Current Nanoscience, 2009, 5, 15-25 15 1573-4137/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. Promises of Nanotechnology for Drug Delivery to Brain in Neurodegenerative Diseases Sara Baratchi 1 , Rupinder Kaur Kanwar 1 , Khashayar Khoshmanesh 2 , Punj Vasu 3 , Chauhan Ashok 4 , Matta Hittu 3 , Andrew Parratt 1 , Subramanian Krishnakumar 5 , Xueying Sun 6 , Sanjeeb K. Sahoo 7 and Jagat Rakesh Kanwar 1,* 1 Institute for Technology Research and Innovation, Institute of Biotechnology, Deakin University, Geelong, VIC 3217, Australia 2 School of Engineering and IT, Deakin University, Geelong, VIC 3217, Australia 3 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania-15213, USA 4 Department of Pathology, University of South Carolina School of Medicine, Columbia, SC 29209, USA 5 Department of Ocular Pathology Vision, Research Foundation, Tamil Nadu, India 6 The Hepatosplenic Surgery Center, The First Clinical Medical School of Herbin Medical University, 150001, China 7 Institute of Life Sciences, Orissa, India Abstract: Brain is a delicate organ, isolated from general circulation and characterized by the presence of relatively impermeable endo- thelial cells with tight junctions, enzymatic activity and the presence of active efflux transporter mechanisms. These formidable obstacles often block drug delivery to the brain across the blood-brain barrier (BBB). Although several promising molecules have the potential in the in vitro settings but lack of in vivo response is probably because the molecule cannot reach the brain in a sufficient concentration. Drug delivery across the BBB is a major limitation in the treatment of central nervous system (CNS) disorders and CNS infections. This review deals with the role of nanobiotechnology in CNS drug delivery, in which three categories of carbon nanotubes, nanowires and nanoparticles (NPs) are explained. The small size of the NPs makes them an ideal choice to penetrate the BBB. Several mechanisms are involved in this process and various strategies are used. There are some concerns about the safety of NP entry in the brain that need to be resolved before human use. Although there is no approved nanotechnology-based CNS drug available the future for such neuro- nanobiotechnology based delivery system developments is promising. Key Words: Blood-brain barrier, nanotechnology, drug delivery, inflammatory diseases, neurodegenerative diseases, multiple sclerosis. 1. INTRODUCTION The nervous system traditionally was considered as an immu- nologically privileged organ. This concept originally was derived from observations that tissue graft implanted in brain was not re- jected officially. The BBB controls the regulation of fluids from brain to serum and vice versa through a number of mechanisms including diffusion, specific carrier system, vesicular transport and cytoplasmic channels. By these means serum and glia cells are tightly protected from blood and their immediate environment. However, the barrier imposes lots of limitations in the process of drug delivery toward the brain. The most challenging part of CNS treatment is drug delivery through the BBB rather than designing a new treatment. Most of the drugs that have been designed for treatment of brain disorders such as antibiotics, anticancer agents do not pass the BBB [1]. The BBB is composed of continuous layers of capillary endo- thelial cells, which are sheeted by astrocytes end feet through the basement membrane. This barrier is different from the peripheral capillaries because it is influenced by astrocytes and neurons. So the brain micro vasculature is formed by triad of capillary pericytes, perivascular astrocytes foot processes and brain capillary endothe- lial cells Fig. (1A), which cause a restriction to drug entry into brain through different mechanisms such as physical endothelial barrier, an enzymatic BBB and an efflux barrier [2]. Endothelial tight junc- tion and minimal endothelial pinocytosis are physical barriers im- posed to drug delivery. Different cell types of BBB express a vari- ety of ecto-enzymes, which inactivate many drugs although these *Address correspondence to this author at the Institute for Technology Research and Innovation, Deakin University, Institute of Biotechnology (BioDeakin), Geelong Technology Precinct (GTP), Pigdons Road, Waurn Ponds, Geelong, Victoria 3217, Australia; Tel: (0061 3 52271148); Fax: (0061 3 52272539); E-mail: jagat.kanwar@deakin.edu.au enzymes may have an activation role like in case of L-DOPA [2]. If a drug is a substrate of one of the active efflux transporters, it could go influx again to the blood. To overcome the efflux barrier and increase drug uptake into brain, co-drug systems, which are inhibi- tors of BBB active efflux transporters (AET) system, have been developed [3]. To cross the BBB in active forms drugs should have different characters in their chemical structure such as having mo- lecular weight of less than 400Da, being lipid soluble or not being substrate of active efflux. Having all these characters together make it difficult to design drug for the CNS disorders [4,5]. In the Com- prehensive Medicinal Chemistry (CMC) database, more than thou- sands of drugs have been reported while only a small percentage of them are active in the brain [3, 6]. Common aims for drug delivery to CNS is passing the BBB, administration of active substances with short in vivo half lives and using the micro devices to operate drug release from several days to one year. Basically three strategies have been described for trans- ferring drug through the BBB, which are as follows: neurosurgical based strategy, chemical based strategy and biology based strategy. Because of the difficulties in direct access to the CNS and BBB, noninvasive drug delivery has a great value. Nano technology is eliminating the application of molecular biology in diagnosis of CNS disorders through the application of nanochips and this new emerging science seems to revolutionize different aspects of drug delivery. In this review, the recent advances in nanomaterial tech- nology for the CNS drug delivery have been summarized. The BBB performs many functions. Firstly, maintaining inter- nal environment of the brain, i.e. maintaining brain interstitial fluid (ISF) and the cerebrospinal fluid (CSF) composition within ex- tremely fine limits, far more than the somatic extracellular fluid, so that the neurons can perform their complex integrative functions [6, 7]. This integrative neural function of the CNS relies almost solely on accurate synaptic transmission and spatial and temporal summa-