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Sample records for polymeric micellar doxorubicin

  1. Small-angle neutron scattering study of polymeric micellar structures

    SciTech Connect

    Wu, G.; Chu, B. ); Schneider, D.K. )

    1994-11-17

    Polymeric micellar structures formed by a PEO-PPO-PEO copolymer in o-xylene in the presence of water were investigated by small-angle neutron scattering. In order to reveal the detailed micellar structure, different contrasts among the micellar core, the micellar shell, and the dispersing medium (background) were constructed by selectively changing the protonated/deuterated combination of water and xylene. The micellar structure could be well described by a core-shell structure with the scattering behavior of the micellar shell being very similar to that of a star polymer. The solubilized water existed not only in the micellar core but also in the micellar shell. The volume fraction of a copolymer segments in the micellar shell was rather low, being of the order of 0.2. There seemed to be no sharp interface between the micellar core and the micellar shell. 25 refs., 11 figs., 4 tabs.

  2. Doxorubicin loaded Polymeric Nanoparticulate Delivery System to overcome drug resistance in osteosarcoma

    PubMed Central

    2009-01-01

    Background Drug resistance is a primary hindrance for the efficiency of chemotherapy against osteosarcoma. Although chemotherapy has improved the prognosis of osteosarcoma patients dramatically after introduction of neo-adjuvant therapy in the early 1980's, the outcome has since reached plateau at approximately 70% for 5 year survival. The remaining 30% of the patients eventually develop resistance to multiple types of chemotherapy. In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) tumor cells, we explored the possibility of loading doxorubicin onto biocompatible, lipid-modified dextran-based polymeric nanoparticles and evaluated the efficacy. Methods Doxorubicin was loaded onto a lipid-modified dextran based polymeric nano-system. The effect of various concentrations of doxorubicin alone or nanoparticle loaded doxorubicin on KHOS, KHOSR2, U-2OS, and U-2OSR2 cells was analyzed. Effects on drug retention, immunofluorescence, Pgp expression, and induction of apoptosis were also analyzed. Results Dextran nanoparticles loaded with doxorubicin had a curative effect on multidrug resistant osteosarcoma cell lines by increasing the amount of drug accumulation in the nucleus via Pgp independent pathway. Nanoparticles loaded with doxorubicin also showed increased apoptosis in osteosarcoma cells as compared with doxorubicin alone. Conclusion Lipid-modified dextran nanoparticles loaded with doxorubicin showed pronounced anti-proliferative effects against osteosarcoma cell lines. These findings may lead to new treatment options for MDR osteosarcoma. PMID:19917123

  3. Polymeric micellar nanocarriers of benzoyl peroxide as potential follicular targeting approach for acne treatment.

    PubMed

    Kahraman, Emine; Özhan, Gül; Özsoy, Yıldız; Güngör, Sevgi

    2016-10-01

    The aim of this work was to optimize polymeric nano-sized micellar carriers of the anti-acne compound benzoyl peroxide (BPO) and to examine the ability of these carriers to deposit into hair follicles with the objective of improving skin delivery of BPO. BPO loaded polymeric micelles composed of Pluronic(®) F127 were prepared by the thin film hydration method and characterized in terms of size, loading capacity, morphology and physical stability. The optimized micelle formulation was then selected for skin delivery studies. The penetration of BPO loaded micellar carriers into skin and skin appendages across full thickness porcine skin was examined in vitro. Confocal microscopy images confirmed the penetration of Nile Red into hair follicles, which was loaded into micellar carriers as a model fluorescent compound. The relative safety of the polymeric micelles was evaluated with the MTT viability test using mouse embryonic fibroblasts. The results indicated that nano-sized polymeric micelles of BPO composed of Pluronic(®) F127 offer a potential approach to enhance skin delivery of BPO and that targeting of micelles into hair follicles may be an effective and safe acne treatment.

  4. Doxorubicin

    MedlinePlus

    Doxorubicin is used in combination with other medications to treat certain types of bladder, breast, lung, stomach, ... leukemia (ALL) and acute myeloid leukemia (AML, ANLL). Doxorubicin is also used alone and in combination with ...

  5. A core cross-linked polymeric micellar platium(IV) prodrug with enhanced anticancer efficiency.

    PubMed

    Hou, Jie; Shang, Jincai; Jiao, Chengbin; Jiang, Peiyue; Xiao, Huijie; Luo, Lan; Liu, Tongjun

    2013-07-01

    A core cross-linked polymeric micellar cisplatin(IV) conjugate prodrug is prepared by attaching the cisplatin(IV) to mPEG-b-PLL biodegradable copolymers to form micellar nanoparticles that can disintegrate to release the active anticancer agent cisplatin(II) in a mild reducing environment. Moreover, in vitro studies show that this cisplatin(IV) conjugate prodrug displays enhanced cytotoxicity against HepG2 cancer cells compared with cisplatin(II). Further studies demonstrate that the high cellular uptake and platinum-DNA adduct of this cisplatin(IV) conjugate prodrug can induce more cancer-cell apoptosis than cisplatin(II), which is responsible for its enhanced anticancer activity.

  6. Nuclease Resistant DNA via High-Density Packing in Polymeric Micellar Nanoparticle Coronas

    PubMed Central

    Rush, Anthony M.; Thompson, Matthew P.; Tatro, Erick T.

    2013-01-01

    Herein, we describe a polymeric micellar nanoparticle capable of rendering nucleic acids resistant to nuclease digestion. This approach relies on utilizing DNA as the polar head group of a DNA-polymer amphiphile in order to assemble well-defined, discrete nanoparticles. Dense packing of DNA in the micelle corona allows for hybridization of complementary oligonucleotides while prohibiting enzymatic degradation. We demonstrate the preparation, purification and characterization of the nanoparticles, then describe their resistance to treatment with endo- and exonucleases including snake-venom phosphodiesterase (SVP) a common, general DNA digestion enzyme. PMID:23379679

  7. New approach in synthesis, characterization and release study of pH-sensitive polymeric micelles, based on PLA-Lys- b-PEGm, conjugated with doxorubicin

    NASA Astrophysics Data System (ADS)

    Efthimiadou, E. K.; Tapeinos, C.; Bilalis, P.; Kordas, G.

    2011-12-01

    Amphiphilic block copolymers are well established as building blocks for the preparation of micellar drug carriers. The functional polymer micelles possess several advantages, such as high drug efficiency, targeted delivery, and minimized cytotoxicity. The synthesis of block copolymers using nano-structured templates has emerged as a useful and versatile approach for preparing drug carriers. Here, we report the synthesis of a smart polymeric compound of a diblock PLA-Lys- b-PEG copolymer containing doxorubicin. We have synthesized functionalized diblock copolymers, with lysinol, poly(lactide) and monomethoxy poly(ethylene glycol) via thermal ring-opening polymerization and a subsequent six-step substitution reaction. A variety of spectroscopic methods were employed here to verify the product of our synthesis. 1H-Nuclear magnetic resonance and Fourier transform infrared studies validated the expected synthesis of copolymers. Doxorubicin is chemically loaded into micelles, and the ex vitro release can be evaluated either in weak acidic or in SBF solution by UV-vis spectroscopy. Dynamic light scattering, thermo gravimetric analysis, and size exclusion chromatography have also been used.

  8. Co-delivery of doxorubicin and (131)I by thermosensitive micellar-hydrogel for enhanced in situ synergetic chemoradiotherapy.

    PubMed

    Huang, Pingsheng; Zhang, Yumin; Wang, Weiwei; Zhou, Junhui; Sun, Yu; Liu, Jinjian; Kong, Deling; Liu, Jianfeng; Dong, Anjie

    2015-12-28

    Combined chemoradiotherapy is potent to defeat malignant tumor. Concurrent delivery of radioisotope with chemotherapeutic drugs, which also act as the radiosensitizer, to tumor tissues by a single vehicle is essential to achieve this objective. To this end, a macroscale injectable and thermosensitive micellar-hydrogel (MHg) depot was constructed by thermo-induced self-aggregation of poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)-poly(ethyleneglycol)-poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) triblock copolymer micelles (Ms), which could not only serve as a micellar drug reservoir to locally deliver concentrated nano chemotherapeutic drugs, but also immobilize radioisotopes at the internal irradiation hot focus. Doxorubicin (DOX) and iodine-131 labeled hyaluronic acid ((131)I-HA) were used as the model therapeutic agents. The aqueous mixture of drug-loaded PECT micelles and (131)I-HA exhibited sol-to-gel transition around body temperature. In vitro drug release study indicated that PECT/DOX Ms were sustainedly shed from the native PECT/DOX MHg formulation, which could be internalized by tumor cells with rapid intracellular DOX release. This hydrogel formulation demonstrated considerable in vitro antitumor effect as well as remarkable radiosensitization. In vivo subcutaneous injection of PECT MHg demonstrated that (131)I isotope was immobilized stably at the injection location and no obvious indication of damage to major organs were observed as indicated by the histopathological analysis. Furthermore, the peritumoral injection of chemo-radiation therapeutic agents-encapsulated MHg formulation on tumor-bearing nude mice resulted in the desired combined treatment effect, which significantly improved the tumor growth inhibition efficiency with minimized drug-associated side effects to major organs. Consequently, such a thermosensitive MHg formulation, which enabled the precise control over the dosage and ratio of combination

  9. Synergistic Cisplatin/Doxorubicin Combination Chemotherapy for Multidrug-Resistant Cancer via Polymeric Nanogels Targeting Delivery.

    PubMed

    Wu, Haiqiu; Jin, Haojie; Wang, Cun; Zhang, Zihao; Ruan, Haoyu; Sun, Luyan; Yang, Chen; Li, Yongjing; Qin, Wenxin; Wang, Changchun

    2017-03-08

    Combination chemotherapy has been proposed to achieve synergistic effect and minimize drug dose for cancer treatment in clinic application. In this article, the stimuli-responsive polymeric nanogels (<100 nm in size) based on poly(acrylic acid) were designed as codelivery system for doxorubicin and cisplatin to overcome drug resistance. By chelation, electrostatic interaction, and π-π stacking interactions, the nanogels could encapsulate doxorubicin and cisplatin with designed ratio and high capacity. Compared with free drugs, the nanogels could deliver more drugs into MCF-7/ADR cells. Significant accumulation in tumor tissues was observed in the biodistribution experiments. The in vitro antitumor studies demonstrated the superior cell-killing activity of the nanogel drug delivery system with a combination index of 0.84, which indicated the great synergistic effect. All the antitumor experimental data revealed that the combination therapy was effective for the multidrug-resistant MCF-7/ADR tumor with reduced side effects.

