6-Mercaptopurine (6-MP) Entrapped Stealth Liposomes for Improvement of Leukemic Treatment without Hepatotoxicity and Nephrotoxicity

Umrethia, Manish; Ghosh, Pradip; Majithya, Rita; Murthy, R. S. R.

doi:10.1080/07357900701224862

Cited by 18 publications

(10 citation statements)

References 28 publications

(27 reference statements)

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“…Captopril, acetylcysteine, penicillamine, and mercaptopurine are all well established drugs that are used to treat a variety of diseases ranging from hypertension to childhood leukemia 39. Typical doses of these drugs are in the range of mg of drug per kg body weight, and concentrations in plasma are typically in the low micromolar range prior to excretion of the excess dose in the urine 52–54. Other sulfhydryl compounds such as cysteine, homocysteine, glutathione, and cysteinylglycine are meaningful components of the human metabolome, with normal concentrations in the low to mid micromolar range 55.…”

Section: Resultsmentioning

confidence: 99%

Rapid and Selective Screening for Sulfhydryl Analytes in Plasma and Urine Using Surface-Enhanced Transmission Mode Desorption Electrospray Ionization Mass Spectrometry

2010

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Nylon mesh substrates were derivatized to include VICAT SH , a biotinylated reagent that contains both a photolabile linking group and a thiol specific capture agent. The enhanced mesh substrates were then used to capture sulfhydryl analytes directly from urine and plasma samples via covalent reaction between the reactive thiols of the analytes and the iodoacetaminyl unit of VICAT SH . Photocleavage of the labile linker was followed by direct analysis of the mesh surface via transmission mode desorption electrospray ionization (TM-DESI). This chemoselective capture method promoted enrichment of sulfhydryl analytes and reduced matrix interferences, thereby resulting in increased analytical performance of surface enhanced TM-DESI-MS when compared to standard DESI-MS. The present work describes the manufacture of the derivatized mesh substrates and the quality control assessments made during the manufacturing process; the optimization of the chemoselective capture method; and results of experiments pertinent to biological applications. Integration of the chemoselective capture materials with ambient ionization and tandem mass spectrometry results in a powerful combination of speed and selectivity for targeted analyte screening.Chemoselective and affinity based capture methods are sample preparation techniques used throughout chemistry, biochemistry, and molecular biology to recover targeted analytes of interest from complex matrices, thereby increasing analytical specificity and sensitivity through analyte enrichment and the reduction of interferences. [1][2][3][4] For example, medical diagnostics and proteomics studies routinely employ affinity based capture methods to investigate the relationship between antibodies and antigens, often resulting in the development of detection assays for metabolic biomarkers, peptides and proteins. 1,2 Similarly, metabolite enrichment by tagging and proteolytic release (METPR), utilizes chemoselective probes to capture and covalently conjugate small molecule metabolites containing targeted functional groups to solid phase resins. 3,4 In some capture methods, such as western or Southern blotting techniques, the captured analytes are physically transferred to a secondary nitrocellulose surface for analysis. 5,6 In other cases, including METPR and various affinity chromatography methods, a secondary liquid extraction step is used to re-introduce the captured analytes to solution for standard LC-MS analysis. 3,4,7 In either of these scenarios, extraction of captured analytes from the affinity or chemoselective substrate to a secondary surface or solution inevitably results in some analyte loss; therefore, there is continued interest in developing methods to analyze capture surfaces directly (i.e., without additional extraction steps.) jbrodbelt@mail NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptFluorometry, surface plasmon resonance, and mass spectrometry are the detection methods most often utilized for direct analysis of capture surfaces. Due to i...

