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“Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases,” Gabathuler, Neurobiology of Disease (2010)

The central nervous system is protected by barriers which control the entry of compounds into the brain, thereby regulating brain homeostasis.  The blood-brain barrier, formed by the endothelial cells of the brain capillaries, restricts access to brain cells of blood-borne compounds and facilitates nutrients essential for normal metabolism to reach brain cells.  This very tight regulation of the brain homeostasis results in the inability of some small and large therapeutic compounds to cross the blood-brain barrier (BBB).  Therefore, various strategies are being developed to enhance the amount and concentration of therapeutic compounds in the brain.  In this review, we will address the different approaches used to increase the transport of therapeutics from blood into the brain parenchyma.  We will mainly concentrate on the physiologic approach which takes advantage of specific receptors already expressed on the capillary endothelial cells forming the BBB and necessary for the survival of brain cells.

Among all the approaches used for increasing brain delivery of therapeutics, the most accepted method is the use of the physiological approach which takes advantage of the transcytosis capacilty of specific receptors expressed at the BBB.  The low density lipoprotein receptor related protein (LRP) is the most adapted for such use with the engineered peptide compound (EPiC) platform incorporating the Angiopep peptide in new therapeutics the most most advanced with promising data in the clinic.

1. Invasive approach

a. Intra-cerebro-ventricular (ICV) infusion

Not efficient unless the target is close to the ventricles/ ependymal surface of the brain

b. Convection-enhanced delivery (CED)

Stereotactically guided insertion of small-caliber catheter into the brain parenchyma.  Infusate is actively pumped into the brain parenchyma and penetrates in the interstitial space.  Placement must be perfect.

c. Intra-cerebral injection or use of implants

High concentrations of the drug; relies on the principle of diffusion to drive the drug into the brain.  Note that distribution in the brain by diffusion decreases exponentially with distance.

d. Disruption of the BBB

Osmotic disruption: Osmotic shock causes endothelial cells to shrink

MRI-guided focused ultrasound BBB disruption technique: ultrasound is capable of BBB disruption

Limitations: non-patient friendly, may enhance tumor dissemination or cause neuronal damage from unwanted blood components entering the brain

2. Pharmacological approach

Some molecules freely enter the brain

Size/ less than 500 D, charge/low hydrogen bonding capabilities, lipophility/ more lipophilicà better transport

Modification of drugs through reduction in relative number of polar groups

Use of lipid carriers for transport

Modification of antioxidants with pyrrolopyrimidines

Incorporation of fatty acids

Limitations: these modifications to molecules reduce their efficacy

Formulation of drugs facilitates brain delivery by increasing the drug solubility and stability in plasma

Incorporation of low molecular mass drugs into pluronic micelles

*3. Physiological approaches* — considered most promising

a) Transporter-mediated delivery

At least 8 different nutrient transport systems have been identified

Drugs must closely mimic endogenous carrier substrates

b) Receptor-mediated transcytosis

Receptors at the blood-brain barrier

Specific receptors for large molecules required for normal brain function

Transferrin receptor (TR) – function is to provide iron to cells

Insulin Receptor

Antibodies against TR and HIR for brain drug targeting

Liposomes coated with targeting molecules such as antibodies, Trojan Horse Liposomes (THL)

Nanoparticles coated with transferring or transferring receptor antibodies

c) Low-density lipoprotein receptor related proteins 1 and 2 (LRP-1 and 2)


“Breaching the Blood-Brain Barrier: Finding May Permit Drug Delivery to the Brain for Alzheimer’s, Multiple Sclerosis and Brain Cancers,” Science Daily (2011)

ScienceDaily (Sep. 13, 2011) — Cornell University researchers may have solved a 100-year puzzle: How to safely open and close the blood-brain barrier so that therapies to treat Alzheimer’s disease, multiple sclerosis and cancers of the central nervous system might effectively be delivered.

The researchers found that adenosine, a molecule produced by the body, can modulate the entry of large molecules into the brain. For the first time, the researchers discovered that when adenosine receptors are activated on cells that comprise the blood-brain barrier, a gateway into the blood-brain barrier can be established.

Although the study was done on mice, the researchers have also found adenosine receptors on these same cells in humans. They also discovered that an existing FDA-approved drug called Lexiscan, an adenosine-based drug used in heart imaging in very ill patients, can also briefly open the gateway across the blood-brain barrier.

The researchers also successfully delivered an anti-beta amyloid antibody across the blood-brain barrier and observed it binding to beta-amyloid plaques that cause Alzheimer’s in a transgenic mouse model.

Although there are many known antagonists (drugs or proteins that specifically block signaling) for adenosine receptors in mice, future work will try to identify such drugs for humans.


“Adenosine receptor signaling modulates permeability of the blood-brain barrier,” Carman et al., Journal of Neuroscience (2011)

The blood–brain barrier (BBB) is comprised of specialized endothelial cells that form the capillary microvasculature of the CNS and is essential for brain function. It also poses the greatest impediment in the treatment of many CNS diseases because it commonly blocks entry of therapeutic compounds. Here we report that adenosine receptor (AR) signaling modulates BBB permeability in vivo. A1 and A2A AR activation facilitated the entry of intravenously administered macromolecules, including large dextrans and antibodies to β-amyloid, into murine brains. Additionally, treatment with an FDA-approved selective A2A agonist, Lexiscan, also increased BBB permeability in murine models. These changes in BBB permeability are dose-dependent and temporally discrete. Transgenic mice lacking A1 or A2A ARs showed diminished dextran entry into the brain after AR agonism. Following treatment with a broad-spectrum AR agonist, intravenously administered anti-β-amyloid antibody was observed to enter the CNS and bind β-amyloid plaques in a transgenic mouse model of Alzheimer’s disease (AD). Selective AR activation resulted in cellular changes in vitro including decreased transendothelial electrical resistance, increased actinomyosin stress fiber formation, and alterations in tight junction molecules. These results suggest that AR signaling can be used to modulate BBB permeability in vivo to facilitate the entry of potentially therapeutic compounds into the CNS. AR signaling at brain endothelial cells represents a novel endogenous mechanism of modulating BBB permeability. We anticipate these results will aid in drug design, drug delivery and treatment options for neurological diseases such as AD, Parkinson’s disease, multiple sclerosis and cancers of the CNS.


“Nanotechnology approaches for drug and small molecule delivery across the blood brain barrier,” Silva, Surgical Neurology (2007)

One area in which nanotechnology may have a significant clinical impact in neuroscience is the selective transport and delivery of drugs and other small molecules across the blood brain barrier that cannot cross otherwise.  Using a variety of nanoparticles composed of different chemical compositions, different groups are exploring proof-of-concept approaches for the delivery of different antineoplastic drugs, oligonucleotides, genes, and magnetic resonance imaging contrast agents.  This review discusses some of the main technical challenges associated with the development of nanotechnologies for delivery across the blood brain barrier and summarizes ongoing work.