Nanobiotechnology-Based Strategies for Crossing the Blood–Brain Barrier

Kewal K Jain


Nanomedicine. 2012;7(8):1225-1233. 

In This Article

NPs Used to Cross the BBB

The use of NPs to deliver drugs to the brain across the BBB may provide a significant advantage over currently used strategies. In contrast to methods of forced delivery, NPs can be transported across the BBB by carriers, also referred to as nanocarriers, without any damage to the BBB.[2] The primary advantage of NP carrier technology is that NPs compensate for the BBB-limiting characteristics of the therapeutic drug molecule.[3] Furthermore, this system may slow drug release in the brain, thus decreasing peripheral toxicity. Various factors that influence the transport include: type of polymer or surfactant used, NP size and the drug molecule. Several NPs have been used for drug delivery by a variety of methods for various systems of the body, but only those relevant to the BBB will be described briefly in this section. One example of a drug that has been successfully transported into the brain using NPs is the anticancer agent doxorubicin.

Most of the strategies described for the passage of drugs across the BBB can be enhanced by nanotechnology and some of the mechanisms involved include:

  • NPs open the tight junctions between endothelial cells and enable the drug to penetrate the BBB;

  • NPs are transcytosed through the endothelial cell layer;

  • NPs are endocytosed by endothelial cells and release the drug inside the cell;

  • Coating agents for NPs such as polysorbates inhibit the transmembrane efflux systems (i.e., P-glycoprotein);

  • NPs may induce local toxic effects on the brain vasculature leading to a limited permeabilization of the brain endothelial cells.[4]

Lipid NPs

Lipid NPs are nanometer-sized spheres surrounded by a lipid bilayer and embedded with conformationally intact integral membrane proteins. Their lipophilic features facilitate crossing the BBB to enter the brain by endocytosis.[5] Several drugs have been incorporated into solid lipid NPs (SLNs), which are potentially useful for the treatment of brain diseases. SLNs have limited drug-loading capacities but their advantages are:

  • Unlike conventional bilayer liposomes, there is no random fusion between the particles or with other membranes;

  • Surface charge and molecular makeup can be easily modified with the possibility of multivalent attachment of small molecule ligands;

  • Stability with controlled release.

SLNs, measuring 33–63 nm, and loaded with the antioxidant agent idebenone, have been shown to cross an in vitro model of the BBB via a transcellular pathway.[6] This is a promising strategy that should be tested in vivo.


Liposome properties vary substantially with lipid composition, size, surface charge and the method of preparation. Small liposomes, nanoliposomes, measure 25–50 nm in diameter. Liposomes are biocompatible but production costs are high. Liposomes can be used in strategies for therapeutic delivery across the BBB (e.g., delivery of anticancer drugs for malignant brain tumors). Functionalization of liposomes with ApoE-derived peptides facilitates cellular uptake and drug transport across a model of the BBB.[7]

Polymeric NPs as Carriers Across the BBB

Some examples of polymeric NPs are: chitosans, dendrimers, nanogels, poly(D,L-lactide-co-glycolide (PLGA), poly(D,L-lactide) (PLA) and polybutylcyanoacrylate (PBCA). Polymeric NPs for delivery across the BBB should be biocompatible, nontoxic, nonthrombogenic and nonimmunogenic.[8] A polysorbate 80 coating on the surface of PBCAs adsorbs ApoB and E, which facilitates their uptake by brain capillary endothelial cells via receptor-mediated endocytosis and passage across the BBB. Polymeric NPs have been shown to be promising carriers for CNS drug delivery due to their potential both in encapsulating drugs, hence protecting them from excretion and metabolism, and in delivering active agents across the BBB without inflicting any damage to the barrier.[9] Polymeric NPs enable targeted drug delivery across the BBB with controlled release at the desired target. Another advantage of polymeric NPs is that they are biodegradable. Most polymer NPs are constructed from approved materials and are relatively inexpensive with ease of scale-up production. However, some polymer NPs, particularly those with a complex structure, are expensive.