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Section: Resultsmentioning

confidence: 99%

Rapid and Selective Screening for Sulfhydryl Analytes in Plasma and Urine Using Surface-Enhanced Transmission Mode Desorption Electrospray Ionization Mass Spectrometry

2010

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“…Three batches of liposomes were prepared with SPC: CH - 4:1 (FL), DSPC: CH - 4:1 (DSPCL) and DSPC: CH: PE-PEG - 4:1:0.2 (SL) molar compositions by thin film hydration technique,[2223] using rotary evaporator (HS-3001NS). SPC, cholesterol, and drug were weighed accurately and then dissolved in organic phase, that is, chloroform and methanol (2:1, v/v) in a 250 mL round bottom flask.…”

Section: Methodsmentioning

confidence: 99%

Flurbiprofen-Loaded Stealth Liposomes: Studies on the Development, Characterization, Pharmacokinetics, and Biodistribution

Abbulu²,

Sudhakar

2012

Journal of Young Pharmacists

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Flurbiprofen (FP) is a phenyl alkanoic acid derivative and a family of non–steroidal anti-inflammatory drug used in the treatment of arthritis. The aim of this study was to prepare a new parenteral formulation for FP that can prolong the biologic half-life of the drug, improve its therapeutic efficacy, and reduce its associated side effects targeting the inflammation due to arthritis. PEG-anchored (stealth) and non–PEG-anchored liposomes were prepared by thin film hydration technique followed by extrusion cycle and characterized for in vitro and in vivo. Stealth liposomes (SLs) exhibited increase in percent encapsulation efficiency (68%) and percent drug retention during release studies in 24 h (71%) with good stability for a period of 1 month at –20°C and 4°C (refrigerated temperature) compared with other liposomes. The maximum percent edema inhibition (58%) and significant analgesic effect of 13 s were determined for SLs. The pharmacokinetic parameters after i.v. administration to arthritis induced rats were determined and compared with non-SLs. The marked differences produced for SLs over those of non-SL (conventional) formulations with an increase in area under plasma concentration time curve, t1/2, mean residence time, and reduced clearance. The drug localization in liver, spleen, and kidney were significantly higher for non-PEGylated liposomes than the SLs. Nearly 3-fold increase in drug concentration was measured in arthritic paw when compared with the other liposome formulations. Thus SLs may help to increase the therapeutic efficacy of FP by increasing the targeting potential at the site of action.

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“…Thus, liposome-encapsulated doxorubicin was shown to be efficacious with reduced cardiac toxicity in breast cancer patients (Batist et al, 2001). In rats, 6-mercaptopurine entrapped in a liposome formulation also exhibited improved safety profile with respect to hepatotoxicity and nephrotoxicity, as measured by liver and kidney enzyme activities in serum (Umrethia et al, 2007).…”

Section: Optimizing Drug Exposures For Efficacymentioning

confidence: 95%

Metabolic bioactivation and drug-related adverse effects: current status and future directions from a pharmaceutical research perspective

Tang

2009

Drug Metabolism Reviews

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Retrospective studies indicate that many drugs that cause clinical adverse reactions, such as hepatotoxicity, undergo metabolic bioactivation, resulting in the formation of electrophilic intermediates capable of covalently modifying biological macromolecules. A logical extension of these findings is a working hypothesis that compounds with reduced levels of bioactivation should be inherently safer drug molecules and thus have a greater likelihood of success in drug development. Whereas some research-based pharmaceutical companies have adopted a strategy of addressing metabolic bioactivation early in drug discovery, much skepticism remains on whether such an approach would enable the industry to reach the desired objectives. The debate is centered on the question of whether there is a quantitative correlation between bioactivation and the severity of drug-treatment-related toxicity, and whether covalent protein modification represents only one of several possible mechanisms underlying observed tissue injury. This communication is intended to briefly review the current understanding of drug-induced hepatotoxicity and to discuss the controversy and future directions with respect to the effort of minimizing the probability of clinical adverse reactions.

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6-Mercaptopurine (6-MP) Entrapped Stealth Liposomes for Improvement of Leukemic Treatment without Hepatotoxicity and Nephrotoxicity

Cited by 18 publications

References 28 publications

Rapid and Selective Screening for Sulfhydryl Analytes in Plasma and Urine Using Surface-Enhanced Transmission Mode Desorption Electrospray Ionization Mass Spectrometry

Rapid and Selective Screening for Sulfhydryl Analytes in Plasma and Urine Using Surface-Enhanced Transmission Mode Desorption Electrospray Ionization Mass Spectrometry

Flurbiprofen-Loaded Stealth Liposomes: Studies on the Development, Characterization, Pharmacokinetics, and Biodistribution

Metabolic bioactivation and drug-related adverse effects: current status and future directions from a pharmaceutical research perspective

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