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Properties and Preparation of GSH-sensitive Polymeric Prodrug: 6-Mercaptopurine-Carboxymethyl Chitosan

Author: RaoYan
Tutor: ZhengHua
School: Wuhan University of Technology
Course: Pharmacy
Keywords: Mercapto purine - carboxymethyl chitosan Polymer prodrug Glutathione sensitivity Release properties Prodrug nanoparticles
CLC: TQ463.2
Type: Master's thesis
Year: 2010
Downloads: 145
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Abstract

Amphipathic polymer having a prodrug improve drug targeting and drug bioavailability and to reduce the side effects of drugs, etc., due to the smaller size of the physiological environment to be able to self-assemble to form a prodrug nanoparticles can avoid network like endothelial system (RES) macrophages, it is of concern in terms of the treatment of cancer. Wherein the concentration of glutathione disulfide bond in vivo specific response, and the concentration of glutathione in the cells (approximately 10 mM), higher than the glutathione (GSH) concentration in the blood (about 2 - 10μM), four times the concentration of glutathione in cancer cells is approximately normal cells, disulfide bond-based pharmaceutical carrier can be in response to the variation of the concentration of intracellular glutathione and thereby release the drug. Will be based the disulfide polymer prodrug, as well as self-assembly of the prodrug nanoparticles used in cancer treatment is potential to use this feature. In order to prepare the response to the stimulation of intracellular glutathione concentration of polymer prodrug, this study vary based bi-functional cross-linker SPDP connection carboxymethyl chitosan (carboxymethyl chitosan, CMC) and mercaptopurine (6-mercaptopurine, 6-MP) preparing polymeric prodrugs mercaptopurine - carboxymethyl chitosan (6-mercaptopurine-carboxymethyl chitosan, 6-MP-CMC). Such prodrug GSH-sensitive polymer to maintain its structure under low concentrations of GSH (2-10μM), disulfide disconnected from the high concentration of GSH concentrations (2 mM and 10 mM) so that the drug is released. And prodrugs of the amphiphilic polymer in phosphate buffer (pH 7.4) through the self-aggregation to form nanoparticles, the nanoparticles in the low concentration of GSH concentration (2-10μM) to maintain its structure, while in high concentrations of GSH concentration (2 mM and 10 mM) under nanostructures collapsed. The main contents and conclusions are as follows: (1) raw materials, synthetic carboxymethyl chitosan chitosan. CMC and N-succinimidyl-3 - (2 - pyridyldithio) propionate (N-succinimidyl-3-(2-pyridyldithio) propionate, SPDP) to the connecting arm of the PDP-CMC, prepared by the reaction, then a PDP- CMC drug 6-MP by mercapto - disulfide exchange reaction of mercaptopurine - carboxymethyl chitosan amphiphilic polymer prodrug; synthesized by controlling the ratio of the feedstock material, the product of three different mercaptopurine content. The structure of the intermediates and target compounds were characterized by IR and NMR spectroscopy; elemental analyzer and UV spectrophotometry PDP and 6-MP, the degree of substitution. Experimental results show that the successful synthesis of the the compound structural characterization confirmatory mercaptopurine - carboxymethyl chitosan; the PDP group of the highest degree of substitution of 0.39; The highest the mercaptopurine content of 19.0%. (2) 6-MP-CMC polymer ScS prodrug vitro release properties. The analog blood the GSH concentration conditions (2μM) and intracellular environment GSH concentrations (2 mM and 10 mM) of the release medium in vitro release behavior of the polymer prodrug dialysis method, followed by analog cytoplasm and endocytosis in vivo different pH environment of the release medium (GSH concentration of 10 mM) in vitro release behavior, performance and compare different the mercaptopurine content of 6-MP-CMC polymer prodrug in vitro release. Experimental results show that 6-MP-CMC in the presence of stable the glutathione concentration under the conditions simulated blood environment, while in the concentration of glutathione analog cellular environment conditions can quickly release the drug. And with the increase in the concentration of glutathione, the rate of drug release rate will be increased; 6-MP-CMC not only in the cytoplasm under conditions of pH 7.4 to maintain a fast release rate and release, and endocytosis body pH 5.0 under the conditions of the rapid release of the drug, the total cumulative release rate is significantly improved; Further, as mercaptopurine, 6-MP-CMC of increasing the content of the polymeric prodrug glutathione more easily broken chain, the cumulative release rate of the drug increases, the more significant this phenomenon in the endosome pH 5.0 analog environment. (3) The probe ultrasound prepared mercaptopurine - carboxymethyl chitosan prodrug nanoparticles. Transmission electron microscopy to examine the shape of nanoparticles; dynamic light scattering method for the determination of the particle size of the nanoparticles; investigated by nanoparticles of different glutathione concentrations, particle size and distribution index nanoparticles glutathione peptide sensitivity. The experimental results show that, by TEM observation, under normal physiological conditions ,6-MP-CMC Movement a complete monodisperse spherical structure, an average particle diameter of the nanoparticles is between 134.1-210.8 nm, and with the increase of the content of mercaptopurine decreases. In addition, the nanoparticles having glutathione sensitivity remained stable the glutathione concentration under the conditions of the simulated blood environment exist structural disintegration in analog intracellular glutathione concentration conditions; with with the increase of the concentration of glutathione, such nanoparticles disintegration phenomenon is even more obvious. Therefore, mercaptopurine - carboxymethyl chitosan polymeric prodrug has a higher concentration of glutathione can respond to intracellular stimuli and can be self-assembled prodrug nanoparticle characteristics expected as a glutathione-sensitive nano prodrug , by the introduction of the surface of the targeted group for targeted cancer therapy.

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