Brain delivery

Tadayoni, B.M., Friden, P.M., Walus, L.R., and Musso, G.F. (1993) Synthesis in vitro kinetics, and in vivo studies on protein conjugates of AZT Evaluation as a transport system to increase brain delivery. Bioconjugate Chem. 4, 139-145. 

Vannucci, S. J., Maher, F. and Simpson, I. A. Glucose transporter proteins in brain delivery of glucose to neurons and glia. Gfia 21 2-21,1997. 

Kreuter J (2001) Nanoparticulate systems for brain delivery of drugs. Adv Drug Debv Rev 47 65-81... 

A further condition for good brain delivery, one that is particularly relevant in the present context, is that e) direct hydrolysis of the dihydropyridine pro-prodrug (Fig. 8.14, Reaction c) does not compete with oxidation, especially in the periphery, since this would decrease the amount of CDS available for brain delivery. In fact, the pyridinium metabolite is more susceptible than the dihydropyridine pro-prodrug to alkaline and enzymatic hydrolysis, since the carbonyl C-atom of the pyridinium compound (B, Fig. 8.15) is much more electrophilic than that of the dihydropyridine (A, Fig. 8.15). 

Brain delivery of steroid hormones is also of interest to medicinal chemists. Again, most data available on CDSs of steroids pertain to rates of oxidation of the dihydropyridine carrier, to blood and brain concentrations, and to pharmacological activities. The latter can then be taken as proof of efficient cerebral hydrolysis of the pyridinium metabolite. Thus, the dihydrotrigonelline carrier allowed good brain delivery of estradiol and some other estrogens [181][182],... 

E. Pop, E. Shek, T. Murakami, N. S. Bodor, Improved Anticonvulsant Activity of Phen-ytoin by a Redox Brain Delivery System. I Synthesis and Some Properties of the Dihydropyridine Derivatives , J. Pharm. Sci. 1989, 78, 609 - 616. 

A. Namane, C. Gouyette, M. P. Fillion, G. Fillion, T. Huynh-Dinh, Improved Brain Delivery of AZT Using a Glycosyl Phosphotriester Prodrug ,./. Med. Chem. 1992, 35, 3039-3044. 

Mishra V, Mahor S, Rawat A, Gupta PN, Dubey P, Khatri K, Vyas SP (2006) Targeted brain delivery of AZT via transferrin anchored pegylated albumin nanoparticles. J Drug Target 14 45-53 Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Shringarpure R, Hideshima T, Akiyama M, Chauhan D, Munshi N, Gu X, Bailey C, Joseph M, Libermann TA, Richon VM, Marks PA,... 

While X in increases with lipophilicity, AUC decreases due to higher uptake across all cell membranes including those of peripheral tissues. Therefore limits are imposed on the gain in brain delivery by the lipidization strategy. In fact, for azidothymidine lipidization with the lipophilic adamantane moiety, CSF concentrations decreased by a factor of 10 as a result of a decrease in AUC [54]. 

Initial studies of brain delivery based on the chimeric peptide strategy used the absorptive-mediated uptake of cationized albumin which was chemically coupled to the opioid peptide P-endorphin [80] or its metabohcaUy stabilized analogue [D-Ala ]P-endorphin. Tracer experiments in which the chimeric peptide was labelled in the endorphin moiety provided evidence of internalization by isolated brain capillaries and transport into brain tissue in vivo [81]. 

Brain uptake data for some vectors are compared in Table 2.1. Quantitative comparisons within the same species are possible for the rat with vectors derived from the anti-TfR monoclonal antibody 0X26 and from cationized human serum albumin. To put the efficiency of brain delivery into perspective, the comparison to a classical neuroactive drug may be informative. In the rat, brain concentrations of morphine following systemic administration never exceed 0.08% of injected dose per gram [%ID g ] [82]. In contrast, 0X26 easily reaches concentrations in rat brain that are three to four times higher. Vectors based on cationized hu-... 

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.

Figure 2.9. Differential pharmacological effect elicited by vector-mediated delivery of a VIP analogue. The organ blood flow in brain and salivary gland was measured in conscious rats after i.v. administration of vehicle (saline), the brain delivery vector OX26-SA, the VIP peptide alone, or the chimeric peptide. While cerebral blood flow increased in the chimeric peptide group by 60% compared to the saline control, the increase in salivary gland blood flow seen with the peptide alone was abolished by coupling to the vector. The VIP analogue was biotinylated with a non-cleavable 14-atom spacer (biotin-XX) for coupling to the vector. Data from reference [95].

Brain delivery of the anticancer drug daunomycin provides an example of the in vivo application of OX26-inununoliposomes [111]. Different formulations of [ H]-daunomycin were i.v. administered to rats either as the free drug or encapsulated in conventional liposomes, sterically-stabilized liposomes, or PEG-conjugated immunohposomes (Table 2.3). Plasma samples were taken at defined time points and after 1 h the animal was killed and drug concentrations in brain tissue were determined. 

Al-Ghananeem, A. M., A. A. Traboulsi, L. W. Dittert, and A. A. Hussain. 2002. Targeted brain delivery of 17p-estradiol via nasally administered water soluble prodrAg S PharmSciTecllSiE5. 

SPECIAL CONSIDERATIONS IN NASAL DELIVERY 19.6.1 Nose-Brain Delivery... 

Dufes, C., et al. 2003. Brain delivery of vasoactive intestinal peptide (VIP) following nasal administration to rats. Int J Pharm 255 87. 

Kang, Y.S., and W.M. Pardridge. 1994. Brain delivery of biotin bound to a conjugate of neutral avidin and cationized human albumin. Pharm Res 11 1257. 

Mora, M., et al. 2002. Design and characterization of liposomes containing long-chain N-acylPEs for brain delivery Penetration of liposomes incorporating GM1 into the rat brain. Pharm Res 19 1430. 

As of today, there are no commercially available pharmaceutical products of this technology. The pharmaceutical industry however, is involved in developing nanoparticle-based delivery systems. Use of nanospheres to modify the blood-brain barrier (BBB)—limiting characteristics of the drug enables targeted brain delivery via BBB transporters and provides a sustained release in brain tissue and vaccine delivery systems to deliver therapeutic protein antigens into the potent immune cells are under investigation.103... 

Mishra, V.,Mahor, S.,Rawat, A., Gupta, P. N., Dubey, R, Khatri, K., and Vyas, S. P. (2006), Targeted brain delivery of AZT via transferrin anchored pegylated albumin nanoparticles, J. Drug Target., 14(1), 45-53. 

TABLE 4 Nose-to-Brain Delivery of Agents in Different Species... 

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