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Senior Member
Join Date: Mar 2006
Posts: 4,778
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way to hitchhike/hijack freely across the Blood Brain Barrier identified!
A Unique Carrier for Delivery of Therapeutic Compounds beyond the Blood-Brain Barrier
Delara Karkan1#¤a, Cheryl Pfeifer2,3,4*, Timothy Z. Vitalis1,2,3,4#¤b, Gavin Arthur1¤c*, Maki Ujiie2,3,4*, Qingqi Chen1¤d, Sam Tsai1¤e, Gerrasimo Koliatis1,2,3,4¤f, Reinhard Gabathuler1,2,3,4¤g, Wilfred A. Jefferies2,3,4*
1 BioMarin Pharmaceutical Inc., Vancouver, Canada, 2 Department of Medical Genetics, the Michael Smith Laboratories and the Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada, 3 Department of Microbiology and Immunology, the Michael Smith Laboratories and the Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada, 4 Department of Zoology, the Michael Smith Laboratories and the Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada
Abstract Top
Background
Therapeutic intervention in many neurological diseases is thwarted by the physical obstacle formed by the blood-brain barrier (BBB) that excludes most drugs from entering the brain from the blood. Thus, identifying efficacious modes of drug delivery to the brain remains a “holy grail” in molecular medicine and nanobiotechnology. Brain capillaries, that comprise the BBB, possess an endogenous receptor that ferries an iron-transport protein, termed p97 (melanotransferrin), across the BBB. Here, we explored the hypothesis that therapeutic drugs “piggybacked” as conjugates of p97 can be shuttled across the BBB for treatment of otherwise inoperable brain tumors.
Approach
Human p97 was covalently linked with the chemotherapeutic agents paclitaxel (PTAX) or adriamycin (ADR) and following intravenous injection, measured their penetration into brain tissue and other organs using radiolabeled and fluorescent derivatives of the drugs. In order to establish efficacy of the conjugates, we used nude mouse models to assess p97-drug conjugate activity towards glioma and mammary tumors growing subcutaneously compared to those growing intracranially.
Principal Findings
Bolus-injected p97-drug conjugates and unconjugated p97 traversed brain capillary endothelium within a few minutes and accumulated to 1–2% of the injected by 24 hours. Brain delivery with p97-drug conjugates was quantitatively 10 fold higher than with free drug controls. Furthermore, both free-ADR and p97-ADR conjugates equally inhibited the subcutaneous growth of gliomas growing outside the brain. Evocatively, only p97-ADR conjugates significantly prolonged the survival of animals bearing intracranial gliomas or mammary tumors when compared to similar cumulated doses of free-ADR.
Significance
This study provides the initial proof of concept for p97 as a carrier capable of shuttling therapeutic levels of drugs from the blood to the brain for the treatment of neurological disorders, including classes of resident and metastatic brain tumors. 1It may be prudent, therefore, to consider implementation of this novel delivery platform in various clinical settings for therapeutic intervention in acute and chronic neurological diseases.
Citation: Karkan D, Pfeifer C, Vitalis TZ, Arthur G, Ujiie M, et al. (2008) A Unique Carrier for Delivery of Therapeutic Compounds beyond the Blood-Brain Barrier. PLoS ONE 3(6): e2469. doi:10.1371/journal.pone.0002469
Article available for free at PLos One.
Please contact your legislator as asked on the PLos One site to let them know how important it is for taxpayers to have access to the full articles for free--since the vast majority of research is done with taxpayers funds!!!!
Sorry for adding my 2 cents, but information is ammunition and if you have already paid for it with your taxes, why should they deny it to you?
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