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Targeting brain tumors by intra-arterial delivery of cell-penetrating peptides: a novel approach for primary and metastatic brain malignancy

  • Laboratory Investigation
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Abstract

Computational modeling shows that intra-arterial delivery is most efficient when the delivered drugs rapidly and avidly bind to the target site. The cell-penetrating peptide trans-activator of transcription (TAT) is a candidate carrier molecule that could mediate such specificity for brain tumor chemotherapeutics. To test this hypothesis we first performed in vitro studies testing the uptake of TAT by one primary and three potentially metastatic brain cancer cell lines (9L, 4T-1, LLC, SKOV-3). Then we performed in vivo studies in a rat model where TAT was delivered either intra-arterially (IA) or intravenously (IV) to 9L brain tumors. We observed robust uptake of TAT by all tumor cell lines in vitro. Flow cytometry and confocal microscopy revealed a rapid uptake of fluorescein-labeled TAT within 5 min of exposure to the cancer cells. IA injections done under transient cerebral hypoperfusion (TCH) generated a four-fold greater tumor TAT concentration compared to conventional IV injections. We conclude that it is feasible to selectively target brain tumors with TAT-linked chemotherapy by the IA-TCH method.

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Funding

The funding was provided by National Cancer Institute at the National Institutes of Health (Grant No. RO1-CA-138643).

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Authors and Affiliations

  1. Department of Anesthesiology, College of Physicians and Surgeons, Columbia University Medical Center, 630 West 168th Street, P&S Box 46, New York, NY, 10032, USA

    Shailendra Joshi, Johann R. N. Cooke & Charles W. Emala

  2. Department of Neurological Surgery, Columbia University Medical Center, New York, NY, USA

    Jason A. Ellis & Jeffrey N. Bruce

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  1. Shailendra Joshi
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  2. Johann R. N. Cooke
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  4. Charles W. Emala
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  5. Jeffrey N. Bruce
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Correspondence to Shailendra Joshi.

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Joshi, S., Cooke, J.R.N., Ellis, J.A. et al. Targeting brain tumors by intra-arterial delivery of cell-penetrating peptides: a novel approach for primary and metastatic brain malignancy. J Neurooncol 135, 497–506 (2017). https://doi.org/10.1007/s11060-017-2615-5

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  • DOI: https://doi.org/10.1007/s11060-017-2615-5

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