Blood brain barrier delivery

Song, B.W., et al. 2002. Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood-brain barrier delivery vector. J Pharmacol Exp Ther 301 605. 

Kurihara A, Deguchi Y, Pardridge WM. Epidermal growth factor radiopharmaceuticals In chelation, conjugation to a blood-brain barrier delivery vector via a biotin-polyethylene linker, pharmacokinetics, and in vivo imaging of experimental brain tumors. Bio-conjug Chem 1999 10 502-511. 

Decreased cerebral blood flow, resulting from acute arterial occlusion, reduces oxygen and glucose delivery to brain tissue with subsequent lactic acid production, blood-brain barrier breakdown, inflammation, sodium and calcium pump dysfunction, glutamate release, intracellular calcium influx, free-radical generation, and finally membrane and nucleic acid breakdown and cell death. The degree of cerebral blood flow reduction following arterial occlusion is not uniform. Tissue at the... 

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... 

N Bodor, E Shek, T Higuchi. Delivery of a quaternary pyridinium salt across the blood-brain barrier by its dihydropyridine derivative. Science 190 155-156, 1975. 

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. 

Zhang, Y., and Pardridge, W.M. (2005) Delivery of b-Galactosidase to mouse brain via the blood-brain barrier transferrin receptor./. Pharmacol. Exp. Therapeut. 313, 1075-1081. 

Alyautdin RN, Petrov VE, Langer K, Berthold A, Kharkevich DA, Kreuter J (1997) Delivery of loperamide across the blood-brain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles. Pharm Res 14 325-328. 

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],... 

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

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

Using the knowledge that rabies virus can spread into the brain neurons, scientists mimic its delivery system. A short, 29 amino acid peptide chain is derived from the rabies virus glycoprotein (RVG). The RVG binds to the acetylcholine receptor on the neurons and the endothelium cells of the blood-brain barrier. Through this interaction, transvascular delivery is enabled. 

Figure 2.6. Strategies for drug delivery across the blood-brain barrier (BBB). The physical, pharmacological and physiological approaches are discussed in the text. Present experimental attempts at viral gene delivery would also be classified as invasive because of the intracerebral administration of the vector.

Table 2.1. Brain concentration, blood-brain barrier PS product, and plasma AUC (0-60 min) of brain delivery vectors after i.v. bolus injection.

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. 

In an effort to overcome the lack of solubility, poor penetration across the blood-brain barrier and decreased delivery of conventional systemic agents by a compromised intratumoral blood supply, several studies have evaluated various combinations of BCNU alone or with other agents delivered intraarterally. Unfortunately, response rates and median survival times observed in patients treated with intraarterial chemotherapy have not been significantly different than those seen in patients treated with standard intravenous nitrosurea-containing regimens, while increased rates of toxicity such as leukoen-cephalopathy, retinal injury, edema, myelosuppression, sepsis, and thrombotic complications have been noted (40-46). 

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. 

Since propranolol crosses the placenta and enters the fetal circulation, fetal cardiac responses to the stresses of labor and delivery will be blocked. Additionally, propranolol crosses the blood-brain barrier and is associated with mood changes and depression. School difficulties are commonly associated with its use in children. Propranolol may also cause hypoglycemia in infants. 

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]. 

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