Challenges in drug delivery to the brain: nature is against us.

Nanomedicine is a fast evolving field involving nanoparticles or nanostructures for medical applications. Especially in the underdeveloped field of drug delivery to the brain, there are high expectations for the ability of multifunctional nanoparticles (NPs) to cross the blood-brain barrier (BBB). In the present review the challenges nanoparticles face after injection into the body will be summarized. There is a broad range of biological, chemical and physical hurdles for NPs to reach the brain. Perhaps the most challenging task will be to design and develop nanoparticles that specifically target that right subset of diseased neurons without affecting other healthy neurons. This is of immense importance especially in the case of targeting toxic drugs to highly invasive brain tumors. Already, without the additional obstacle in the form of the BBB, targeting nanoparticles against a small subset of cells in the body is a big challenge. While the permeability of the blood vessels in other tissues is comparably higher the brain microvasculature is highly restrictive. The reason for this is that uncontrolled invasion of nano-objects or molecules may lead to a pathological change in neurons responsible for memory, personality, senses and movement. With nanomedicine we have for the first time the possibility to design systems to meet requirements such as reduced side-effects, controlled release, targeted delivery as well as higher drug bioavailability at the target site. If the brain delivery of drugs for neurodegenerative disease or cerebral cancer is to be successful, a far better understanding of the complex processes taking place on the nanoparticles surface, as well as in cell-NP contact with the different transit organs and tissues, will be required.