Chitosan NPs Chitin, a polymer, is commercially extracted from shrimp shells and has several medical applications. Chitosan modification with a variety of ligands specific for cell surface receptors can increase recognition and uptake of nanocarriers into cells through receptor-mediated endocytosis.[10] Chitosan NPs are known for their ability to overcome biological barriers and facilitate the delivery of complex drugs such as insulin, vaccines, plasmid DNA and genes.

A nanomedicine for the delivery of drugs across the BBB has been prepared from chitosan NPs with an incorporated peptide. The surface was modified with polyethylene glycol (PEG) to enhance the plasma residence time by preventing NP capture by the reticuloendothelial system.[11] In this nanomedicine, monoclonal antibodies (mAbs) against the Tf receptor, which is highly expressed on the brain capillary endothelium, were conjugated to NPs via biotin–streptavidin bonds. The activation of Tf receptors by the NP–mAb complex induces transcytosis and thus delivers the loaded drug, a caspase-3 inhibitor, to the brain to inhibit ischemia-induced caspase-3 activity, and provide neuroprotection.

Dendrimers Dendrimers are a novel class of 3D nanoscale, core–shell polymers that can be precisely synthesized for a wide range of applications. Dendrimers are of great interest for drug delivery because of their ability to cross cell membranes, including the BBB. Important examples of dendrimers include poly(amidoamine) (PAMAM), PEGylated, peptide and pH-sensitive dendrimers.

Techniques employing dendrimers are potentially useful for the systemic administration of drugs targeting Alzheimer's disease.[12] A pH-sensitive dual-targeting drug carrier (G4-DOX-PEG-Tf-tamoxifen) has been synthesized with Tf conjugated on the exterior and tamoxifen in the interior of fourth-generation PAMAM dendrimers for enhancing the BBB transportation and improving drug accumulation in glioma cells.[13]

Some advantages of dendrimers include their branching structure and the control of surface functionality, making them excellent carriers for more than one single drug to the brain; they have a high loading capacity and low toxicity. Limitations of their use include the high cost of manufacture and the need for assessment of the long-term human health consequences of dendrimer exposure in vivo.

Nanogels Nanogels are colloidal gel carriers in which a cross-linked protonated polymer network binds oppositely charged drug molecules, encapsulating them into NPs with a core–shell structure. The nanogel network also provides a suitable template for chemical engineering, surface modification and carrier function. Nanogels are nontoxic and have a high loading capacity. Attempts are being made to develop novel drug formulations of nanogels with antiviral and antiproliferative nucleoside analogs in the active form of 5′-triphosphates. Notably, nanogels can improve the CNS penetration of nucleoside analogs that are otherwise restricted from passing through the BBB. An efficient intracellular release of nucleoside analogs has been demonstrated, which encourages applications of nanogel carriers for targeted drug delivery.[14] Nanogel-PEG carriers have been tested for brain delivery of activated nucleoside reverse transcriptase inhibitors for HIV-1 into monocyte-derived macrophages, which act as reservoirs for the virus.[15] Antiviral efficacy and a reduction of neurotoxicity due to mitochondrial DNA depletion were demonstrated. No recent CNS drug development effort has been reported with the use of this method; the reason for this lack of interest is not clear.

PLGA NPs PLGA is a US FDA-approved copolymer that is used in a host of therapeutic devices, owing to its biodegradability and biocompatibility. PLGA is synthesized by the random ring-opening copolymerization of two different monomers. PLGA NPs deliver molecules considered too large and complex to be transported by known vectors. PLGA is nontoxic, does not illicit an immune response, causes comprehensive transfection, crosses the BBB and supports sustained drug release.

A NP system consisting of loperamide and a PLGA–PEG–PLGA triblock with a polysorbate 80 coating has been developed for drug delivery across the BBB.[16] Loperamide, which normally does not cross the BBB but exerts antinociceptive effects after direct injection into the brain, could be delivered across the BBB by the PLGA complex using this method.