mercaptopurine and Hemolysis

A redox-responsive delivery system based on colloidal mesoporous silica (CMS) has been developed, in which 6-mercaptopurine (6-MP) was conjugated to vehicles by cleavable disulfide bonds. The oligosaccharide of hyaluronic acid (oHA) was modified on the surface of CMS by disulfide bonds as a targeting ligand and was able to increase the stability and biocompatibility of CMS under physiological conditions. In vitro release studies indicated that the cumulative release of 6-MP was less than 3% in the absence of glutathione (GSH), and reached nearly 80% within 2 h in the presence of 3 mM GSH. Confocal microscopy and fluorescence-activated cell sorter (FACS) methods were used to evaluate the cellular uptake performance of fluorescein isothiocyanate (FITC) labeled CMS, with and without oHA modification. The CMS-SS-oHA exhibited a higher cellular uptake performance via CD44 receptor-mediated endocytosis in HCT-116 (CD44 receptor-positive) cells than in NIH-3T3 (CD44 receptor-negative) cells. 6-MP loaded CMS-SS-oHA exhibited greater cytotoxicity against HCT-116 cells than NIH-3T3 cells due to the enhanced cell uptake behavior of CMS-SS-oHA. This study provides a novel strategy to covalently link bioactive drug and targeting ligand to the interiors and exteriors of mesoporous silica to construct a stimulus-responsive targeted drug delivery system.

Topics: Animals; Biocompatible Materials; Cattle; Cell Survival; Drug Carriers; Endocytosis; Glutathione; HCT116 Cells; Hemolysis; Humans; Hyaluronan Receptors; Hyaluronic Acid; Mercaptopurine; Mice; Nanoparticles; NIH 3T3 Cells; Oligosaccharides; Oxidation-Reduction; Porosity; Protein Binding; Serum Albumin, Bovine; Silicon Dioxide

In this paper, we describe the development of a redox-responsive delivery system based on 6-mercaptopurine (6-MP)-conjugated colloidal mesoporous silica (CMS) via disulfide bonds. mPEG was modified on the surface of silica to improve the dispersibility and biocompatiblity of CMS by reducing hemolysis and protein adsorption. The CMS carriers with different amounts of thiol groups were prepared to evaluate the impact of modified thiol on the drug loading efficiency. In vitro release studies demonstrated that the CMS nanoparticles exhibited highly redox-responsive drug release. The cumulative release of 6-MP was less than 3% in absence of GSH, and reached more than 70% within 2h in the presence of 3mM GSH. In addition, by comparing the cumulative release profiles of CMS-SS-MP@mPEG with their counterparts without the grafting of hydrophilic PEG, it was found that mPEG chains did not hinder the drug release due to the cleavable disulfide bonds and the improved dispersibility. Overall, this work provides a new strategy to connect thiol-containing/thiolated drugs and hydrophilic polymers to the interior and exterior of silica via disulfide bonds to obtain redox-responsive release and improve the dispersibility and biocompatibility of silica.

Topics: Animals; Disulfides; Drug Carriers; Drug Compounding; Drug Liberation; Erythrocytes; Hemolysis; Mercaptopurine; Microscopy, Electron, Scanning; Oxidation-Reduction; Particle Size; Polyethylene Glycols; Rabbits; Silicon Dioxide; Surface Properties

Antioxidant capacities of captopril (CAP), 6-mercaptopurine (6-MP) and 9-(beta-D-ribofuranosyl)-6-mercaptopurine (6-MPR) were investigated by interacting them with 2,2'-diphenyl-1-picrylhydrazyl (DPPH), galvinoxyl radical, and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cation radical (ABTS(+)(*)), and by protecting DNA and erythrocyte against 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH) induced oxidation. It was found that CAP possessed the highest ability to donate the hydrogen atom in -SH to DPPH and galvinoxyl, while 6-MPR had the strongest ability to reduce ABTS(+)(*). In the process of protecting DNA and erythrocytes against AAPH-induced oxidation, CAP can trap 0.5 and 1.3 radicals, 6-MP can trap 0.6 and 2.2, and 6-MPR can trap 1.0 and 3.0 radicals, respectively. CAP can also protect erythrocytes against hemin-induced hemolysis.

Topics: Antioxidants; Captopril; Erythrocytes; Free Radical Scavengers; Hemin; Hemolysis; Humans; Mercaptopurine; Molecular Structure; Sulfhydryl Compounds

Topics: Amino Acids; Animals; Antilymphocyte Serum; Antineoplastic Agents; Azathioprine; Carbon; Colloids; Cyclopentanes; Emulsions; Half-Life; Hemolysis; Horses; Immune Sera; Immunosuppressive Agents; Iodine Isotopes; Liver; Lung; Macrophages; Mercaptopurine; Mononuclear Phagocyte System; Phagocytosis; Rats; Sheep; Spleen; Triolein

Topics: Androgens; Anemia; Blood Cell Count; Blood Transfusion; Bone Marrow Examination; Cyclophosphamide; Hematocrit; Hemoglobins; Hemoglobinuria, Paroxysmal; Hemolysis; Humans; Iron; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Middle Aged; Plasma; Prednisone; Vincristine

Topics: Animals; Anti-Infective Agents; Antibody Formation; Antimetabolites; Chloroquine; Dactinomycin; Depression, Chemical; Hemolysin Proteins; Hemolysis; Immunosuppressive Agents; In Vitro Techniques; Mercaptopurine; Mice; Nucleosides; Penicillamine; Protein Biosynthesis; Quinolines; Spleen; Uracil

Topics: Animals; Antibody Formation; Hemolysis; Immune Sera; Mercaptopurine; Mice; Spleen; Thioguanine

Topics: Adrenal Cortex Hormones; Blood Transfusion; Erythrocytes; Hemolysis; Humans; Mercaptopurine; Splenectomy

Topics: Animals; Animals, Newborn; Antibody Formation; Antigen-Antibody Reactions; Bacteriophages; Fetus; Hemagglutination; Hemagglutination Tests; Hemolysis; Mercaptopurine; Mice; Pharmacology; Radiation; Radiation Effects; Research; Salmonella paratyphi A; Sheep; Sheep, Domestic; Spleen; Swine