  10. Preparation, characterization, in vivo pharmacokinetics, and biodistribution of polymeric micellar dimethoxycurcumin for tumor targeting

    PubMed Central

    Liu, Hui; Xu, Hui; Jiang, Yunxia; Hao, Shengyuan; Gong, Feirong; Mu, Hongjie; Liu, Ke

    2015-01-01

    Dimethoxycurcumin (DMC) is an analog of curcumin with superior efficacy in various disease models. Currently, drug delivery system research on DMC is very limited, and it has become a huge challenge to realize further developments and clinical applications. In the present study, a kind of amphiphilic block copolymer, N-t-butoxycarbonyl-phenylalanine terminated monomethoxyl poly (ethylene glycol)-b-poly (ε-caprolactone), or mPEG-PCL-Phe(Boc), was prepared from monomethoxyl poly (ethylene glycol)-b-poly (ε-caprolactone) (mPEG-PCL) with its hydroxyl terminal chemically converted into N-t-butoxycarbonyl-phenylalanine (Boc-Phe). This copolymer was determined to have a fairly low critical micelle concentration (2.56×10−3 mg/mL) and passive targeting potential to tumor tissue, and thus was applied to develop a polymeric micellar formulation of DMC for the first time. The DMC-loaded micelles prepared by thin-film hydration method had typical shell–core structure, with an average particle size of 17.9±0.4 nm and a polydispersity index of 0.045±0.011. The drug loading capacity and entrapment efficiency were 9.94%±0.15% and 97.22%±0.18%, respectively, indicating a high-affinity interaction between DMC and the copolymer. At a concentration of 2 mg/mL, the reconstituted micelle solution could be maintained for at least 10 days at room temperature, and displayed a low initial burst release followed by a sustained release in vitro. Pharmacokinetic study in rats revealed that in vivo drug exposure of DMC was significantly increased and prolonged by intravenously administering DMC-loaded micelles when compared with the same dose of free DMC dissolved in dimethyl sulfoxide. Furthermore, in vivo distribution results from tumor-bearing nude mice demonstrated that this micellar formulation significantly changed the biodistribution profile of DMC and increased drug accumulation in tumors. Therefore, the polymeric micellar formulation of DMC, based on the amphiphilic block

  11. Production efficiency of micellar casein concentrate using polymeric spiral-wound microfiltration membranes.

    PubMed

    Beckman, S L; Zulewska, J; Newbold, M; Barbano, D M

    2010-10-01

    Most current research has focused on using ceramic microfiltration (MF) membranes for micellar casein concentrate production, but little research has focused on the use of polymeric spiral-wound (SW) MF membranes. A method for the production of a serum protein (SP)-reduced micellar casein concentrate using SW MF was compared with a ceramic MF membrane. Pasteurized (79°C, 18s) skim milk (1,100 kg) was microfiltered at 50°C [about 3 × concentration] using a 0.3-μm polyvinylidene fluoride spiral-wound membrane, bleed-and-feed, 3-stage process, using 2 diafiltration stages, where the retentate was diluted 1:2 with reverse osmosis water. Skim milk, permeate, and retentate were analyzed for SP content, and the reduction of SP from skim milk was determined. Theoretically, 68% of the SP content of skim milk can be removed using a single-stage 3× MF. If 2 subsequent water diafiltration stages are used, an additional 22% and 7% of the SP can be removed, respectively, giving a total SP removal of 97%. Removal of SP greater than 95% has been achieved using a 0.1-μm pore size ceramic uniform transmembrane pressure (UTP) MF membrane after a 3-stage MF with diafiltration process. One stage of MF plus 2 stages of diafiltration of 50°C skim milk using a polyvinylidene fluoride polymeric SW 0.3-μm membrane yielded a total SP reduction of only 70.3% (stages 1, 2, and 3: 38.6, 20.8, and 10.9%, respectively). The SP removal rate for the polymeric SW MF membrane was lower in all 3 stages of processing (stages 1, 2, and 3: 0.05, 0.04, and 0.03 kg/m(2) per hour, respectively) than that of the comparable ceramic UTP MF membrane (stages 1, 2, and 3: 0.30, 0.11, and 0.06 kg/m(2) per hour, respectively), indicating that SW MF is less efficient at removing SP from 50°C skim milk than the ceramic UTP system. To estimate the number of steps required for the SW system to reach 95% SP removal, the third-stage SP removal rate (27.4% of the starting material SP content) was used to

  12. Flow and Stability of Wormlike Micellar and Polymeric Solutions in Converging and T-Shaped Microchannels

    NASA Astrophysics Data System (ADS)

    Soulages, J.; McKinley, G. H.

    2008-07-01

    The flow and stability of wormlike micellar and polymeric solutions is investigated in two prototypical converging and elongational geometries; (i) microfabricated hyperbolic contractions and (ii) converging flow in T-shaped microchannels. Understanding the flow behavior of such fluids at the microscale is important to the design and optimization of microfluidic devices for lab-on-a-chip processes and fluidic computing applications as well as to industrial applications such as extensional flow through porous media. The controlled flow rates and very well-defined geometries achievable with microfluidic fabrication technologies enable us to gain insight into the extensional rheology of complex fluids at high extension rates and to investigate the onset of elastically-driven flow asymmetries. In the present study, cetyltrimethylammonium bromide (CTAB) wormlike micelles in aqueous solutions of sodium salicylate as well as dilute polyethylene oxide (PEO) solutions are selected as test fluids. Using the micellar fluids, it is possible to quantify the two-dimensional distribution of both the velocity and stress fields in hyperbolic-shaped micro-contractions using a new microscope-based flow-induced birefringence technique in conjunction with microparticle imaging velocimetry (μPIV). The knowledge of both the deformation and velocity data allows us to better understand the behavior of shear-banding fluids in inhomogeneous extensional flows. In the case of dilute PEO solutions flowing through perfectly symmetric T-shaped microchannels, a local extensional flow develops where the two streams meet. The resulting birefringent strand of highly-oriented material can lead to symmetry-breaking bifurcations in the flow at high Weissenberg number which can be quantified using microparticle imaging velocimetry. The spatio-temporal characteristics of these purely elastic flow asymmetries can also be compared to predictions of numerical simulation.

  13. On-demand combinational delivery of curcumin and doxorubicin via a pH-labile micellar nanocarrier.

    PubMed

    Li, Haoyu; Li, Man; Chen, Chao; Fan, Aiping; Kong, Deling; Wang, Zheng; Zhao, Yanjun

    2015-11-10

    The combinational delivery of doxorubicin and curcumin in a physically loaded nanocarrier offers the benefits of enhanced therapeutic efficacy and reduced adverse effects, but this strategy often suffers from the slow drug release followed by delayed onset of pharmacological action. This work reported the hydrazone-linked polymer-curcumin conjugate micelles containing physically loaded doxorubicin to address this problem; the ester-linked conjugate micelles were produced as the control. The pH-labile spherical micelles were less than 100 nm with a loading at 9.3 ± 0.5% (w/w, Curcumin) and 2.5 ± 0.1(w/w, Doxorubicin). Both agents were released at a faster rate in the pH-labile micelles compared to the control. The confocal laser scanning microscopy revealed a time-dependent co-localization of both agents in HepG2 cells. The IC50 of pH-labile conjugate micelles without doxorubicin in HepG2 cells was 27.7 ± 5.3 (μM), whereas the co-loaded micelles was lowered to 10.8 ± 3.4 (μM) (Cur-equivalent dose). The combination index calculation demonstrated a synergistic action of both agents in the co-loading nanocarrier. The current work provided an efficient nanocarrier system to achieve rapid on-demand drug release without onset delay of therapeutic action, which might add value to the clinical translation of the combinational delivery systems.

  14. Covalent and non-covalent curcumin loading in acid-responsive polymeric micellar nanocarriers

    NASA Astrophysics Data System (ADS)

    Gao, Min; Chen, Chao; Fan, Aiping; Zhang, Ju; Kong, Deling; Wang, Zheng; Zhao, Yanjun

    2015-07-01

    Poor aqueous solubility, potential degradation, rapid metabolism and elimination lead to low bioavailability of pleiotropic impotent curcumin. Herein, we report two types of acid-responsive polymeric micelles where curcumin was encapsulated via both covalent and non-covalent modes for enhanced loading capacity and on-demand release. Biodegradable methoxy poly(ethylene glycol)-poly(lactic acid) copolymer (mPEG-PLA) was conjugated with curcumin via a hydrazone linker, generating two conjugates differing in architecture (single-tail versus double-tail) and free curcumin was encapsulated therein. The two micelles exhibited similar hydrodynamic size at 95 ± 3 nm (single-tail) and 96 ± 3 nm (double-tail), but their loading capacities differed significantly at 15.0 ± 0.5% (w/w) (single-tail) and 4.8 ± 0.5% (w/w) (double-tail). Under acidic sink conditions (pH 5.0 and 6.0), curcumin displayed a faster release from the single-tail nanocarrier, which was correlated to a low IC50 of 14.7 ± 1.6 (μg mL-1) compared to the value of double-tail micelle (24.9 ± 1.3 μg mL-1) in HeLa cells. The confocal imaging and flow cytometry analysis demonstrated a superior capability of single-tail micelle for intracellular curcumin delivery, which was a consequence of the higher loading capacity and lower degree of mPEG surface coverage. In conclusion, the dual loading mode is an effective means to increase the drug content in the micellar nanocarriers whose delivery efficiency is highly dependent on its polymer-drug conjugate architecture. This strategy offers an alternative nanoplatform for intracellularly delivering impotent hydrophobic agents (i.e. curcumin) in an efficient stimuli-triggered way, which is valuable for the enhancement of curcumin’s efficacy in managing a diverse range of disorders.

  15. Doxorubicin and siRNA Codelivery via Chitosan-Coated pH-Responsive Mixed Micellar Polyplexes for Enhanced Cancer Therapy in Multidrug-Resistant Tumors.

    PubMed

    Butt, Adeel Masood; Amin, Mohd Cairul Iqbal Mohd; Katas, Haliza; Abdul Murad, Nor Azian; Jamal, Rahman; Kesharwani, Prashant

    2016-12-05

    This study investigated the potential of chitosan-coated mixed micellar nanocarriers (polyplexes) for codelivery of siRNA and doxorubicin (DOX). DOX-loaded mixed micelles (serving as cores) were prepared by thin film hydration method and coated with chitosan (CS, serving as outer shell), and complexed with multidrug resistance (MDR) inhibiting siRNA. Selective targeting was achieved by folic acid conjugation. The polyplexes showed pH-responsive enhanced DOX release in acidic tumor pH, resulting in higher intracellular accumulation, which was further augmented by downregulation of mdr-1 gene after treatment with siRNA-complexed polyplexes. In vitro cytotoxicity assay demonstrated an enhanced cytotoxicity in native 4T1 and multidrug-resistant 4T1-mdr cell lines, compared to free DOX. Furthermore, in vivo, polyplexes codelivery resulted in highest DOX accumulation and significantly reduced the tumor volume in mice with 4T1 and 4T1-mdr tumors as compared to the free DOX groups, leading to improved survival times in mice. In conclusion, codelivery of siRNA and DOX via polyplexes has excellent potential as targeted drug nanocarriers for treatment of MDR cancers.

  16. Characteristic of core materials in polymeric micelles effect on their micellar properties studied by experimental and dpd simulation methods.

