A Unique Carrier for Delivery of Therapeutic Compounds beyond the Blood-Brain Barrier

Abstract

BackgroundTherapeutic 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.ApproachHuman 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 FindingsBolus-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.SignificanceThis 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. It 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.

Developing Therapeutic Antibodies for Neurodegenerative Disease

“…Among their many interacting ligands are receptor-associated protein, apolipoprotein E, and melanotransferrin/p97 [131][132][133]. Drug targeting using p97 is perhaps the most studied of these ligands, where injections of the p97-conjugated chemotherapeutics paclitaxel or adriamycin were reported to result in increased brain uptake, with the latter also improving survival in a rat model of intracranial glioma [134]. More recently, Angiochem Inc. has developed a 19-amino-acid peptide against Lrp1, called Angiopep-2, to which paclitaxel was conjugated [135].…”

Enhanced BBB permeability of osmotically active poly(mannitol-co-PEI) modified with rabies virus glycoprotein via selective stimulation of caveolar endocytosis for RNAi therapeutics in Alzheimer's disease

“…To determine the function of mannitol backbone in PMT on BBB permeability, PEI (25 kDa) modified with RVG ligand with bridge of PEG (5 kDa) (R-PEG-PEI) was employed as a control group. Some pharmaceutical nanoparticles use the paracellular route to cross over BBB by accelerating the breakdown of the tight junction [39], while other use the transcellular transport via specific interaction with surface of endothelial cells [14,40]. We examined the integrity of in vitro BBB tight junction at pre-and pro-treatment of complexes to assess the possible risk by breakdown of BBB.…”

In Vivo Labeling of Brain Capillary Endothelial Cells after Intravenous Injection of Monoclonal Antibodies Targeting the Transferrin Receptor

“…Evidence for BCEC targeting and subsequent brain transport in vivo have been published with peptide vectors (Kumar et al, 2007;Demeule et al, 2008;Hervé et al, 2008), lowdensity lipoprotein receptor (Pan et al, 2004), transferrin (Skarlatos et al, 1995), and melanotransferrin (Demeule et al, 2002;Karkan et al, 2008). However, the most numerous data were obtained with monoclonal antibodies (MAbs) targeting the insulin (Coloma et al, 2000;Zhang et al, 2003a) or transferrin receptors (TfR) Shi and Pardridge, 2000;Zhang et al, 2003b).…”