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

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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.

Article Information

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.

© AANS, except where prohibited by US copyright law.

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Figures

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    Cytotoxic potency of BZM against glioma cell lines. Three different established glioma cell lines derived from mouse (GL26), rat (RG2), and human (U251) were seeded into 96-well plates and exposed to different concentrations of BZM. After 48 hours, standard MTT assay was performed to determine viability of cells. Percent survival was determined as compared to vehicle-treated cells (n ≥ 3, mean ± SD [error bars]).

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    Concentrations of perillyl alcohol and perillic acid in rat brain. At different time points after intranasal delivery of NEO100 to Fisher rats, brains were collected for analysis. Two animals were used for each time point. A: One brain was used to determine POH concentrations in different brain regions (R1–R5; see schematic). B: The second brain was used to determine overall POH concentrations, as well as concentrations of its metabolite perillic acid.

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    Concentrations of BZM in rat brain. A: Three rats received BZM via bolus tail vein injection. After 1 hour, serum and brains were collected. Tissue concentrations of BZM were determined as described in Methods. B: Rats with intracranially implanted RG2 glioma cells were administered with intranasal BZM in the presence or absence of NEO100. At different times thereafter, 3 animals per time point were euthanized. Their brains were collected and separated into tumor tissue and normal tissue (contralateral hemisphere). BZM concentrations were analyzed. Means and SDs (error bars) are shown.

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    Effect of intranasal BZM plus NEO100 on survival of tumor-bearing mice. Human U251 GBM cells were implanted into the brains of athymic nude mice. Ten days after implantation, the animals were separated into different groups (5 animals per group) and treated with vehicle or drugs. Shown here are Kaplan-Meier survival curves. A: Animal survival in response to intravenous (IV) delivery of vehicle, BZM, or BZM plus NEO100. B: Animal survival in response to intranasal (IN) delivery of vehicle, BZM, NEO100, or BZM plus NEO100. In all cases, the dosage of BZM was 1 mg/kg per cycle, and the concentration of NEO100 was 0.3%. Animals were monitored for behavioral signs of neurological toxicity, which is also relevant in view of BZM’s known neurotoxic potential.23 Such signs emerged on occasion in a few animals but were aligned with late-stage intracranial tumor growth, not with BZM treatment. Figure is available in color online only.

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    BZM content in CSF versus serum and stability. A: Six rats per time point were treated with intranasal BZM (3 with co-administered NEO100, 3 with vehicle). CSF and serum were collected, processed, and analyzed for BZM content. B: BZM was mixed with 0.3% NEO100, or vehicle only, and incubated at 37°C. Aliquots were removed and processed at different times, as indicated, to measure BZM content. Starting concentration of BZM was set at 100%. Shown in both figure parts are the means of the triplicate samples and the standard errors (error bars).

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