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A Switching Mechanism in Doxorubicin Bioactivation Can Be Exploited to Control Doxorubicin Toxicity  [PDF]
Nnenna A. Finn,Harry W. Findley,Melissa L. Kemp
PLOS Computational Biology , 2011, DOI: 10.1371/journal.pcbi.1002151
Abstract: Although doxorubicin toxicity in cancer cells is multifactorial, the enzymatic bioactivation of the drug can significantly contribute to its cytotoxicity. Previous research has identified most of the components that comprise the doxorubicin bioactivation network; however, adaptation of the network to changes in doxorubicin treatment or to patient-specific changes in network components is much less understood. To investigate the properties of the coupled reduction/oxidation reactions of the doxorubicin bioactivation network, we analyzed metabolic differences between two patient-derived acute lymphoblastic leukemia (ALL) cell lines exhibiting varied doxorubicin sensitivities. We developed computational models that accurately predicted doxorubicin bioactivation in both ALL cell lines at high and low doxorubicin concentrations. Oxygen-dependent redox cycling promoted superoxide accumulation while NADPH-dependent reductive conversion promoted semiquinone doxorubicin. This fundamental switch in control is observed between doxorubicin sensitive and insensitive ALL cells and between high and low doxorubicin concentrations. We demonstrate that pharmacological intervention strategies can be employed to either enhance or impede doxorubicin cytotoxicity in ALL cells due to the switching that occurs between oxygen-dependent superoxide generation and NADPH-dependent doxorubicin semiquinone formation.
Effect of formulation and processing variables on the particle size of sorbitan monopalmitate niosomes  [cached]
Essa Ebtessam
Asian Journal of Pharmaceutics , 2010,
Abstract: In the last two decades, there was an extensive research focused on the study of synthetic amphiphilic vesicles, prepared by nonionic surfactants (niosomes). The particle size of these vesicles is critical for their intended therapeutic benefits. Formulation and processing factors affect greatly the physical characteristics of the resulted nanosystems. Therefore, the present work was adopted to investigate how proper manipulation of various formulations and processing factors on vesicular Z-average particle size. The selected variables were membrane additives, [including cholesterol (CHO), dicetylphosphate (DCP) and stearylamine (SA)], sonication time as well as drug loading factor (using mannitol and estradiol). Sorbitan monopalmitate (span 40) niosomes were prepared by the conventional thin film hydration method. Particle size, measured by Photon Correlation Spectroscopy, and polydispersity indices were measured and compared. The results indicated that CHO increased the vesicular size, with 2:1 and 1:1 (span 40:CHO) ratios showing the same size. Sonication reduced the vesicle size by 23, 35 and 42% after 10, 20 and 30 min, respectively. After 30 min, the effect of sonication was minor. The addition of charge inducing agents changed the zeta potential depending on the type of the additives. Surface charge increased the size by 24 and 11% when using DCP and SA, respectively. Drug incorporation increased the vesicle size to an extent based on its aqueous solubility. There were about 35 and 6.2% increase in vesicular size for estradiol and mannitol, respectively, supporting the partitioning of lipophilic drug within the fatty acyl side chains of the bilayer membrane.
Effect of fat chain length of sorbitan surfactant on the porosity of mesoporous silica  [cached]
Marco Antonio Utrera Martines,Larissa Souza Mendes,Juliana Jorge,Gustavo Rocha de Castro
Orbital : the Electronic Journal of Chemistry , 2009,
Abstract: The influence of the fat chain length of sorbitan surfactant was systematically explored, especially its influence on the material pore size. Then, mesoporous silica was synthesized according to a two-step process that provides intermediary stable hybrid micelles using ethoxylated derivative of fatty esters of sorbitan surfactants as the directing-structure agent and tetraethyl orthosilicate Si(OEt)4 as the silica source. Finally, the materials’ porosity could be controlled by adjusting the preparation parameters during the two steps synthesis of mesoporous silica.