    PubMed

    Cheng, Furong; Guan, Xuewa; Cao, Huan; Su, Ting; Cao, Jun; Chen, Yuanwei; Cai, Mengtan; He, Bin; Gu, Zhongwei; Luo, Xianglin

    2015-08-15

    Polymeric micelles are one important class of nanoparticles for anticancer drug delivery, but the impact of hydrophobic segments on drug encapsulation and release is unclear, which deters the rationalization of drug encapsulation into polymeric micelles. This paper focused on studying the correlation between the characteristics of hydrophobic segments and encapsulation of structurally different drugs (DOX and β-carotene). Poly(ϵ-caprolactone) (PCL) or poly(l-lactide) (PLLA) were used as hydrophobic segments to synthesize micelle-forming amphiphilic block copolymers with the hydrophilic methoxy-poly(ethylene glycol) (mPEG). Both blank and drug loaded micelles were spherical in shape with sizes lower than 50 nm. PCL-based micelles exhibited higher drug loading capacity than their PLLA-based counterparts. Higher encapsulation efficiency of β-carotene was achieved compared with DOX. In addition, both doxorubicin and β-carotene were released much faster from PCL-based polymeric micelles. Dissipative particle dynamics (DPD) simulation revealed that the two drugs tended to aggregate in the core of the PCL-based micelles but disperse in the core of PLLA based micelles. In vitro cytotoxicity investigation of DOX loaded micelles demonstrated that a faster drug release warranted a more efficient cancer-killing effect. This research could serve as a guideline for the rational design of polymeric micelles for drug delivery.

  17. Doxorubicin loaded polymeric gold nanoparticles targeted to human folate receptor upon laser photothermal therapy potentiates chemotherapy in breast cancer cell lines.

    PubMed

    Banu, Hussaina; Sethi, Dipinder Kaur; Edgar, Andre; Sheriff, Adhnaan; Rayees, Nuthan; Renuka, N; Faheem, S M; Premkumar, Kumpati; Vasanthakumar, Geetha

    2015-08-01

    The current research focuses on the application of folate conjugated and doxorubicin loaded polymeric gold nanoparticles (GNPs) for the targeted treatment of folate receptor overexpressing breast cancers, augmented by adjunctive laser photothermal therapy. Herein, GNPs surface modified with folate, drug doxorubicin and polyethylene glycol were engineered and were used as vehicles for folate receptor targeted delivery of doxorubicin into cancer cells. Subsequently, the GNPs were photo-excited using laser light for mediating hyperthermia in the cancer cells. In vitro studies were performed to validate the efficacy of the combined modality of folate conjugated and doxorubicin loaded polymeric GNP mediated chemotherapy followed by photothermal therapy in comparison to treatment with free drug; and the combination modality showed better therapeutic efficacy than that of plain doxorubicin treatment in MDA-MB-231 breast cancer cells that express increased levels of surface folate receptors when compared to MCF-7 breast cancer cells that express low levels of folate receptor. The mechanism of cell death was investigated using fluorescent microscopy. Immunoassays showed the up-regulation of the pro-apoptotic protein p53 and down-regulation of the anti-apoptotic protein Bcl-2. Collectively, these results suggest that the folate tagged doxorubicin loaded GNPs are an attractive platform for targeted delivery of doxorubicin and are agents suitable for photothermal cancer therapy.

  18. Polymeric micelles based on poly(ethylene oxide) and α-carbon substituted poly(ɛ-caprolactone): An in vitro study on the effect of core forming block on polymeric micellar stability, biocompatibility, and immunogenicity.

    PubMed

    Garg, Shyam M; Vakili, Mohammad Reza; Lavasanifar, Afsaneh

    2015-08-01

    A series of block copolymers based on methoxy poly(ethylene oxide)-block-poly(ɛ-caprolactone) (PEO-b-PCL), PEO-b-PCL bearing side groups of benzyl carboxylate (PEO-b-PBCL), or free carboxyl (PEO-b-PCCL) on the PCL backbone with increasing degrees of polymerization of the PCL backbone were synthesized. Prepared block copolymers assembled to polymeric micelles by co-solvent evaporation. The physical stability of prepared micelles was assessed by measuring their tendency toward aggregation over time using dynamic light scattering (DLS). The resistance of micelles against dissociation in the presence of a micelle destabilizing agent, i.e., sodium dodecyl sulfate (SDS), was also investigated using DLS. The rate of micellar core degradation was determined using (1)H NMR for polymer molecular weight measurement upon incubation of micelles in PBS (pH=7.4) at 37°C followed by dialysis of the remaining polymer at different time intervals. The effect of pendent group chemistry in the micellar core on the adsorption of serum proteins to micellar structure was then evaluated using Bradford Protein assay kit. Finally, the effect of micellar core structure on the induction of bone marrow derived dendritic cell (BMDC) maturation and secretion of IL-12 was studied as a measure of micellar immunogenicity. The results showed micelle structures from polymers with higher degree of polymerization in the hydrophobic block and/or those with more hydrophobic substituents on the core-forming block, to be more stable. This was reflected by a decreased tendency for micellar aggregation, reduced dissociation of micelles in the presence of SDS, and diminished core degradation. All micelles were shown to have insignificant adsorption of serum protein suggesting that the hydrophilic PEO shell provided sufficient protection of the core. However, the protein adsorption increased with increase in the hydrophobicity and molecular weight of the core-forming block. Irrespective of the micellar core

  19. An in vivo mechanism for the reduced peripheral neurotoxicity of NK105: a paclitaxel-incorporating polymeric micellar nanoparticle formulation

    PubMed Central

    Nakamura, Iwao; Ichimura, Eiji; Goda, Rika; Hayashi, Hitomi; Mashiba, Hiroko; Nagai, Daichi; Yokoyama, Hirofumi; Onda, Takeshi; Masuda, Akira

    2017-01-01

    In our previous rodent studies, the paclitaxel (PTX)-incorporating polymeric micellar nanoparticle formulation NK105 had showed significantly stronger antitumor effects and reduced peripheral neurotoxicity than PTX dissolved in Cremophor® EL and ethanol (PTX/CRE). Thus, to elucidate the mechanisms underlying reduced peripheral neurotoxicity due to NK105, we performed pharmacokinetic analyses of NK105 and PTX/CRE in rats. Among neural tissues, the highest PTX concentrations were found in the dorsal root ganglion (DRG). Moreover, exposure of DRG to PTX (Cmax_PTX and AUC0-inf._PTX) in the NK105 group was almost half that in the PTX/CRE group, whereas exposure of sciatic and sural nerves was greater in the NK105 group than in the PTX/CRE group. In histopathological analyses, damage to DRG and both peripheral nerves was less in the NK105 group than in the PTX/CRE group. The consistency of these pharmacokinetic and histopathological data suggests that high levels of PTX in the DRG play an important role in the induction of peripheral neurotoxicity, and reduced distribution of PTX to the DRG of NK105-treated rats limits the ensuing peripheral neurotoxicity. In further analyses of PTX distribution to the DRG, Evans blue (Eb) was injected with BODIPY®-labeled NK105 into rats, and Eb fluorescence was observed only in the DRG. Following injection, most Eb dye bound to albumin particles of ~8 nm and had penetrated the DRG. In contrast, BODIPY®–NK105 particles of ~90 nm were not found in the DRG, suggesting differential penetration based on particle size. Because PTX also circulates as PTX–albumin particles of ~8 nm following injection of PTX/CRE, reduced peripheral neurotoxicity of NK105 may reflect exclusion from the DRG due to particle size, leading to reduced PTX levels in rat DRG (275). PMID:28243090

  20. Evaluation of polymeric nanoparticle formulations by effective imaging and quantitation of cellular uptake for controlled delivery of doxorubicin.

    PubMed

    Win, Khin Yin; Teng, Choon Peng; Ye, Enyi; Low, Michelle; Han, Ming-Yong

    2015-03-01

    Various polymeric nanoparticles have been extensively engineered for applications in controlled drug release delivery in the last decades. Currently, there is a great demand to develop a strategy to qualitatively and quantitatively evaluate these polymeric nanoparticle formulations for producing innovative delivery systems. In this work, a screening platform is developed using luminescent quantum dots as drug model and imaging label to evaluate nanoparticle formulations incorporating either hydrophilic or hydrophobic drugs and imaging agents. It is validated that there is no influence of the incorporated entities on the cellular uptake profile. The use of quantum dots enables efficient detection and precise quantitation of cellular uptake of particles which occupy 25% of the cell volume. The correlation of quantum dot- and doxorubicin-incorporated nanoparticles is useful to develop an evaluation platform for nanoparticle formulations through imaging and quantitation. This platform is also used to observe the surface properties effect of other polymers such as chitosan and poly(ethylene) glycol on the cellular interaction and uptake. Moreover, quantum dots can be used to study microparticle theranostic delivery formulations by deliberately incorporating as visible ring surrounding the microparticles for their easy identifying and tracing in diagnostic and chemotherapeutic applications.

  1. Biodegradable polymeric micelle-encapsulated doxorubicin suppresses tumor metastasis by killing circulating tumor cells

    NASA Astrophysics Data System (ADS)

    Deng, Senyi; Wu, Qinjie; Zhao, Yuwei; Zheng, Xin; Wu, Ni; Pang, Jing; Li, Xuejing; Bi, Cheng; Liu, Xinyu; Yang, Li; Liu, Lei; Su, Weijun; Wei, Yuquan; Gong, Changyang

    2015-03-01

    Circulating tumor cells (CTCs) play a crucial role in tumor metastasis, but it is rare for any chemotherapy regimen to focus on killing CTCs. Herein, we describe doxorubicin (Dox) micelles that showed anti-metastatic activity by killing CTCs. Dox micelles with a small particle size and high encapsulation efficiency were obtained using a pH-induced self-assembly method. Compared with free Dox, Dox micelles exhibited improved cytotoxicity, apoptosis induction, and cellular uptake. In addition, Dox micelles showed a sustained release behavior in vitro, and in a transgenic zebrafish model, Dox micelles exhibited a longer circulation time and lower extravasation from blood vessels into surrounding tissues. Anti-tumor and anti-metastatic activities of Dox micelles were investigated in transgenic zebrafish and mouse models. In transgenic zebrafish, Dox micelles inhibited tumor growth and prolonged the survival of tumor-bearing zebrafish. Furthermore, Dox micelles suppressed tumor metastasis by killing CTCs. In addition, improved anti-tumor and anti-metastatic activities were also confirmed in mouse tumor models, where immunofluorescent staining of tumors indicated that Dox micelles induced more apoptosis and showed fewer proliferation-positive cells. There were decreased side effects in transgenic zebrafish and mice after administration of Dox micelles. In conclusion, Dox micelles showed stronger anti-tumor and anti-metastatic activities and decreased side effects both in vitro and in vivo, which may have potential applications in cancer therapy.

  2. Improving anticancer activity and reducing systemic toxicity of doxorubicin by self-assembled polymeric micelles

    NASA Astrophysics Data System (ADS)

    Gou, MaLing; Shi, HuaShan; Guo, Gang; Men, Ke; Zhang, Juan; Zheng, Lan; Li, ZhiYong; Luo, Feng; Qian, ZhiYong; Zhao, Xia; Wei, YuQuan

    2011-03-01

    In an attempt to improve anticancer activity and reduce systemic toxicity of doxorubicin (Dox), we encapsulated Dox in monomethoxy poly(ethylene glycol)-poly(ɛ-caprolactone) (MPEG-PCL) micelles by a novel self-assembly procedure without using surfactants, organic solvents or vigorous stirring. These Dox encapsulated MPEG-PCL (Dox/MPEG-PCL) micelles with drug loading of 4.2% were monodisperse and ~ 20 nm in diameter. The Dox can be released from the Dox/MPEG-PCL micelles; the Dox-release at pH 5.5 was faster than that at pH 7.0. Encapsulation of Dox in MPEG-PCL micelles enhanced the cellular uptake and cytotoxicity of Dox on the C-26 colon carcinoma cell in vitro, and slowed the extravasation of Dox in the transgenic zebrafish model. Compared to free Dox, Dox/MPEG-PCL micelles were more effective in inhibiting tumor growth in the subcutaneous C-26 colon carcinoma and Lewis lung carcinoma models, and prolonging survival of mice bearing these tumors. Dox/MPEG-PCL micelles also induced lower systemic toxicity than free Dox. In conclusion, incorporation of Dox in MPEG-PCL micelles enhanced the anticancer activity and decreased the systemic toxicity of Dox; these Dox/MPEG-PCL micelles are an interesting formulation of Dox and may have potential clinical applications in cancer therapy.

