substances reach the brainstem via other means such as diffusion though brain CSF via olfactory pathway entry. Notably, projections from the central amygdala and PVN extend to brainstem nuclei that regulate cardiovascular functioning (Viviani et al., 2011). "
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    • "As GRN163L can penetrate plasma membranes through its lipid conjugation, it does not require additional vehicles for its delivery.39 Through intranasal or systemic treatment, both GRN163 and GRN163L can bypass the blood-brain barrier and preferentially affect brain tumor cells with minimum toxicity to normal brain tissue.43,44 These studies provide the basis for using both GRN163 and GRN163L as potent drugs against brain tumors, and both have already reached clinical trial stages. "
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    • "Intranasal delivery is a promising alternative to standard delivery systems as it provides a practical, painless method for delivering therapeutic agents to the brain (Fig. 3). Rats bearing brain tumors were treated intranasally with an oligonucleotide against Telomerase (TERT).122 The intranasally delivered treatment bypassed the blood-brain barrier, reached the tumor and inhibited tumor growth, leading to a prolonged lifespan in treated rats. "
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