Blood-brain barrier drug delivery

Wu, D., et al. 2002. Pharmacokinetics and brain uptake of biotinylated basic fibroblast growth factor conjugated to a blood-brain barrier drug delivery system. J Drug Target 10 239. 

Pardridge WM, Wu D, Sakane T. Combined use of carboxyl-directed protein pegylation and vector-mediated blood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenous administration. Pharm Res 1998 15 576-82. 

Systemic administration of therapeutic substances for CNS action Intravenous injection for targeted action in the CNS Direct administration of therapeutic substances to the CNS Introduction into cerebrospinal fluid pathways intraventricular, subarachnoid pathways Introduction into the cerebral arterial circulation Introduction into the brain substance Direct positive pressure infusion Drug delivery by manipulation of the blood-brain barrier Drug delivery using novel formulations Conjugates Gels... 

Introduction Drug Delivery through the Blood-Brain Barrier Drug Delivery through the Cerebrospinal Fluid Acknowledgments References... 

Pardridge WM, 2006. Molecular Trojan horses for blood-brain barrier drug delivery. Curr. Opin. Pharm. 6(5) 494. 

T. S. Olson, P. M. Friden, Delivery of Therapeutic Proteins across the Blood-Brain Barrier , Drug News Perspect. 1994, 7, 224-227. 

Lockman, P.R., et al. 2002. Nanoparticle technology for drug delivery across the blood-brain barrier. Drug Dev Ind Pharm 28 1. 

Another very important site for drug delivery is the central nervous system (CNS). The blood-brain barrier presents a formidable barrier to the effective delivery of most agents to the brain. Interesting work is now advancing in such areas as direct convective delivery of macromolecules (and presumably in the future macromolecular drug carriers) to the spinal cord [238] and even to peripheral nerves [239]. For the interested reader, the delivery of therapeutic molecules into the CNS has also been recently comprehensively reviewed... 

Pardridge, W. M., Brain drug delivery and blood-brain barrier transport, Drug Deliv., 1996, 3, 99-115. 

Banks WA. Physiology and pathology of the blood-brain barrier implications for microbial pathogenesis, drug delivery and neurodegenerative disorders. J Neu-rovirol 1999 5 538-555. 

The density of cerebral capillaries, especially in the cortical grey matter, is very high with mean distances of 40 /xm. The capillary network has a total length of 600-650 km, the mean velocity of the blood flow is below 0.1 cm/s, and the luminal surface extends to 15-30 m2. Thus the blood-brain barrier represents an important surface for potential drug delivery besides gut (30CM100 m2), lung (70-120 m2), or skin (1.8 m2) [24-26, 33-37],... 

One possibility to enhance, in a controlled manner, entry of drugs into the CNS would be to alter P-glycoprotein function at the blood-brain barrier. Such an enhancement could result from (1) direct modification of export pump function by inhibitors and intracellular signals or (2) bypassing the export pump by delivery systems not being recognized as substrates (e.g., nanoparticles or vector-coupled liposomes, which are taken up by endocytotic mechanisms) [58-65],... 

Exhibit 5.4 Drug Delivery Across the Blood-Brain Barrier... 

As an alternative to targeting brain tumours which express the TfR, the transferrin approach can be used for the delivery of fusion proteins which bind to pharmacological receptors inside the central nervous system. An example of this is the construct consisting of nerve growth factor (NGF) and transferrin described in Section 11.8.2.3. The transferrin moiety in this type of construct will enable it to enter the brain, upon which the drug moiety will act by binding to its receptor. This approach seems especially suitable for compounds that cannot pass the blood-brain barrier, such as peptides and other hydrophilic substances. 

Cecchelli, R., Dehouck, B., Descamps, L., Fenart, L., Buee-Scherrer, V., Duhem, C., Lundquist, S., Rentfel, M., Torpier, G. and Dehouck, M.P. (1999) In vitro model for evaluating drug transport across the blood-brain barrier. Advanced Drug Delivery Reviews, 36, 165-178. 

The ocular endotamponades of the future could be a combination of tampo-nading and drug delivery device. Vitrectomy removes the natural vitreous after it has become opaque, inflamed, or unable to keep the retina in place. In many cases, the necessity to remove it is the result of retinal disorders, which are still existent after vitrectomy [50]. In equivalence to the blood-brain barrier, there is also a blood-retina barrier, with the effect that it is difficult to treat retinal disorders systemically. Therefore, the delivery of appropriate drugs via the vitreous cavity would open new treatment options. 

Appropriate microbubble/sound combinations can provide novel therapeutic tools. Blood clots can, for example, be broken up by a proper targeted bubble/ focused sound wave association [60]. Such combinations may also enable non-invasive brain surgery, [61] as well as targeted drug delivery via transient acoustically induced opening of the blood-brain barrier [62]. 

---