Nanobiotechnology-Based Strategies for Crossing the Blood–Brain Barrier

Kewal K Jain


Nanomedicine. 2012;7(8):1225-1233. 

In This Article

Abstract and Introduction


The blood–brain barrier (BBB) is meant to protect the brain from noxious agents; however, it also significantly hinders the delivery of therapeutics to the brain. Several strategies have been employed to deliver drugs across this barrier and some of these may do structural damage to the BBB by forcibly opening it to allow the uncontrolled passage of drugs. The ideal method for transporting drugs across the BBB should be controlled and should not damage the barrier. Among the various approaches that are available, nanobiotechnology-based delivery methods provide the best prospects for achieving this ideal. This review describes various nanoparticle (NP)-based methods used for drug delivery to the brain and the known underlying mechanisms. Some strategies require multifunctional NPs combining controlled passage across the BBB with targeted delivery of the therapeutic cargo to the intended site of action in the brain. An important application of nanobiotechnology is to facilitate the delivery of drugs and biological therapeutics for brain tumors across the BBB. Although there are currently some limitations and concerns for the potential neurotoxicity of NPs, the future prospects for NP-based therapeutic delivery to the brain are excellent.


For over a century it has been recognized that the entry of certain substances into the brain is restricted. The previous theory that the blood–brain barrier (BBB) is a passive impermeable barrier that segregates blood and brain interstitial fluid has given way to the concept that the BBB is a dynamic conduit for transport between the blood and the brain for nutrients, peptides proteins and immune cells. The classically accepted function of the BBB is to protect the brain against the entry of noxious agents. Recent cell and molecular biology studies have provided new insights into the function of the BBB. Several carrier or transport systems, enzymes and receptors that control the penetration of molecules in the BBB endothelium have been identified.[1] Brain microvascular endothelial cells, which constitute the anatomical basis of BBB, form tight junctions due to a lack of fenestration and reduce the diffusion of molecules across the vessels. Figure 1 shows a simplified scheme of the passage of substances across the BBB.

Figure 1.

Forms of passage of substances across the blood–brain barrier.
(A) Passive diffusion: fat-soluble substances dissolve in the cell membrane and cross the barrier (e.g., alcohol, nicotine and caffeine). Water-soluble substances such as penicillin have difficulty in getting through. (B) Active transport: substances that the brain needs such as glucose and amino acids are carried across by special transport proteins. (C) Receptor-mediated transport: molecules link up to receptors on the surface of the brain and are escorted through (e.g., insulin).

Compared with the vasculature of many other organs, the normal BBB severely restricts the passage of most drugs from plasma to the extracellular space, with more than an 8-log difference in the entry rate of small, lipid-soluble molecules compared with large proteins. Knowledge of BBB characteristics, therefore, is important for understanding the mechanisms of drug delivery to the CNS. In addition to the unidirectional and bidirectional transport of small molecules, other macromolecules are able to enter the brain tissue from the blood by a receptor-mediated process. An example of this is the transport of transferrin (Tf) across the BBB. Brain cells require a constant supply of iron to maintain their function and the brain may substitute its iron through transcytosis of iron-loaded Tf across the brain microvasculature. Other biologically active proteins, such as insulin and immunoglobulin G, are actively transcytosed through BBB endothelial cells. The presence of receptors involved in the transcytosis of ligands from the blood to the brain offers opportunities for developing new approaches to the delivery of therapeutic compounds across the BBB.

Another important consideration is an increase of permeability of the BBB in some disorders of the brain as a part of the pathogenesis, for example, traumatic brain injury and malignant brain tumors. This is a widely variable phenomenon and cannot be relied on for the delivery of therapeutics through the BBB.

Various strategies that have been used for manipulating the BBB for drug delivery to the brain include osmotic and chemical opening of the BBB as well as the use of transport/carriers. Bypassing the BBB by an alternative route of delivery such as transnasal may be considered. If targeted delivery to brain parenchyma is not the goal, alternative methods for crossing the blood–cerebrospinal fluid barrier may be considered or drugs may be introduced directly in the cerebrospinal fluid pathways by lumbar puncture. Invasive procedures for bypassing the BBB include direct introduction in the brain by surgical procedures. The drawbacks of strategies to forcibly open the BBB include causing damage to the barrier as well as uncontrolled passage of drugs into the brain. Several potentially effective therapeutic agents for neurological disorders are available but their use is limited because of insufficient delivery across the BBB. Advances in the understanding of the cell biology of the BBB have opened new avenues and possibilities for crossing this barrier.

The upper limit of pore size in the BBB that enables passive flow of molecules across it is usually <1 nm; however, particles that have a diameter of several nanometers can also cross the BBB by carrier-mediated transport. Although very small nanoparticles (NPs) may just pass through the BBB, this uncontrolled passage into the brain may not be desirable and strategies are being developed for controlled passage as well as targeted drug delivery to the brain.