Role of aldo-keto reductases and other doxorubicin pharmacokinetic genes in doxorubicin resistance, DNA binding, and subcellular localization  [cached]
Heibein Allan D,Guo Baoqing,Sprowl Jason A,MacLean David A
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-381
Abstract: Background Since proteins involved in chemotherapy drug pharmacokinetics and pharmacodynamics have a strong impact on the uptake, metabolism, and efflux of such drugs, they likely play critical roles in resistance to chemotherapy drugs in cancer patients. Methods To investigate this hypothesis, we conducted a whole genome microarray study to identify difference in the expression of genes between isogenic doxorubicin-sensitive and doxorubicin-resistant MCF-7 breast tumour cells. We then assessed the degree of over-representation of doxorubicin pharmacokinetic and pharmacodynamic genes in the dataset of doxorubicin resistance genes. Results Of 27,958 Entrez genes on the array, 7.4 per cent or 2,063 genes were differentially expressed by ≥ 2-fold between wildtype and doxorubicin-resistant cells. The false discovery rate was set at 0.01 and the minimum p value for significance for any gene within the “hit list” was 0.01. Seventeen and 43 per cent of doxorubicin pharmacokinetic genes were over-represented in the hit list, depending upon whether the gene name was identical or within the same gene family, respectively. The most over-represented genes were within the 1C and 1B families of aldo-keto reductases (AKRs), which convert doxorubicin to doxorubicinol. Other genes convert doxorubicin to other metabolites or affect the influx, efflux, or cytotoxicity of the drug. In further support of the role of AKRs in doxorubicin resistance, we observed that, in comparison to doxorubicin, doxorubincol exhibited dramatically reduced cytotoxicity, reduced DNA-binding activity, and strong localization to extra nuclear lysosomes. Pharmacologic inhibition of the above AKRs in doxorubicin-resistant cells increased cellular doxorubicin levels, restored doxorubicin cytotoxicity and re-established doxorubicin localization to the nucleus. The properties of doxorubicinol were unaffected. Conclusions These findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledge bases to identify highly relevant genes associated with doxorubicin resistance. The induction of one or more of these genes was found to be correlated with changes in the drug’s properties, while inhibiting one specific class of these genes (the AKRs) increased cellular doxorubicin content and restored drug DNA binding, cytotoxicity, and subcellular localization.
Cholesterol Derivatives Based Charged Liposomes for Doxorubicin Delivery: Preparation, In Vitro and In Vivo Characterization
Yu Nie, Li Ji, Hong Ding, Li Xie, Li Li, Bin He, Yao Wu, Zhongwei Gu
Theranostics , 2012,
Abstract: Cholesterol plays a critical role in liposome composition. It has great impact on the behavior of liposome in vitro and in vivo. In order to verify the possible effects from cholesterol charge, surface shielding and chemical nature, two catalogs of liposomes with charged and PEGylated cholesterols were synthesized. Anionic liposomes (AL) and cationic liposomes (CL) were prepared, with charges from hemisuccinate and lysine in cholesterol derivatives, respectively. Characteristics of different formulated liposomes were investigated after doxorubicin encapsulation, using neutral liposomes (NL) as control. Results showed that after PEGylation, AL and CL liposomes displayed prolonged retention release profile, while kept similar size distribution, encapsulation efficiency, low cytotoxicity and hemolysis comparing with NL. Confocal laser scanning microscopy and flow cytometry experiments confirmed the significantly higher cell uptake from AL and CL vesicles than the NL in mouse breast carcinoma and melanoma cells, human epithelial carcinoma and hepatoma cells. It was in accordance with our corresponding cellular mortality studies of DOX-loaded liposomes. The in vivo anti-tumor effect experiments from charged liposomes also presented much higher tumor inhibition effect (70% vs 45%, p < 0.05) than NL liposomes. This is the first time reporting anti-cancer effect from charged cholesterol liposome with/without PEGylation. It may give deeper understanding on the liposome formulation which is critical for liposome associated drug research and development.
Exploding vesicles
Ting F Zhu, Jack W Szostak
Journal of Systems Chemistry , 2011, DOI: 10.1186/1759-2208-2-4
Abstract: Vesicles are bilayer membrane structures that encapsulate an internal aqueous compartment. Fatty acid vesicles have been studied as models of primitive cell membranes at the origin of life [1-7], and phospholipid vesicles (liposomes) have been widely studied as models of modern cell and organelle membranes [8,9] and as drug delivery vehicles [10-12]. We first observed the phenomenon of "exploding vesicles" during microscopic observations of large (approximately 4 μm in diameter) oleate vesicles containing 10 mM HPTS (8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt, a water-soluble, membrane-impermeable fluorescent dye), in 0.2 M Na-bicine buffer, pH 8.5. The vesicles were prepared by extrusion and dialysis, so that the fluorescent dye was present only inside the vesicles while the buffer was present in both inner and outer solutions [13]. To our surprise, we observed that these vesicles suddenly exploded shortly (approximately 0.5 sec) after being exposed to intense illumination from a metal halide lamp (estimated irradiance 2.5 W/mm2), and released their encapsulated dye along with smaller internal vesicles (Figure 1A; Additional File 1 Figure S1; Additional File 2). The actual vesicle rupture appeared to take place in < 2 ms (3 frames in a recording from a high-speed camera: Additional File 3); this estimate is an upper limit because of the time required for diffusion of the released dye away from the vesicle. We observed similar vesicle explosions using vesicles containing different internal fluorescent dyes, such as calcein and Rose Bengal (a photodynamic therapy drug).To distinguish between physical rupture and rapid permeabilization of the vesicle membrane, we labeled the vesicles with a membrane-localized dye (Rh-DHPE, Lissamine rhodamine B 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine). Upon illumination, we observed that the vesicle membrane burst open on one side and then quickly recoiled (Figure 1B; Additional File 4). When using slightly lowe
Polyhedral vesicles  [PDF]
Hiroshi Noguchi
Physics , 2002, DOI: 10.1103/PhysRevE.67.041901
Abstract: Polyhedral vesicles with a large bending modulus of the membrane such as the gel phase lipid membrane were studied using a Brownian dynamics simulation. The vesicles exhibit various polyhedral morphologies such as tetrahedron and cube shapes. We clarified two types of line defects on the edges of the polyhedrons: cracks of both monolayers at the spontaneous curvature of monolayer $C_{\text {0}}<0$, and a crack of the inner monolayer at $C_{\text {0}}\ge0$. Around the latter defect, the inner monolayer curves positively. Our results suggested that the polyhedral morphology is controlled by $C_{\text {0}}$.