  3. Folate Receptor Targeted Polymeric Micellar Nanocarriers for Delivery of Orlistat as a Repurposed Drug against Triple Negative Breast Cancer

    PubMed Central

    Paulmurugan, Ramasamy; Bhethanabotla, Rohith; Mishra, Kaushik; Devulapally, Rammohan; Foygel, Kira; Sekar, Thillai V; Ananta, Jeyarama S; Massoud, Tarik F; Joy, Abraham

    2015-01-01

    Triple negative breast cancer (TNBC) is a recalcitrant malignancy with no available targeted therapy. Off target effects and poor bioavailability of the FDA approved anti-obesity drug orlistat hinder its clinical translation as a repurposed new drug against TNBC. Here we demonstrate a newly engineered drug formulation for packaging orlistat tailored to TNBC treatment. We synthesized TNBC-specific folate receptor targeted micellar nanoparticles (NPs) carrying orlistat, which improved the solubility (70-80 μg/ml) of this water insoluble drug. The targeted NPs also improved the delivery and bioavailability of orlistat to MDA-MB-231 cells in culture and to tumor xenografts in nude mouse model. We prepared HEA-EHA copolymer micellar NPs by copolymerization of 2-hydroxyethylacrylate (HEA) and 2-ethylhexylacrylate (EHA), and functionalized them with folic acid and an imaging dye. Fluorescence activated cell sorting (FACS) analysis of TNBC cells indicated a dose dependent increase in apoptotic populations in cells treated with free orlistat, orlistat NPs, and folate-receptor targeted Fol-HEA-EHA-orlistat NPs in which Fol-HEA-EHA-orlistat NPs showed significantly higher cytotoxicity than free orlistat. In vitro analysis data demonstrated significant apoptosis at nanomolar concentrations in cells activated through caspase 3 and PARP inhibition. In vivo analysis demonstrated significant antitumor effects in living mice after targeted treatment of tumors, and confirmed by fluorescence imaging. Moreover, Folate receptor targeted Fol-DyLight747-orlistat NPs treated mice exhibited significantly higher reduction in tumor volume compared to control group. Taken together, these results indicate that orlistat packaged in HEA-b-EHA micellar NPs is a highly promising new drug formulation for TNBC therapy. PMID:26553061

  4. Polymeric Sulfated Amino Acid Surfactants: A New Class of Versatile Chiral Selectors for Micellar Electrokinetic Chromatography (MEKC) and MEKC-MS

    PubMed Central

    Ali Rizvi, Syed Asad; Zheng, Jie; Apkarian, Robert P.; Dublin, Steven N.; Shamsi, Shahab A.

    2008-01-01

    In this work, three amino acids derived (L-leucinol, L-isoleucinol and L-valinol) sulfated chiral surfactants are synthesized and polymerized. These chiral sulfated surfactants are thoroughly characterized to determine critical micelle concentration, aggregation number, polarity, optical rotation and partial specific volume. For the first time the morphological behavior of polymeric sulfated surfactants is revealed using cryogenic high-resolution electron microscopy (cryo-HRSEM). The polysodium N-undecenoyl-L-leucine sulfate (poly-L-SUCLS) shows distinct tubular structure, while polysodium N-undecenoyl-L-valine sulfate (poly-L-SUCVS) also shows tubular morphology but without any distinct order of the tubes. On the other hand, polysodium N-undecenoyl-L-isoleucine sulfate (poly-L-SUCILS) displays random distribution of coiled/curved filaments with heavy association of tightly and loosely bound water. All three polymeric sulfated surfactants are compared for enantio-separation of broad range of structurally diverse racemic compounds at very acidic, neutral and basic pH conditions in micellar electrokinetic chromatography (MEKC). A small combinatorial library of 10 structurally related phenylethylamines (PEAs) is investigated for chiral separation under acidic and moderately acidic to neutral pH conditions using an experimental design. In contrast to neutral pH conditions, at acidic pH, significantly enhanced chiral resolution is obtained for class I and class II PEAs due to the compact structure of polymeric sulfated surfactants. It is observed that the presence of hydroxy group on the benzene ring of PEAs resulted in deterioration of enantioseparation. A sensitive MEKC-mass spectrometry (MS) method is developed for one of the PEA (e.g., (±)-pseudoephedrine) in human urine. Very low limit of detection (LOD) is obtained at pH 2.0 (LOD 325 ng/mL), which is ca 16 times better compared to pH 8.0 (LOD 5.2 µg/mL). Other broad range of chiral analytes (

  5. [Study of rat blood serum biochemical indicators of cardiotoxic action of novel antitumor 4-thiazolidinone derivatives and doxorubicin in complexes with polyethylene glycol-containing polymeric carrier in the rat blood serum].

    PubMed

    Kobylyns'ka, L I; Havryliuk, D Ia; Riabtseva, A O; Mitina, N Ie; Zaichenko, O S; Zimenkovskyĭ, B S; Stoĭka, R S

    2014-01-01

    The aim of this study was to measure the activity of enzymes which reflect cardiotoxic action in rats of novel synthetic 4-thiazolidone derivatives--3882, 3288 and 3833 that demonstrated antineoplastic effect in vitro towards 60 lines of human tumor cells tested in the framework of the program of screening new anticancer drugs at the National Cancer Institute (USA). Such action of these compounds was compared with the effect of well known anticancer agent doxorubicin and after conjugation of all above mentioned substances with new polyethylenglycol-containing polymeric comb-like carrier that was synthesized by the authors. Among the biochemical indicators of cardiotoxic action of anticancer agents, activity of the following enzymes in rat blood serum showed to be the most informative: creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransterase. Tenfold injection of doxorubicin in a dose of 5.5 mg/kg of weight caused rats' death, while 3882, 3288 and 3833 preparations had not such action. Application of the doxorubicin in combination with polymeric carrier prolonged the survival time to 20 days. Thus, the injection of anticancer agents in a complex with polymeric carrier provides a significant decrease in their cardiotoxicity that was confirmed by the corresponding changes in the activity of marker enzymes: creatine kinase, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase in blood serum of treated rats.

  6. Doxorubicin Cardiomyopathy

    PubMed Central

    Chatterjee, Kanu; Zhang, Jianqing; Honbo, Norman; Karliner, Joel S.

    2010-01-01

    Established doxorubicin cardiomyopathy is a lethal disease. When congestive heart failure develops, mortality is approximately 50%. Extensive research has been done to understand the mechanism and pathophysiology of doxorubicin cardiomyopathy, and considerable knowledge and experience has been gained. Unfortunately, no effective treatment for established doxorubicin cardiomyopathy is presently available. Extensive research has been done and is being done to discover preventive treatments. However an effective and clinically applicable preventive treatment is yet to be discovered. PMID:20016174

  7. BIOCHEMICAL INDICATORS OF HEPATOTOXICITY IN BLOOD SERUM OF RATS UNDER THE EFFECT OF NOVEL 4-THIAZOLIDINONE DERIVATIVES AND DOXORUBICIN AND THEIR COMPLEXES WITH POLYETHYLENEGLYCOL-CONTAINING NANOSCALE POLYMERIC CARRIER.

    PubMed

    Kobylinska, L I; Havrylyuk, D Ya; Ryabtseva, A O; Mitina, N E; Zaichenko, O S; Lesyk, R B; Zimenkovsky, B S; Stoika, R S

    2015-01-01

    The aim of this study was to compare the effect of new synthetic 4-tiazolidinone derivatives (compounds 3882, 3288 and 3833) and doxorubicin (positive control) in free form and in their complexes with synthetic polyethyleneglycol-containing nanoscale polymeric carrier on the biochemical indicators of hepatotoxicity in blood serum of rats. The activity of enzymes considered as the markers of hepatotoxicity, as well as. the concentration of total protein, urea and creatinine were measured in blood serum of rats. It was found that after injection of investigated compounds the activities ofalanine aminotransferase, alkaline phosphatase and α-amylase increased in comparison to control. Doxorubicin injection was accompanied by 4-fold increase in the activity of γ-glutamyltransferase, and injection ofcompound 3833 led to 2.5-fold elevation ofthe activity of this enzyme. Complexation ofthese antineoplastic derivatives with a synthetic nanocarrier lowered the activity ofthe investigated enzymes substantially if compared to the effect of these compounds infreeform. The most evident decrease was measured for α-amylase, γ-glutamyltransferase and lactate dehydrogenase activities. The normalization of concentrations of total protein, urea and creatinine in blood serum of rats treated with complexes of the studied compounds with a polymeric carrier comparing with their introduction infreeform was also detected. Thus, the immobilization by novel polymeric carrier of anticancer drugs possessing high general toxicity in the treated organism mitigates their toxic effect, which is evident as normalization of specific biochemical indicators of the hepatodestructive effects of the anticancer drugs.

  8. Matrix-assisted laser desorption/ionization mass spectrometric analysis of poly(3,4-ethylenedioxythiophene) in solid-state dye-sensitized solar cells: comparison of in situ photoelectrochemical polymerization in aqueous micellar and organic media.

    PubMed

    Zhang, Jinbao; Ellis, Hanna; Yang, Lei; Johansson, Erik M J; Boschloo, Gerrit; Vlachopoulos, Nick; Hagfeldt, Anders; Bergquist, Jonas; Shevchenko, Denys

    2015-04-07

    Solid-state dye-sensitized solar cells (sDSCs) are devoid of such issues as electrolyte evaporation or leakage and electrode corrosion, which are typical for traditional liquid electrolyte-based DSCs. Poly(3,4-ethylenedioxythiophene) (PEDOT) is one of the most popular and efficient p-type conducting polymers that are used in sDSCs as a solid-state hole-transporting material. The most convenient way to deposit this insoluble polymer into the dye-sensitized mesoporous working electrode is in situ photoelectrochemical polymerization. Apparently, the structure and the physicochemical properties of the generated conducting polymer, which determine the photovoltaic performance of the corresponding solar cell, can be significantly affected by the preparation conditions. Therefore, a simple and fast analytical method that can reveal information on polymer chain length, possible chemical modifications, and impurities is strongly required for the rapid development of efficient solar energy-converting devices. In this contribution, we applied matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) for the analysis of PEDOT directly on sDSCs. It was found that the PEDOT generated in aqueous micellar medium possesses relatively shorter polymeric chains than the PEDOT deposited from an organic medium. Furthermore, the micellar electrolyte promotes a transformation of one of the thiophene terminal units to thiophenone. The introduction of a carbonyl group into the PEDOT molecule impedes the growth of the polymer chain and reduces the conductivity of the final polymer film. Both the simplicity of sample preparation (only application of the organic matrix onto the solar cell is needed) and the rapidity of analysis hold the promise of making MALDI MS an essential tool for the physicochemical characterization of conducting polymer-based sDSCs.

