Cystein delivery systems

Williamson, J.M., Boettcher, B. and Meister, A. (1982). Intracellular cysteine delivery system that protects against toxicity by promoting glutathione synthesis. Proc. Natl Acad. Sci. USA 79, 6246-6249. 

L ADP -H Pi FIGURE 36.39 L-2-Oxothiazolidine-4-carboxy-iate an intraceiiular cysteine delivery system. ... 

B Site-specific delivery 568 cysteine delivery system 579... 

Cyclic. S -Mannich bases are rarely encountered in medicinal chemistry. The (R)-thiazolidine-4-carboxylic acids (11.113, Fig. 11.15), which are used as derivatives and chemical delivery systems for L-cysteine (11.114), provide an excellent example of S-Mannich bases. These compounds underwent activation by two distinct mechanisms, directly by nonenzymatic hydrolysis to cysteine and the original aldehyde (Fig. 11.15, Pathway a), and oxidatively (Pathway b) [138]. The latter route involved first oxidation by mitochondrial enzymes to the (f )-4,5-dihydrothiazole-4-carboxylic acid (11.115), followed by (presumably nonenzymatic) hydrolysis to /V-acylcysleine, and, finally, cytosolic hydrolysis to cysteine (11.114). 

Bernkop-Schniirch, A., and S. Thaler. 2000. Polycarbophil-cysteine conjugates as platforms for oral (poly)peptide delivery systems. J Pharm Sci 89 901. 

In order to improve the mucosal absorption of poorly absorbed drugs such as peptides and proteins, newer delivery systems with higher mucoadhesive and permeation-enhancing polymers have been developed. While the first generation of mucoadhesive polymers provided adhesion to the mucus gel layer via secondary bonds, the new generation of mucoadhesive polymers is able to form covalent bonds with the mucous layer. The immobilization of thiol groups on mucoadhesive polymers results in thiolated polymers or thiomers that can form disulfide bonds with cysteine-rich subdomains of mucus glycoproteins [84,85]. 

Bernkop-Schnurch A, Marschtitz MK (1997) Development and in vivo evaluation of systems to protect peptide drugs from aminopeptidase N. Pharm Res 14 181-185 Bernkop-Schnurch A, Paikl C, Valenta C (1997) Novel bioadhesive chitosan-EDTA conjugate protects leucine enkephalin from degradation by aminopeptidase N. Pharm Res 14 917-922 Bernkop-Schnurch A, Thaler S (2000) Polycarbophil-cysteine conjugates as platforms for oral (poly)peptide delivery systems. J Pharm Sci 89 901-909 Bernkop-Schnurch A, Walker G, Zarti H (2001) Thiolation of polycarbophil enhances its inhibition of intestinal brush border membrane bound aminopeptidase N. J Pharm Sci 90 1907-1914... 

Bernkop-Schnurch A, Thaler SC. Polycarbophil-cysteine conjugates as platforms for oral polypeptide delivery systems. / Pharm Sci 2000 89(7h 901-909. 

As for a formulation using another administration route, Leitner et al. developed a nasal delivery system of hGH [194] based on the thiomer polycarbophil-cysteine (PCP-Cys) in combination with the permeation mediator glutathione (GSH). Microparticles were prepared by dissolving PCP-Cys/GSH/hGH (7.5 1 1.5), PCP/ hGH (8.5 1.5), and mannitol/hGH (8.5 1.5) in demineralized water, followed by lyophilization and micronization. PCP-Cys/GSH/hGH and PCP/hGH microparticles showed a comparable size distribution (80% in the range of 4.8 to 23 pm) and swelled to almost four fold size in phosphate-buffered saline. Both formulations exhibited almost identical sustained drug release prohles. The intranasal administration of the PCP-Cys/GSH/hGH microparticulate formulation resulted in a relative bioavailability of 8.11%, which represents a three fold and a 3.3-fold improvement compared with that of PCP/hGH microparticles and mannitol/hGH powder, respectively. The nasal microparticulate formulation based on PCP-Cys/ GSH/hGH might represent a promising novel tool for the systemic delivery of hGH. 

Poly(acrylic acid)-cysteine and chitosan-4-thiobulylamidine were evaluated as anionic and cationic polymers for the preparation of a DDS for riboflavin-S -monophosphate sodium salt dihydrate as a model drug. The particles had a mean diameter of 336.5 16.5 and 396.3 17.0 nm and a zeta potential of - 20.0 1.0 and -I- 27.2 0.5 mV, respectively. It was found that glutathione in combination with thiomers has a significant influence for increasing permeation, and that thiolated particles of both anionic and cationic polymers had improved mucoadhesive and controlled release properties. Therefore, they can be potentially applied as gastroretentive delivery systems. ... 

Meister A, Anderson ME, Hwang O. Intracellular cysteine and glutathione delivery systems. J Am Coll Nutr 1986 5 137-151. 

Mortera, R., Vivero-Escoto, J., Slowing, IJ., Garrone, E., Onida, B., and Lin, V.S.Y. (2009) Cell-induced intracellular controlled release of membrane impermeable cysteine from a mesoporous silica nanoparticle-based drug delivery system. Chem. Commun., (22),... 

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