Nanobiotechnology-Based Strategies for Crossing the Blood–Brain Barrier

Kewal K Jain


Nanomedicine. 2012;7(8):1225-1233. 

In This Article

Nanobiotechnology-Based Strategies for Crossing the BBB

Several strategies for delivering therapeutics across the BBB using NPs have been investigated. Conjugation of the sequence 12–32 (g21) of leptin to PLGA NPs has been shown to facilitate their transfer across the BBB into the brain following intravenous administration in rats, indicating their potential for drug delivery.[17] Nanotechnology-based methods of drug delivery across the BBB include two commercialized technologies LipoBridge™ (Genzyme Pharmaceuticals, MA, USA) and G-Technology® (to-BBB, Leiden, The Netherlands).

NPs for Enhancing mAb Delivery Across the BBB

Intravenously injected mAbs are either unable to cross the BBB or cross it with low efficiency and do not reach therapeutic concentrations within the brain. Several strategies have been proposed to facilitate the delivery of mAbs to the brain. These include direct intracranial delivery of antibodies, disruption of the BBB and conjugation of antibodies to a 'molecular Trojan horse' using NPs.[18] A molecular Trojan horse is an endogenous peptide, or a mAb, used for receptor-mediated transport across the BBB via endogenous peptide receptors.[19] As an extension of this approach, substances, such as some enzymes that do not cross the BBB naturally, can be re-engineered and fused with mAbs to form chimeric mAbs that facilitate passage across the BBB.[20] Boado and Pardridge used the human insulin receptor with a mAb to cross the BBB on the endogenous insulin receptor, which acts as a molecular Trojan horse.[20] NPs can be combined with the Trojan horse approach in a multifunctional construct for targeted delivery across the BBB.

Peptide–NP Conjugates for Crossing the BBB

Conjugation between a biodegradable copolymer, PLGA and short peptides has been achieved by amidic linkage to construct a system that enables the delivery of NPs to the CNS.[21] These peptides were rendered fluorescent so that their passage across the BBB following intravenous injection could be demonstrated by fluorescent microscopy in studies on rats. According to the results of PLGA NPs that were unable to cross the BBB initially, they were able to do so following surface modification with peptides.


G-Technology uses PEGylated liposomes coated with glutathione, an endogenous tripeptide transporter expressed on the BBB, to facilitate the delivery of drugs to the brain.[22] G-Technology has been applied for the delivery of methylprednisolone, which is used to treat several diseases with a neuroinflammatory component. A product, 2B3–201(to-BBB), is in preclinical studies for potential applications in multiple sclerosis, acute spinal cord injury and lupus erythematosus involving the CNS. Its application for targeted chemotherapy of brain cancer is described in the section entitled 'Nanobiotechnology-based delivery of therapy for brain tumors across the BBB'.

Exosome-Mediated Delivery of siRNA Into the Brain

siRNAs are an important part of the RNAi approach to several diseases and a number of clinical trials are in progress; however, none of these involve delivery to the brain. This class of therapeutic agents suffers from high sensitivity to enzymatic degradation, poor cellular uptake and rapid renal and liver clearance, limiting their in vivo applications. Delivery of siRNA, particularly to the brain, is a challenge. Some experimental studies have shown the feasibility of siRNA delivery across the BBB.

A 29-amino acid peptide derived from rabies virus glycoprotein (RVG) enables the transvascular delivery of siRNA to the brain. After intravenous injection into mice, RVG-9R delivered siRNA to the neuronal cells, resulting in specific gene silencing within the brain.[23] Furthermore, intravenous treatment with RVG-9R-bound antiviral siRNA afforded robust protection against fatal viral encephalitis in mice. Repeated administration of RVG-9R-bound siRNA did not induce inflammatory cytokines or antipeptide antibodies. Thus, RVG-9R provides a safe and noninvasive approach for the delivery of siRNA and potentially other therapeutic molecules across the BBB.

Targeted exosomes, nanovesicles measuring 40–100 nm in diameter, have been administered intravenously for the delivery of siRNA into the brains of mice.[24] This method of delivery avoids uptake by other tissues outside the brain and any resulting immune reaction. There is no loss of efficiency following repeated administration of targeted exosomes. This method of siRNA delivery was shown to be effective for knockdown of BACE1, a target for the treatment of Alzheimer's disease, in mouse models.