  9. Ring opening metathesis polymerization-derived block copolymers bearing chelating ligands: synthesis, metal immobilization and use in hydroformylation under micellar conditions

    PubMed Central

    Pawar, Gajanan M; Weckesser, Jochen

    2010-01-01

    Summary Norborn-5-ene-(N,N-dipyrid-2-yl)carbamide (M1) was copolymerized with exo,exo-[2-(3-ethoxycarbonyl-7-oxabicyclo[2.2.1]hept-5-en-2-carbonyloxy)ethyl]trimethylammonium iodide (M2) using the Schrock catalyst Mo(N-2,6-Me2-C6H3)(CHCMe2Ph)(OCMe(CF3)2)2 [Mo] to yield poly(M1-b-M2). In water, poly(M1-b-M2) forms micelles with a critical micelle-forming concentration (cmc) of 2.8 × 10−6 mol L−1; Reaction of poly(M1-b-M2) with [Rh(COD)Cl]2 (COD = cycloocta-1,5-diene) yields the Rh(I)-loaded block copolymer poly(M1-b-M2)-Rh containing 18 mg of Rh(I)/g of block copolymer with a cmc of 2.2 × 10−6 mol L−1. The Rh-loaded polymer was used for the hydroformylation of 1-octene under micellar conditions. The data obtained were compared to those obtained with a monomeric analogue, i.e. CH3CON(Py)2RhCl(COD) (C1, Py = 2-pyridyl). Using the polymer-supported catalyst under micellar conditions, a significant increase in selectivity, i.e. an increase in the n:iso ratio was accomplished, which could be further enhanced by the addition of excess ligand, e.g., triphenylphosphite. Special features of the micellar catalytic set up are discussed. PMID:20502652

  10. Formulation and optimization of doxorubicin loaded polymeric nanoparticles using Box-Behnken design: ex-vivo stability and in-vitro activity.

    PubMed

    Shaikh, Muhammad Vaseem; Kala, Manika; Nivsarkar, Manish

    2017-03-30

    Biodegradable nanoparticles (NPs) have gained tremendous interest for targeting chemotherapeutic drugs to the tumor environment. Inspite of several advances sufficient encapsulation along with the controlled release and desired size range have remained as considerable challenges. Hence, the present study examines the formulation optimization of doxorubicin loaded PLGA NPs (DOX-PLGA-NPs), prepared by single emulsion method for cancer targeting. Critical process parameters (CPP) were selected by initial screening. Later, Box-Behnken design (BBD) was used for analyzing the effect of the selected CPP on critical quality attributes (CQA) and to generate a design space. The optimized formulation was stabilized by lyophilization and was used for in-vitro drug release and in-vitro activity on A549 cell line. Moreover, colloidal stability of the NPs in the biological milieu was assessed. Amount of PLGA and PVA, oil:water ratio and sonication time were the selected independent factors for BBD. The statistical data showed that a quadratic model was fitted to the data obtained. Additionally, the lack of fit values for the models was not significant. The delivery system showed sustained release behavior over a period of 120h and was governed by Fickian diffusion. The multipoint analysis at 24, 48 and 72h showed gradual reduction in IC50 value of DOX-PLGA-NPs (p<0.05, Fig. 9). DOX-PLGA-NPs were found to be stable in the biological fluids indicating their in-vivo applicability. In conclusion, optimization of the DOX-PLGA-NPs by BBD yielded in a promising drug carrier for doxorubicin that could provide a novel treatment modality for cancer.

  11. Development and Characterization of Lecithin-based Self-assembling Mixed Polymeric Micellar (saMPMs) Drug Delivery Systems for Curcumin

    NASA Astrophysics Data System (ADS)

    Chen, Ling-Chun; Chen, Yin-Chen; Su, Chia-Yu; Wong, Wan-Ping; Sheu, Ming-Thau; Ho, Hsiu-O.

    2016-11-01

    Self-assembling mixed polymeric micelles (saMPMs) were developed for overcoming major obstacles of poor bioavailability (BA) associated with curcumin delivery. Lecithin added was functioned to enlarge the hydrophobic core of MPMs providing greater solubilization capacity. Amphiphilic polymers (sodium deoxycholate [NaDOC], TPGS, CREMOPHOR, or a PLURONIC series) were examined for potentially self-assembling to form MPMs (saMPMs) with the addition of lecithin. Particle size, size distribution, encapsulation efficacy (E.E.), and drug loading (D.L.) of the mixed micelles were optimally studied for their influences on the physical stability and release of encapsulated drugs. Overall, curcumin:lecithin:NaDOC and curcumin:lecithin:PLURONIC P123 in ratios of 2:1:5 and 5:2:20, respectively, were optimally obtained with a particle size of < 200 nm, an E.E. of >80%, and a D.L. of >10%. The formulated system efficiently stabilized curcumin in phosphate-buffered saline (PBS) at room temperature or 4 °C and in fetal bovine serum or PBS at 37 °C and delayed the in vitro curcumin release. In vivo results further demonstrated that the slow release of curcumin from micelles and prolonged duration increased the curcumin BA followed oral and intravenous administrations in rats. Thus, lecithin-based saMPMs represent an effective curcumin delivery system, and enhancing BA of curcumin can enable its wide applications for treating human disorders.

  12. Development and Characterization of Lecithin-based Self-assembling Mixed Polymeric Micellar (saMPMs) Drug Delivery Systems for Curcumin

    PubMed Central

    Chen, Ling-Chun; Chen, Yin-Chen; Su, Chia-Yu; Wong, Wan-Ping; Sheu, Ming-Thau; Ho, Hsiu-O

    2016-01-01

    Self-assembling mixed polymeric micelles (saMPMs) were developed for overcoming major obstacles of poor bioavailability (BA) associated with curcumin delivery. Lecithin added was functioned to enlarge the hydrophobic core of MPMs providing greater solubilization capacity. Amphiphilic polymers (sodium deoxycholate [NaDOC], TPGS, CREMOPHOR, or a PLURONIC series) were examined for potentially self-assembling to form MPMs (saMPMs) with the addition of lecithin. Particle size, size distribution, encapsulation efficacy (E.E.), and drug loading (D.L.) of the mixed micelles were optimally studied for their influences on the physical stability and release of encapsulated drugs. Overall, curcumin:lecithin:NaDOC and curcumin:lecithin:PLURONIC P123 in ratios of 2:1:5 and 5:2:20, respectively, were optimally obtained with a particle size of < 200 nm, an E.E. of >80%, and a D.L. of >10%. The formulated system efficiently stabilized curcumin in phosphate-buffered saline (PBS) at room temperature or 4 °C and in fetal bovine serum or PBS at 37 °C and delayed the in vitro curcumin release. In vivo results further demonstrated that the slow release of curcumin from micelles and prolonged duration increased the curcumin BA followed oral and intravenous administrations in rats. Thus, lecithin-based saMPMs represent an effective curcumin delivery system, and enhancing BA of curcumin can enable its wide applications for treating human disorders. PMID:27848996

  13. Folate-Modified Poly(malic acid) Graft Polymeric Nanoparticles for Targeted Delivery of Doxorubicin: Synthesis, Characterization and Folate Receptor Expressed Cell Specificity.

    PubMed

    Yang, Yang; Li, Ning; Nie, Yu; Sheng, Mingming; Yue, Dong; Wang, Gang; Tang, James Z; Gu, Zhongwei

    2015-09-01

    A novel amphiphilic biodegradable cholesterol and poly(ethylene glycol)-folate grafted poly(α,β-malic acid) (PMA-g-Chol/PEG-FA) was synthesized and characterized as self-assembled nanoparticles for targeted delivery of doxorubicin (DOX). The nanoparticles showed extremely low critical aggregation concentrations (CAC), appropriate zeta potential, narrow size distribution, good stability in serum conditions and negligible toxicity. After encapsulation'of DOX, PMA-g-Chol/PEG-FA nanoparticles showed significantly reduced cell viability (up to 30% for Hela and 27% for 4T1 cells) compared with the non-targeted ones on carcinoma cells with different levels of folate receptor (FR) expression. While no difference was detected on HEK293 cells (FR receptor negative) between the two nanoparticles. Addition of extra free folate obviously decreased the cellular mortality and inhibited the cellular uptake of targeted nanoparticles. In the Hela/HEK293 co-culture model, folate conjugated nanoparticles showed specific affiliation with Hela cells other than HEK293 cells, indicating good targeting property of the delivery system. As detected from ex vivo fluorescent imaging, PMA-g-Chol/PEG-FA nanoparticles could accumulate at tumor site with higher selectivity compared to PMA-g-Chol/PEG nanoparticles and DOX x HCl. In vivo antitumor studies confirmed the significant tumor inhibition efficacy of drug-loaded PMA-g-Chol/PEG-FA nanoparticles with lower toxicity to normal tissues than DOX x HCI at the same dosage.

  14. Enhanced Micellar Catalysis LDRD.

    SciTech Connect

    Betty, Rita G.; Tucker, Mark D; Taggart, Gretchen; Kinnan, Mark K.; Glen, Crystal Chanea; Rivera, Danielle; Sanchez, Andres; Alam, Todd Michael

    2012-12-01

    The primary goals of the Enhanced Micellar Catalysis project were to gain an understanding of the micellar environment of DF-200, or similar liquid CBW surfactant-based decontaminants, as well as characterize the aerosolized DF-200 droplet distribution and droplet chemistry under baseline ITW rotary atomization conditions. Micellar characterization of limited surfactant solutions was performed externally through the collection and measurement of Small Angle X-Ray Scattering (SAXS) images and Cryo-Transmission Electron Microscopy (cryo-TEM) images. Micellar characterization was performed externally at the University of Minnesotas Characterization Facility Center, and at the Argonne National Laboratory Advanced Photon Source facility. A micellar diffusion study was conducted internally at Sandia to measure diffusion constants of surfactants over a concentration range, to estimate the effective micelle diameter, to determine the impact of individual components to the micellar environment in solution, and the impact of combined components to surfactant phase behavior. Aerosolized DF-200 sprays were characterized for particle size and distribution and limited chemical composition. Evaporation rates of aerosolized DF-200 sprays were estimated under a set of baseline ITW nozzle test system parameters.

  15. Doxorubicin Lipid Complex Injection

    MedlinePlus

    Doxorubicin lipid complex is used to treat ovarian cancer that has not improved or that has worsened after treatment with other medications. Doxorubicin lipid complex is also used to treat Kaposi's sarcoma ( ...