The comparison of cytotoxicity of the anticancer drugs doxorubicin and ellipticine to human neuroblastoma cells
Jitka Poljaková, Tomá Eckschlager, Jana H eba ková, Jan Hraběta, Marie Stiborová
Interdisciplinary Toxicology , 2008, DOI: 10.2478/v10102-010-0036-9
Abstract: Ellipticine is an antineoplastic agent, whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of covalent DNA adducts mediated by cytochromes P450 and peroxidases. Here, the cytotoxicity of ellipticine to human neuroblastoma derived cell lines IMR-32 and UKF-NB-4 was investigated. Treatment of neuroblastoma cells with ellipticine was compared with that of these cancer cells with doxorubicin. The toxicity of ellipticine was essentially the same as that of doxorubicin to UKF-NB-4 cells, but doxorubicin is much more effective to inhibit the growth of the IMR-32 cell line than ellipticine. Hypoxic conditions used for the cell cultivation resulted in a decrease in ellipticine and/or doxorubicin toxicity to IMR-32 and UKF-NB-4 neuroblastoma cells.
Study of the Effects of Polyethylene Glycol Sorbitan Esters Surfactants Group on Biological Membranes  [PDF]
Gholamreza Dehghan Noudeh,Payam Khazaeli,Pedram Rahmani
International Journal of Pharmacology , 2008,
Abstract: The aim of this study is the evaluation of the effect of one group of surfactants including polyethylene glycol sorbitan esters (Tweens: 20, 40, 60 and 80) on Red Blood Cells (RBC) as a model for biological membranes. Also in this study some of physicochemical properties including Emulsification index (E24) and Foam producing activity (Fh) were studied. In this study the hemolytic effect of four surfactants from Tween category were evaluated. Surfactants solutions were prepared in McIvan`s buffer in specific concentration. 0.2 mL of RBC was mixed with 0.2 mL of one of surfactants solution incubated in four different temperatures for two different times. The absorbance of the samples was determined by UV spectrophotometer. Each test was done nine times. The results were shown by mean±SD. E24 and Fh were also determined for each surfactant solutions. In comparison of the four studied surfactants, Tween 20 have the highest hemolytic effect and the Tween 80 is the lowest one. The values of E24 and Fh have good correlation with Hydrophilic-Lipophilic Balance (HLB) values. Increasing in HLB value lead to increasing in those parameters.
Determination of the Toxicity Effect of Sorbitan Esters Surfactants Group on Biological Membrane  [PDF]
G. Dehghan Noudeh,P. Khazaeli,S. Mirzaei,F. Sharififar
Journal of Biological Sciences , 2009,
Abstract: The aim of this study is to investigate the effect of one group of surfactants including sorbitan esters (span 20, 40, 60 and 80) on biologic membrane by using human red blood cells as a model. In this study, the hemolytic effect of four surfactants from span category were evaluated. Surfactants solution were prepared in Mclvane’s buffer in specific concentration. Red blood cells were mixed with surfactants solution incubated in three different time and three temperature. The UV absorbances of the samples were determined by UV spectrophotometer. Each test was done in 9 times. Emulsification index, foam producing activity, also determined for each surfactant solution. The results showed that these agents had hemolytic effects. Span 20 caused more hemolysis and membrane demolishing effect than the others. Their hemolysis effects were enhanced by increasing temperature and time of incubation. According to hemolysis results, foam activity test and E24, the interaction between span 80 and biological membrane is the least and it means has least toxic effect on cells. Anyway because these agents are used as excipients in pharmaceutical preparations, their membrane toxic effect should be considered.
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