Abstract
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.
Highlights
Chemotherapy and more recently targeted therapy directed at specific tumor targets, are important modalities for treatment of pediatric brain tumors
In order to test if the novel HAV6 peptide would increase the blood-brain barrier (BBB) permeability, we injected mice with HAV6 peptide or vehicle and imaged their brains using magnetic resonance imaging (MRI) and Gadolinium diethylene-triamine-penta-acetate (Gd-DTPA) contrast
There was a significant increase in the signal intensity of the Gd-DTPA contrast agent in the brain following IV injection of HAV6 peptide (0.01 mmol/kg) (Figure 1)
Summary
Chemotherapy and more recently targeted therapy directed at specific tumor targets, are important modalities for treatment of pediatric brain tumors. Within the EC1 domain, the highly conserved region of His-Ala-Val (HAV) is crucial for the formation of the cis-dimer formation of cadherins Synthetic peptides targeting this HAV region sequence of the EC1 domain display concentration-dependent binding to E-cadherin molecules and can prevent homodimer complex formation in brain microvessel endothelial cells [13]. Concurrent use of HAV6 peptide to transiently open the BBB resulted in Ade entry into the brain and significantly prolonged the survival of mice bearing Group-3 MBL tumors. Those tumor bearing mice receiving HAV6 showed no additional adverse responses to the treatment compared to mice receiving placebo. These findings provide proof-of-principle for the use of cadherin peptides in the modulation of BBB permeability and improved treatment of brain tumors
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