  16. Combination chemotherapy of doxorubicin, all-trans retinoic acid and low molecular weight heparin based on self-assembled multi-functional polymeric nanoparticles

    NASA Astrophysics Data System (ADS)

    Zhang, Ting; Xiong, Hui; Zohra Dahmani, Fatima; Sun, Li; Li, Yuanke; Yao, Li; Zhou, Jianping; Yao, Jing

    2015-04-01

    Based on the complementary effects of doxorubicin (DOX), all-trans retinoic acid (ATRA) and low molecular weight heparin (LMWH), the combination therapy of DOX, ATRA and LMWH was expected to exert the enhanced anti-tumor effects and reduce the side effects. In this study, amphiphilic LMWH-ATRA conjugate was synthesized for encapsulating the DOX. In this way, DOX, ATRA and LMWH were assembled into a single nano-system by both chemical and physical modes to obtain a novel anti-tumor targeting drug delivery system that can realize the simultaneous delivery of multiple drugs with different properties to the tumor. LMWH-ATRA nanoparticles exhibited good loading capacities for DOX with excellent physico-chemical properties, good biocompatibility, and good differentiation-inducing activity and antiangiogenic activity. The drug-loading capacity was up to 18.7% with an entrapment efficiency of 78.8%. It was also found that DOX-loaded LMWH-ATRA nanoparticles (DHR nanoparticles) could be efficiently taken up by tumor cells via endocytic pathway, and mainly distributed in cytoplasm at first, then transferred into cell nucleus. Cell viability assays suggested that DHR nanoparticles maintained the cytotoxicity effect of DOX on MCF-7 cells. Moreover, the in vivo imaging analysis indicated that DiR-loaded LMWH-ATRA nanoparticles could target the tumor more effectively as compared to free DiR. Furthermore, DHR nanoparticles possessed much higher anticancer activity and reduced side effects compared to free drugs solution. These results suggested that DHR nanoparticles could be considered as a promising targeted delivery system for combination cancer chemotherapy with lower adverse effects.

  17. Micellar Electrokinetic Chromatography

    NASA Astrophysics Data System (ADS)

    Bald, Edward; Kubalczyk, Paweł

    Since the introduction of micellar electrokinetic chromatography by Terabe, several authors have paid attention to the fundamental characteristics of this separation method. In this chapter the theoretical and practical aspects of resolution optimization, as well as the effect of different separation parameters on the migration behavior are discussed. These among others include fundamentals of separation, retention factor and resolution equation, efficiency, selectivity, and various surfactants and additives. Initial conditions for method development and instrumental approaches such as mass spectrometry detection are also mentioned covering the proposals for overcoming the difficulties arising from the coupling micellar electrokinetic chromatography with mass spectrometry detection.

  18. Micellar slug for oil recovery

    SciTech Connect

    Morita, H.; Kawada, Y.; Yamada, J. I.

    1985-07-30

    A micellar slug for use in the recovery of oil, the slug containing a hydrocarbon, an aqueous medium, a surfactant, and a cosurfactant. The surfactant contains as an essential component an internal olefin sulfonate. This micellar slug has an excellent capability for decreasing an interfacial tension between oil and water and an excellent salinity tolerance and hard-water resistance. Furthermore, the micro-emulsion can be formed from this micellar slug in a wide composition range.

  19. Polymerization of anionic wormlike micelles.

    PubMed

    Zhu, Zhiyuan; González, Yamaira I; Xu, Hangxun; Kaler, Eric W; Liu, Shiyong

    2006-01-31

    Polymerizable anionic wormlike micelles are obtained upon mixing the hydrotropic salt p-toluidine hydrochloride (PTHC) with the reactive anionic surfactant sodium 4-(8-methacryloyloxyoctyl)oxybenzene sulfonate (MOBS). Polymerization captures the cross-sectional radius of the micelles (approximately 2 nm), induces micellar growth, and leads to the formation of a stable single-phase dispersion of wormlike micellar polymers. The unpolymerized and polymerized micelles were characterized using static and dynamic laser light scattering, small-angle neutron scattering, 1H NMR, and stopped-flow light scattering. Stopped-flow light scattering was also used to measure the average lifetime of the unpolymerized wormlike micelles. A comparison of the average lifetime of unpolymerized wormlike micelles with the surfactant monomer propagation rate was used to elucidate the mechanism of polymerization. There is a significant correlation between the ratio of the average lifetime to the monomer propagation rate and the average aggregation number of the polymerized wormlike micelles.

  20. Micellar liquid chromatography

    NASA Astrophysics Data System (ADS)

    Basova, Elena M.; Ivanov, Vadim M.; Shpigun, Oleg A.

    1999-12-01

    Background and possibilities of practical applications of micellar liquid chromatography (MLC) are considered. Various retention models in MLC, the effects of the nature and concentration of surfactants and organic modifiers, pH, temperature and ionic strength on the MLC efficiency and selectivity are discussed. The advantages and limitations of MLC are demonstrated. The performance of MLC is critically evaluated in relationship to the reversed-phase HPLC and ion-pair chromatography. The potential of application of MLC for the analysis of pharmaceuticals including that in biological fluids and separation of inorganic anions, transition metal cations, metal chelates and heteropoly compounds is described. The bibliography includes 146 references.

  1. Micellar slug for oil recovery

    SciTech Connect

    Morita, H.; Kawada, Y.; Ukigai, T.; Yamada, J.

    1985-08-27

    A micellar slug for use in the recovery of oil is described, the slug containing a hydrocarbon, an aqueous medium, a surfactant, and a cosurfactant. The surfactant contains as an essential component an alpha-olefin sulfonate having 10 to 26 carbon atoms and containing 0.1% to 15% by weight by weight of a disulfonate. This micellar slug has an excellent salinity tolerance and hard-water resistance. Furthermore, the micellar slugs of the present invention are capable of forming micro-emulsions having a sufficiently low interfacial tension and, therefore, can improve oil recovery efficiency.

  2. Micellar slug for oil recovery

    SciTech Connect

    Morita, H.; Kowada, Y.; Ukigai, T.; Yamada, J.

    1985-04-23

    A micellar slug for use in the recovery of oil is described, the slug containing a hydrocarbon, an aqueous medium, a surfactant, and a cosurfactant. The surfactant contains, as an essential component, a divalent metal salt of an alpha-olefin sulfonic acid. This micellar slug has an excellent salinity tolerance and hard-water resistance. Furthermore, the micro-emulsion formed from the present micellar slug is maintained stable in a subterranean reservoir formed by alkaline earth metal carbonates and, therefore, the oil recovery efficiency can be improved.

  3. pH- and NIR Light-Responsive Polymeric Prodrug Micelles for Hyperthermia-Assisted Site-Specific Chemotherapy to Reverse Drug Resistance in Cancer Treatment.

    PubMed

    Li, Zuhong; Wang, Haibo; Chen, Yangjun; Wang, Yin; Li, Huan; Han, Haijie; Chen, Tingting; Jin, Qiao; Ji, Jian

    2016-05-01

    Despite the exciting advances in cancer chemotherapy over past decades, drug resistance in cancer treatment remains one of the primary reasons for therapeutic failure. IR-780 loaded pH-responsive polymeric prodrug micelles with near infrared (NIR) photothermal effect are developed to circumvent the drug resistance in cancer treatment. The polymeric prodrug micelles are stable in physiological environment, while exhibit fast doxorubicin (DOX) release in acidic condition and significant temperature elevation under NIR laser irradiation. Phosphorylcholine-based biomimetic micellar shell and acid-sensitive drug conjugation endow them with prolonged circulation time and reduced premature drug release during circulation to conduct tumor site-specific chemotherapy. The polymeric prodrug micelles combined with NIR laser irradiation could significantly enhance intracellular DOX accumulation and synergistically induce the cell apoptosis in DOX-resistant MCF-7/ADR cells. Meanwhile, the tumor site-specific chemotherapy combined with hyperthermia effect induces significant inhibition of MCF-7/ADR tumor growth in tumor-bearing mice. These results demonstrate that the well-designed IR-780 loaded polymeric prodrug micelles for hyperthermia-assisted site-specific chemotherapy present an effective approach to reverse drug resistance.

  4. Doxorubicin: nanotechnological overviews from bench to bedside.

    PubMed

    Cagel, Maximiliano; Grotz, Estefanía; Bernabeu, Ezequiel; Moretton, Marcela A; Chiappetta, Diego A

    2017-02-01

    Doxorubicin (DOX) is considered one of the most effective chemotherapeutic agents, used as a first-line drug in numerous types of cancer. Nevertheless, it exhibits serious adverse effects, such as lethal cardiotoxicity and dose-limiting myelosuppression. In this review, we focus on the description and the clinical benefits of different DOX-loaded nanotechnological platforms, not only those commercially available but also the ones that are currently in clinical phases, such as liposomes, polymeric nanoparticles, polymer-drug conjugates, polymeric micelles and ligand-based DOX-loaded nanoformulations. Although some DOX-based nanoproducts are currently being used in the clinical field, it is clear that further research is necessary to achieve improvements in cancer therapeutics.

  5. Micellar slug for oil recovery

    SciTech Connect

    Morita, H.; Kawada, Y.; Ukigai, T.; Yamada, J.

    1985-10-29

    A micellar slug for use in the recovery of oil, the slug containing a hydrocarbon, an aqueous medium, a surfactant, and a cosurfactant. The surfactant contains as an essential component an internal olefin sulfonate or sulfonates having 10 to 30 carbon atoms and an alpha-olefin sulfonate or sulfonates having 10 to 30 carbon atoms. This micellar slug has a sufficiently low interfacial tension, good salinity tolerance, hard-water resistance, ability to maintain the micro-emulsion against change in the composition of the micro-emulsion, and mobility controlled viscosity.

  6. Ultrasound-Mediated Polymeric Micelle Drug Delivery.

    PubMed

    Xia, Hesheng; Zhao, Yue; Tong, Rui

    2016-01-01

    The synthesis of multi-functional nanocarriers and the design of new stimuli-responsive means are equally important for drug delivery. Ultrasound can be used as a remote, non-invasive and controllable trigger for the stimuli-responsive release of nanocarriers. Polymeric micelles are one kind of potential drug nanocarrier. By combining ultrasound and polymeric micelles, a new modality (i.e., ultrasound-mediated polymeric micelle drug delivery) has been developed and has recently received increasing attention. A major challenge remaining in developing ultrasound-responsive polymeric micelles is the improvement of the sensitivity or responsiveness of polymeric micelles to ultrasound. This chapter reviews the recent advance in this field. In order to understand the interaction mechanism between ultrasound stimulus and polymeric micelles, ultrasound effects, such as thermal effect, cavitation effect, ultrasound sonochemistry (including ultrasonic degradation, ultrasound-initiated polymerization, ultrasonic in-situ polymerization and ultrasound site-specific degradation), as well as basic micellar knowledge are introduced. Ultrasound-mediated polymeric micelle drug delivery has been classified into two main streams based on the different interaction mechanism between ultrasound and polymeric micelles; one is based on the ultrasound-induced physical disruption of the micelle and reversible release of payload. The other is based on micellar ultrasound mechanochemical disruption and irreversible release of payload.

  7. Construction of block copolymers for the coordinated delivery of doxorubicin and magnetite nanocubes.

    PubMed

    Wang, Yong; Ibrahim, Nor Lizawati; Jiang, Jiang; Gao, Shujun; Erathodiyil, Nandanan; Ying, Jackie Y

    2013-08-10

    Multifunctional nanoparticles combine drug and imaging agent together to assign both therapeutic and diagnostic functions. However, particle aggregation/dissociation and/or major differences in the bio-distribution and targeting capability of drugs and imaging probes are main obstacles for the efficient, coordinated delivery of multiple agents, unless the different agents can be tightly bound and well-protected during their circulation in vivo. In this paper, we report the coordinated in vivo delivery of anti-cancer drugs and imaging agents by chemically loading doxorubicin and magnetite nanocubes (MNs) in the core of polymeric nanoparticles. Living polymerization, nitroxide-mediated radical polymerization (NMP), was applied to construct the optimal polymers to co-deliver doxorubicin and MNs. The resulting diblock polymers consisted of one block with triethylene glycol brushes and another block with carboxylic acid groups to bind doxorubicin and Fe3O4 MNs. The optimal polymer has narrow polydispersity (PDI=1.2) and high doxorubicin/MN loading (30wt.%/28wt.%). Core-shell particles were obtained with good stability and a suitable particle size of ~100nm. The doxorubicin and MNs loaded in this polymeric system showed highly coordinated bio-distribution in the balb/C mice model. This system may have important impact on the design of effective and stable dual-agent co-delivery systems.

