Drug Delivery Across the Blood–Brain Barrier – Current Realities and Future Expectations
Table 1: Selected Companies with Technologies and Therapeutics Targeting the Blood–Brain Barrier Company
BBB Technology Allon Therapeutics AngioChem ArmaGen BiOasis BrainsGate Capsulution Medtronic Pharmidex + Genzyme Raptor Targacept Engineered neuropeptides ANG1005, a taxane derivative created from the
EPiC platform designed to cross the BBB via the LRP-1 transporter
AGT-120, an engineered protein fused with a neurotrophin variant that crosses the BBB and initiates neuroprotection
p97, a membrane-associated protein used as a vehicle for BBB penetration
Ischaemic stroke system, implanted electrical
stimulation of spheno-palatine ganglion to momentarily disrupt the BBB
PBCA, a degradable nanoparticle vehicle Medtronic Reclaim DBS therapy for obsessive–
compulsive disorder, and Medtronic DBS therapy for Parkinson’s disease
Cerense, optimised oligoglycerols as a generic BBB-penetrating drug platform
NeuroTrans, a receptor-associated protein vehicle for CNS-targeted drugs
NNR Therapeutics – TC5214, a drug targeted for the treatment of major depressive disorder
Tetragenex Pharmaceuticals Engineered neuropeptides to-BBB
TransMolecular XenoPort
G-Technology, a glutathione-coated liposome vehicle for therapeutics crossing the BBB Engineered peptide
Prodrug formulation to allow barrier permeability of existing drugs
Pre-clinical stage for the treatment of brain cancer
Pre-clinical studies have shown it can be conjugated with a variety of protein drugs and still retain functions of both proteins Completed phase IIb clinical trial
Nemifitide for depression in phase II
G-Technology coupled with doxorubicin has shown reduced brain tumour growth in initial proof-of-concept studies 131I-TM601 for glioma in phase II
XP21279 currently in phase I for the treatment of Parkinson’s disease
BBB = blood–brain barrier; CNS = central nervous system; DBS = deep brain stimulation; LRP-1 = low-density-lipoprotein-receptor-related protein-1; PBCA = polybutyl-cyanoacrylate. Source: Company reports.
increases blood flow to the brain. This increase in blood flow can assist in the treatment of CNS disorders such as ischemic stroke and vascular dementia. This device has also been proved to open the endothelial junctions for long enough to allow paclitaxel, a chemotherapeutic agent, to perfuse into the CSF.
Vector-mediated Transportation
This approach allows non-penetrating CNS-active drugs to permeate the barrier with the aid of a vector. This system for drug delivery is becoming popular, with numerous biotech companies producing their own version of vectors.
Cerense is an optimised oligoglycerol technology developed by Genzyme Pharmaceuticals partnered with Pharmidex Pharmaceutical Services Ltd, where the drug active of interest and the oligoglycerol compound self-form nanoparticles. When the nanoparticle comes into contact with the BBB it rapidly and reversibly opens the barrier and releases the active compound into the relevant cells. Once the drug is released from its nanoparticle, the oligoglycerol is excreted and allows the drug active to follow its own distinct PK pathway. NanoDel and Capsulution Pharma AG have also produced a coated degradable polybutyl-cyanoacrylate (PBCA) nanoparticle and are currently at the pre-clinical stage to assess its effectiveness to deliver the chemotherapeutic agent doxorubicin. to-BBB technologies BV, a BBB drug delivery company, has developed a glutathione-coated liposome vehicle (G-Technology) that delivers different classes of drug to the brain.
DRUG DISCOVERY Utilising Receptors
One way of delivering a drug active to the brain is by using receptor- mediated transporters.5
Since large protein molecules such as
hormones are able to permeate the BBB, it is possible to engineer a protein that mimics these molecules and uses the same receptors as vehicles for the drug of interest. AngioChem Inc. uses peptide linkers that transfer the chemotherapeutic agent, paclitaxel, through the BBB. ArmaGen Technologies Inc. has engineered fusion proteins, one of which is AGT-120, which targets and crosses the BBB. It has been shown in pre-clinical studies that AGT-120 not only crosses the BBB but also activates the neuroprotection receptors in the brain.
BiOasis Technologies utilises melanotransferrins (p97), a monomeric membrane-associated protein, as a carrier molecule for the delivery of drugs such as paclitaxel and adriamycin to the CNS. Proteus Sciences has also developed a brain-targeting peptide that utilises the natural permeability properties of microglia to produce BT- Technology, Proteus’ core technology. Raptor Pharmaceuticals is exploring its NeuroTrans product, which is a receptor-associated protein acting as a vehicle for CNS-targeted therapeutics.
Targacept, a biopharmaceutical company, is involved in the design and development of a new class of drug, NNR Therapeutics, that selectively targets the neuronal nicotinic receptors. TransMolecular employs synthetically derived chlorotoxin, which has BBB-crossing properties. The ligands utilised have receptors in the vasculature as well as in the brain capillaries. In addition, there will be endogenous
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Pre-clinical stage for PBCA loaded with doxorubicin for the treatment of glioblastoma
Both devices currently approved for use
Pre-clinical studies have shown that AGT-120 prototype reduced infarct volume by 70% in a rat stroke mode
Initial proof of concept has shown p97 is capable of delivering chemotherapeutic agents to the CNS
Currently under clinical trials for acute ischaemic stroke treatment Development Phase
AL-108 (intranasal): phase II completed for cognitive impairment; AL-208 (intravenous): in phase II for cognitive impairment Two phase I/II studies with antitumour drug paclitaxel
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