Efficient brain targeting and therapeutic intracranial activity of bortezomib through intranasal co-delivery with NEO100 in rodent glioblastoma models

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  • 1 Departments of Neurosurgery,
  • 2 Pathology, and
  • 3 Molecular Microbiology & Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California
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OBJECTIVE

Many pharmaceutical agents are highly potent but are unable to exert therapeutic activity against disorders of the central nervous system (CNS), because the blood-brain barrier (BBB) impedes their brain entry. One such agent is bortezomib (BZM), a proteasome inhibitor that is approved for the treatment of multiple myeloma. Preclinical studies established that BZM can be effective against glioblastoma (GBM), but only when the drug is delivered via catheter directly into the brain lesion, not after intravenous systemic delivery. The authors therefore explored alternative options of BZM delivery to the brain that would avoid invasive procedures and minimize systemic exposure.

METHODS

Using mouse and rat GBM models, the authors applied intranasal drug delivery, where they co-administered BZM together with NEO100, a highly purified, GMP-manufactured version of perillyl alcohol that is used in clinical trials for intranasal therapy of GBM patients.

RESULTS

The authors found that intranasal delivery of BZM combined with NEO100 significantly prolonged survival of tumor-bearing animals over those that received vehicle alone and also over those that received BZM alone or NEO100 alone. Moreover, BZM concentrations in the brain were higher after intranasal co-delivery with NEO100 as compared to delivery in the absence of NEO100.

CONCLUSIONS

This study demonstrates that intranasal delivery with a NEO100-based formulation enables noninvasive, therapeutically effective brain delivery of a pharmaceutical agent that otherwise does not efficiently cross the BBB.

ABBREVIATIONS BBB = blood-brain barrier; BZM = bortezomib; cGMP = current good manufacturing practice; CNS = central nervous system; CSF = cerebrospinal fluid; GBM = glioblastoma; HPLC = high-performance liquid chromatography; IS = internal standard; MTT = methylthiazoletetrazolium; NEO100 = enriched perillyl alcohol manufactured under cGMP conditions; POH = perillyl alcohol; TMZ = temozolomide; USC = University of Southern California.

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Contributor Notes

Correspondence Thomas C. Chen: University of Southern California, Los Angeles, CA. tcchen@usc.edu.

INCLUDE WHEN CITING Published online March 15, 2019; DOI: 10.3171/2018.11.JNS181161.

Disclosures Dr. Chen reports an ownership interest (founder and stakeholder) in NeOnc Technologies, Los Angeles, CA.

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