  8. Characterization and classification of pseudo-stationary phases in micellar electrokinetic chromatography using chemometric methods.

    PubMed

    Fu, Cexiong; Khaledi, Morteza G

    2014-03-04

    Two types of chemometric methods, principal component analysis (PCA) and cluster analysis, are employed to characterize and classify a total of 70 pseudostationary phases (54 distinct systems and 16 decoy systems) in micellar electrokinetic chromatography (MEKC). PCA excels at removing redundant information for micellar phase characterization and retaining principal determinants for phase classification. While PCA is useful in the characterization of micelle selectivities, it is ineffective in defining the grouping of micellar phases. Hierarchical clustering yields a complete dendrogram of cluster structures but provides only limited cluster characterizations. The combination of these two chemometric methods leads to a comprehensive interpretation of the micellar phase classification. Moreover, the k-means analysis can further discern subtle differences among those closely located micellar phases. All three chemometric methods result in similar classifications with respect to the similarities and differences of the 70 micelle systems investigated. These systems are categorized into 3 major clusters: fluoro-surfactants represent cluster I, identified as strong hydrogen bond donors and dipolar but weak hydrogen bond acceptors. Cluster II includes sulfonated acrylamide/acrylate copolymers and surfactants with trimethylammonium head groups, characterized by strong hydrophobicity (v) and weak hydrogen bond acidity (b). The last cluster consists of two subclusters: clusters III and IV. Cluster III includes siloxane-based polymeric micelles, exhibiting weak hydrophobicity and medium hydrogen bond acidity and basicity (a), and the cluster IV micellar systems are characterized by their strong hydrophobicity and medium hydrogen bond acidity and basicity but rather weak dipolarity. Cluster III differs from cluster IV by its slightly weaker hydrophobicity and hydrogen bond donating capability. The classification by chemometric methods is in good agreement with the

  9. Phase Behavior and Micellar Packing of Impurity-Free Pluronic Block Copolymers in Water

    NASA Astrophysics Data System (ADS)

    Ryu, Chang Yeol; Park, Hanjin

    We have investigated the impacts of the non-micellizable polymeric impurities on the micellar packing and solution phase behavior of Pluronic block copolymers in water. In particular, small angle x-ray scattering, rheology and dynamic light scattering techniques have been employed to elucidate how the low MW impurities affect the micellar packing and solution phase diagram in water, when ordered cubic structures of spherical micelles are formed. A silica slurry method has been developed using the competitive adsorption of the PEO-PPO-PEO triblock copolymers over the low MW polymeric impurities for a large scale purification of Pluronics and it purity of Pluronics has been assessed by interaction chromatography. Based on the comparative studies on micellar packing between As-Received (AR) and Purified (Pure) Pluronic F108 solutions, we found experimental evidence to support the hypothesis that the inter-micellar distance of Pluronic cubic structures in aqueous solution is governed by the effective polymer concentration in terms of PEO-PPO-PEO triblock copolymers. Removal of the impurities in AR F108 offers an important clue on window into the onset of BCC ordering via hydrodynamic contact between micelles in solution. NSF DMR Polymers.

  10. Micellar systems: Novel family for drug carriers

    NASA Astrophysics Data System (ADS)

    Rana, Meenakshi; Chowdhury, Papia

    2016-05-01

    Micellar systems have attracted a great deal of interest, especially in the field of biomedical sciences. The paper deals with the encapsulation behavior of Pyrrole-2-carboxyldehyde (PCL) an anti-cancer drug in different micellar systems. The inculsion capability of PCL is verified experimentally (UV-Vis, Photoluminescence and Raman spectroscopy) in polymer matrix. Two-micellar systems sodium dodecyl sulfate (SDS) and Polysorbate 80 (TWEEN 80) have been studied with a poorly water soluble PCL. The present work provides the effects of biocompatible organic PCL molecule entrap in micellar system in polymer phase due to its vast applicability in drug industry.

  11. One-pot synthesis of doxorubicin-loaded multiresponsive nanogels based on hyperbranched polyglycerol.

    PubMed

    Sousa-Herves, Ana; Wedepohl, Stefanie; Calderón, Marcelo

    2015-03-28

    Doxorubicin-loaded nanogels with multiresponsive properties are prepared using hyperbranched polyglycerol as a biocompatible scaffold. The nanogels are synthesized in a single step combining free-radical polymerization and a mild nanoprecipitation technique. The nanogels respond to different biological stimuli such as low pH and reductive environments, resulting in a more efficient cell proliferation inhibition in A549 cells.

  12. Molecular biology of doxorubicin-induced cardiomyopathy

    PubMed Central

    Umlauf, J; Horký, M

    2002-01-01

    The anthracycline doxorubicin is an antineoplastic agent, eliciting chronic cardiac toxicity. It occurs in patients after prolonged administration of doxorubicin, leading to congestive heart failure. The pathogenesis of the doxorubicin-induced car-diomyopathy is not well understood. The present article summarizes the unique effect of doxorubicin on cardiac-specific gene expression. In addition to binding to DNA, doxorubicin directly affects the function of a variety of proteins. Free radical generation, damage to mitochondria and active cell death are also critical in the development of doxorubicin-induced cardiac toxicity. Agents providing effective cardioprotection are also reviewed. PMID:19644577

  13. Micellar electrokinetic chromatography on microchips.

    PubMed

    Kitagawa, Fumihiko; Otsuka, Koji

    2008-03-01

    This review highlights the methodological and instrumental developments in microchip micellar EKC (MCMEKC) from 1995. The combination of higher separation efficiencies in micellar EKC (MEKC) with high-speed separation in microchip electrophoresis (MCE) should provide high-throughput and high-performance analytical systems. The chip-based separation technique has received considerable attention due to its integration ability without any connector. This advantage allows the development of a multidimensional separation system. Several types of 2-D separation microchips are described in the review. Since complicated channel configurations can easily be fabricated on planar substrates, various sample manipulations can be carried out prior to MCMEKC separations. For example, mixing for on-chip reactions, on-line sample preconcentration, on-chip assay, etc., have been integrated on MEKC microchips. The application of on-line sample preconcentration to MCMEKC can provide not only sensitivity enhancement but also the elucidation of the preconcentration mechanism due to the visualization ability of MCE. The characteristics of these sample manipulations on MEKC microchips are presented in this review. The scope of applications in MCMEKC covers mainly biogenic compounds such as amino acids, peptides, proteins, biogenic amines, DNA, and oestrogens. This review provides a comprehensive table listing the applications in MCMEKC in relation to detection methods.

  14. Combination regimens using doxorubicin and pegylated liposomal doxorubicin prior to autologous transplantation in multiple myeloma.

    PubMed

    Moreau, Philippe

    2009-07-01

    Doxorubicin and pegylated liposomal doxorubicin are key compounds of several induction regimens used prior to autologous stem cell transplantation in patients with de novo multiple myeloma, such as vincristine, doxorubicin, dexamethasone (VAD), vincristine, pegylated liposomal doxorubicin/Doxil, dexamethasone (DVd) or PS-341/bortezomib, doxorubicin, dexamethasone (PAD). The aim of this article is to summarize the more recent data available on the efficacy of these combinations and to discuss their role as part of initial therapy.

  15. Absorption Spectroscopy in Homogeneous and Micellar Solutions.

    ERIC Educational Resources Information Center

    Shah, S. Sadiq; Henscheid, Leonard G.

    1983-01-01

    Describes an experiment which has helped physical chemistry students learn principles of absorption spectroscopy, the effect of solvent polarity on absorption spectra, and some micellar chemistry. Background information and experimental procedures are provided. (JN)

  16. Capillary Separation: Micellar Electrokinetic Chromatography

    NASA Astrophysics Data System (ADS)

    Terabe, Shigeru

    2009-07-01

    Micellar electrokinetic chromatography (MEKC), a separation mode of capillary electrophoresis (CE), has enabled the separation of electrically neutral analytes. MEKC can be performed by adding an ionic micelle to the running solution of CE without modifying the instrument. Its separation principle is based on the differential migration of the ionic micelles and the bulk running buffer under electrophoresis conditions and on the interaction between the analyte and the micelle. Hence, MEKC's separation principle is similar to that of chromatography. MEKC is a useful technique particularly for the separation of small molecules, both neutral and charged, and yields high-efficiency separation in a short time with minimum amounts of sample and reagents. To improve the concentration sensitivity of detection, several on-line sample preconcentration techniques such as sweeping have been developed.

  17. Enhanced cytotoxicity of anticancer drug delivered by novel nanoscale polymeric carrier

    NASA Astrophysics Data System (ADS)

    Stoika, R.; Boiko, N.; Senkiv, Y.; Shlyakhtina, Y.; Panchuk, R.; Finiuk, N.; Filyak, Y.; Bilyy, R.; Kit, Y.; Skorohyd, N.; Klyuchivska, O.; Zaichenko, A.; Mitina, N.; Ryabceva, A.

    2013-04-01

    We compared in vitro action of highly toxic anticancer drug doxorubicin under its delivery to the mammalian tumor cells in free form and after encapsulation in novel bio-functionalized nanoscale polymeric carrier. Such encapsulation was found to enhance significantly drug uptake by the targeted cells, as well as its cytotoxic action. 10 times higher cytotoxicity of the carrier-immobilized doxorubicin comparing to its free form was demonstrated by direct cell counting, and 5 times higher cytotoxicity of encapsulated doxorubicin was shown by FACS analysis. The polymeric carrier itself did not possess significant toxicity in vitro or in vivo (laboratory mice). The carrier protected against negative side effects of doxorubicin in mice with experimental NK/Ly lymphoma. The life duration of tumor-bearing animals treated with doxorubicin-carrier complex was significantly longer than life duration in animals treated with free doxorubicin. Besides, the effective treatment dose of the carrier-delivered doxorubicin in tumor-bearing mice was 10 times lower than such dose of free doxorubicin. Thus, novel nanoscale polymers possess high potential as drug carrier.

  18. Host-guest interaction of ZnBDC-MOF + doxorubicin: A theoretical and experimental study

    NASA Astrophysics Data System (ADS)

    Vasconcelos, Iane B.; Wanderley, Kaline A.; Rodrigues, Nailton M.; da Costa, Nivan B.; Freire, Ricardo O.; Junior, Severino A.

    2017-03-01

    The incorporation of drugs in biodegradable polymeric particles is one of many processes that controllably and significantly increase their release and action. In this paper, we describe the synthesis and physicochemical characterization of ZnBDC-MOF + doxorubicin (DOXO@ZnBDC) and the system's effectiveness in the sustained release of the drug doxorubicin. An experimental and theoretical study is presented of the interaction between the [Zn(BDC)(H2O)2]n MOF and the drug doxorubicin (DOXO). The synthesis was characterized by elemental analysis and X-ray powder diffraction (XRPD). The experimental incorporation was accomplished and analyzed by Fourier transform infrared spectroscopy (FTIR), XRPD and UV-Vis (ultraviolet-visible) spectrophotometry. Based on an analysis of the doxorubicin release profile, our results suggest that the drug delivery system showed slower release than other systems under development. Studies of cytotoxicity by the MTT method showed good results for the system developed with antineoplastic doxorubicin, and together with the other results of this study, suggest the successful development of a MOF-based drug delivery system.

