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Open AccessArticle

Validation of Cadherin HAV6 Peptide in the Transient Modulation of the Blood-Brain Barrier for the Treatment of Brain Tumors

1
Research Institute in Oncology and Hematology, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
2
Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB R3E 0T6, Canada
3
College of Pharmacy Pharmaceutical Analysis Laboratory, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
4
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Safat 13110, Kuwait
5
Department of Pharmaceutical Chemistry, University of Kansas, Kansas, KS 66205, USA
6
Kunming Institute of Botany, Kunming 650201, Yunnan, China
7
Pharmacy and Pharmaceutical Sciences, University of Alberta, Alberta, AB T6G 2R3, Canada
8
Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
*
Authors to whom correspondence should be addressed.
These authors contributed to the work equally.
Pharmaceutics 2019, 11(9), 481; https://doi.org/10.3390/pharmaceutics11090481
Received: 21 July 2019 / Revised: 29 August 2019 / Accepted: 3 September 2019 / Published: 17 September 2019
(This article belongs to the Special Issue Drug Delivery Technology Development in Canada)
The blood-brain barrier (BBB) poses a major obstacle by preventing potential therapeutic agents from reaching their intended brain targets at sufficient concentrations. While transient disruption of the BBB has been used to enhance chemotherapeutic efficacy in treating brain tumors, limitations in terms of magnitude and duration of BBB disruption exist. In the present study, the preliminary safety and efficacy profile of HAV6, a peptide that binds to the external domains of cadherin, to transiently open the BBB and improve the delivery of a therapeutic agent, was evaluated in a murine brain tumor model. Transient opening of the BBB in response to HAV6 peptide administration was quantitatively characterized using both a gadolinium magnetic resonance imaging (MRI) contrast agent and adenanthin (Ade), the intended therapeutic agent. The effects of HAV6 peptide on BBB integrity and the efficacy of concurrent administration of HAV6 peptide and the small molecule inhibitor, Ade, in the growth and progression of an orthotopic medulloblastoma mouse model using human D425 tumor cells was examined. Systemic administration of HAV6 peptide caused transient, reversible disruption of BBB in mice. Increases in BBB permeability produced by HAV6 were rapid in onset and observed in all regions of the brain examined. Concurrent administration of HAV6 peptide with Ade, a BBB impermeable inhibitor of Peroxiredoxin-1, caused reduced tumor growth and increased survival in mice bearing medulloblastoma. The rapid onset and transient nature of the BBB modulation produced with the HAV6 peptide along with its uniform disruption and biocompatibility is well-suited for CNS drug delivery applications, especially in the treatment of brain tumors. View Full-Text
Keywords: blood-brain barrier (BBB); drug delivery; transient modulation; HAV6 cadherin peptide; adenanthin; magnetic resonance imaging (MRI); medulloblastoma blood-brain barrier (BBB); drug delivery; transient modulation; HAV6 cadherin peptide; adenanthin; magnetic resonance imaging (MRI); medulloblastoma
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Sajesh, B.V.; On, N.H.; Omar, R.; Alrushaid, S.; Kopec, B.M.; Wang, W.-G.; Sun, H.-D.; Lillico, R.; Lakowski, T.M.; Siahaan, T.J.; Davies, N.M.; Puno, P.-T.; Vanan, M.I.; Miller, D.W. Validation of Cadherin HAV6 Peptide in the Transient Modulation of the Blood-Brain Barrier for the Treatment of Brain Tumors. Pharmaceutics 2019, 11, 481.

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