  19. Solute-solvent interactions in micellar electrokinetic chromatography: IV. Characterization of electroosmotic flow and micellar markers.

    PubMed

    Fuguet, Elisabet; Ràfols, Clara; Bosch, Elisabeth; Rosés, Martí

    2002-01-01

    A wide study of the compounds and procedures mostly used to determine the electroosmotic flow (EOF) and micelle elution times has been done in seven different micellar electrokinetic chromatography (MEKC) systems. These systems are formed from mixtures of an aqueous buffer with the surfactants sodium dodecyl sulfate, lithium dodecyl sulfate, lithium perfluorooctane sulfonate, sodium cholate, sodium deoxycholate, tetradecyltrimethylammonium bromide and hexadecyltrimethylammonium bromide. The solvation parameter model has been used to evaluate the usefulness of the compounds studied as EOF or micellar markers in each of the seven MEKC systems. It is demonstrated that methanol, acetonitrile and formamide are the best EOF markers, and that dodecanophenone is the best micellar marker.

  20. Doxorubicin as an Antioxidant: Maintenance of Myocardial Levels of Lycopene under Doxorubicin Treatment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The mechanism of doxorubicin-induced cardiotoxicity remains controversial. Wistar-rats (n=96) were randomly assigned to either a control (C), Lycopene (L), Doxorubicin (D) or Doxorubicin + Lycopene (DL) group. The L and DL groups received lycopene (5 mg/Kg-body-wt/d by gavage) for 7 wks. The D and D...

  1. Polymeric microspheres

    DOEpatents

    Walt, David R.; Mandal, Tarun K.; Fleming, Michael S.

    2004-04-13

    The invention features core-shell microsphere compositions, hollow polymeric microspheres, and methods for making the microspheres. The microspheres are characterized as having a polymeric shell with consistent shell thickness.

  2. Micellar Polymer Encapsulation of Enzymes.

    PubMed

    Besic, Sabina; Minteer, Shelley D

    2017-01-01

    Although enzymes are highly efficient and selective catalysts, there have been problems incorporating them into fuel cells. Early enzyme-based fuel cells contained enzymes in solution rather than immobilized on the electrode surface. One problem utilizing an enzyme in solution is an issue of transport associated with long diffusion lengths between the site of bioelectrocatalysis and the electrode. This issue drastically decreases the theoretical overall power output due to the poor electron conductivity. On the other hand, enzymes immobilized at the electrode surface have eliminated the issue of poor electron conduction due to close proximity of electron transfer between electrode and the biocatalyst. Another problem is inefficient and short term stability of catalytic activity within the enzyme that is suspended in free flowing solution. Enzymes in solutions are only stable for hours to days, whereas immobilized enzymes can be stable for weeks to months and now even years. Over the last decade, there has been substantial research on immobilizing enzymes at electrode surfaces for biofuel cell and sensor applications. The most commonly used techniques are sandwich or wired. Sandwich techniques are powerful and successful for enzyme immobilization; however, the enzymes optimal activity is not retained due to the physical distress applied by the polymer limiting its applications as well as the non-uniform distribution of the enzyme and the diffusion of analyte through the polymer is slowed significantly. Wired techniques have shown to extend the lifetime of an enzyme at the electrode surface; however, this technique is very hard to master due to specific covalent bonding of enzyme and polymer which changes the three-dimensional configuration of enzyme and with that decreases the optimal catalytic activity. This chapter details encapsulation techniques where an enzyme will be immobilized within the pores/pockets of the hydrophobically modified micellar polymers such as

  3. Enhanced oral bioavailability of nevirapine within micellar nanocarriers compared with Viramune(®).

    PubMed

    Moretton, Marcela A; Cohen, Laura; Lepera, Leandro; Bernabeu, Ezequiel; Taira, Carlos; Höcht, Christian; Chiappetta, Diego A

    2014-10-01

    In this work, Nevirapine (NVP) was encapsulated within three derivatives of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) block copolymers (Tetronic(®) 904, 1107 and Pluronic(®) F127) with and without the addition of three pharmaceutical cosolvents (glycerin, propylene glycol and polyethylene glycol 400) over a wider range of concentrations (0-40% v/v). Also, we evaluated the effect of addition of the cosolvents on the micellar size as determined by dynamic light scattering (DLS) measurements and transmission electron microscopy (TEM). The solubilization capacity of the systems was investigated by UV-spectrophotometry (282nm) and the systems stability was evaluated for 1 month at 25°C. Finally, oral bioavailability of the NVP-loaded micellar systems (2mg/mL) was assessed in male Wistar rats (8mg/kg) and compared with a pediatric commercially available formulation (Viramune(®)). The present study demonstrates that PEO-PPO-PEO polymeric micelles were able to enhance apparent aqueous solubility of NVP with the addition of cosolvents. Moreover, micellar nanocarriers significantly (p<0.05) improved the oral bioavailability of the drug versus Viramune(®). Overall results support the suitability of the strategy toward the development of an optimized NVP aqueous formulation to prevent HIV/AIDS mother-to-child transmission.

  4. Selective counterion condensation in ionic micellar solutions

    NASA Astrophysics Data System (ADS)

    Aswal, V. K.; Goyal, P. S.

    2003-05-01

    Small-angle neutron scattering experiments have been carried out on micellar solutions of cationic surfactants of cetyltrimethylammonium bromide (CTABr) and chloride (CTACl) in the presence of varying concentrations of salts KBr and KCl. In these systems, while the size of micelles strongly increases with the addition of KBr, the effect of addition of KCl in comparison is much less pronounced. It is found that in equimolar surfactant to salt micellar solutions of CTABr/KCl and CTACl/KBr, the micellar sizes are larger in CTACl/KBr than those in CTABr/KCl. The measurements have been done for different equimolar surfactant to salt concentrations and at different temperatures. We explain these results in terms of selective counterion condensation on the micelles. That is, while the condensation of Cl- counterions on the CTABr micelles in CTABr/KCl takes place around the condensed Br- counterions of CTABr, the Cl- counterions of CTACl in CTACl/KBr are replaced by Br- counterions of the salt. Similar results have also been obtained on micellar solutions of anionic surfactants of sodium dodecyl sulfate and lithium dodecyl sulfate in the presence of salts LiBr and NaBr, respectively.

  5. Selective counterion condensation in ionic micellar solutions.

    PubMed

    Aswal, V K; Goyal, P S

    2003-05-01

    Small-angle neutron scattering experiments have been carried out on micellar solutions of cationic surfactants of cetyltrimethylammonium bromide (CTABr) and chloride (CTACl) in the presence of varying concentrations of salts KBr and KCl. In these systems, while the size of micelles strongly increases with the addition of KBr, the effect of addition of KCl in comparison is much less pronounced. It is found that in equimolar surfactant to salt micellar solutions of CTABr/KCl and CTACl/KBr, the micellar sizes are larger in CTACl/KBr than those in CTABr/KCl. The measurements have been done for different equimolar surfactant to salt concentrations and at different temperatures. We explain these results in terms of selective counterion condensation on the micelles. That is, while the condensation of Cl- counterions on the CTABr micelles in CTABr/KCl takes place around the condensed Br- counterions of CTABr, the Cl- counterions of CTACl in CTACl/KBr are replaced by Br- counterions of the salt. Similar results have also been obtained on micellar solutions of anionic surfactants of sodium dodecyl sulfate and lithium dodecyl sulfate in the presence of salts LiBr and NaBr, respectively.

  6. Ultrafiltration of micellar solutions containing phenols

    SciTech Connect

    Adamczak, H.; Materna, K.; Urbanski, R.; Szymanowski, J.

    1999-10-15

    Micellar-enhanced ultrafiltration represents a potentially attractive tool for the removal of different contaminants from wastewaters. The ultrafiltration of micellar solutions containing phenol or 4-nitrophenol was studied. Sodium dodecyl sulfate (SDS), hexadecylrimethyl ammonium sulfate, alkyl polyglucoside Glucopon 215 SC UP, and oxyethylated methyl dodecanoates with the average degree of oxyethylation equal to 5 and 9 were used as surfactants and NaHCO{sub 3} as an electrolyte and alkalizing agent. Filtration and phenol rejection depends on the presence of NaHCO{sub 3} and the type of surfactant. NaHCO{sub 3} depresses to the filtration rate, especially in the case of SDS and hydrophobic oxyethylated methyl dodecanoate. The highest filtration rates are obtained for hexadecyltrimethyl ammonium bromide (CTAB) and alkyl polyglucoside micellar solutions. The best separations, both of phenol and 4-nitrophenol (almost 100% rejection), are obtained for CTAB micellar solutions at the pH range from 3 to 11. Nonionic surfactants are not effective enough for the separation of phenol and 4-nitrophenol. SDS solutions permit only the separation of phenol.

  7. Acetal-linked paclitaxel prodrug micellar nanoparticles as a versatile and potent platform for cancer therapy.

    PubMed

    Gu, Yudan; Zhong, Yinan; Meng, Fenghua; Cheng, Ru; Deng, Chao; Zhong, Zhiyuan

    2013-08-12

    Endosomal pH-activatable paclitaxel (PTX) prodrug micellar nanoparticles were designed and prepared by conjugating PTX onto water-soluble poly(ethylene glycol)-b-poly(acrylic acid) (PEG-PAA) block copolymers via an acid-labile acetal bond to the PAA block and investigated for potent growth inhibition of human cancer cells in vitro. PTX was readily conjugated to PEG-PAA with high drug contents of 21.6, 27.0, and 42.8 wt % (denoted as PTX prodrugs 1, 2, and 3, respectively) using ethyl glycol vinyl ether (EGVE) as a linker. The resulting PTX conjugates had defined molecular weights and self-assembled in phosphate buffer (PB, pH 7.4, 10 mM) into monodisperse micellar nanoparticles with average sizes of 158.3-180.3 nm depending on PTX contents. The in vitro release studies showed that drug release from PTX prodrug nanoparticles was highly pH-dependent, in which ca. 86.9%, 66.4% and 29.0% of PTX was released from PTX prodrug 3 at 37 °C in 48 h at pH 5.0, 6.0, and pH 7.4, respectively. MTT assays showed that these pH-sensitive PTX prodrug nanoparticles exhibited high antitumor effect to KB and HeLa cells (IC(50) = 0.18 and 0.9 μg PTX equiv/mL, respectively) as well as PTX-resistant A549 cells. Notably, folate-decorated PTX prodrug micellar nanoparticles based on PTX prodrug 3 and 20 wt % folate-poly(ethylene glycol)-b-poly(D,L-lactide) (FA-PEG-PLA) displayed apparent targetability to folate receptor-overexpressing KB cells with IC(50) over 12 times lower than nontargeting PTX prodrug 3 under otherwise the same conditions. Furthermore, PTX prodrug nanoparticles could also load doxorubicin (DOX) to simultaneously release PTX and DOX under mildly acidic pH. These acetal-linked PTX prodrug micellar nanoparticles have appeared as a highly versatile and potent platform for cancer therapy.

  8. Protective effects of berberine against doxorubicin-induced cardiotoxicity in rats by inhibiting metabolism of doxorubicin.

    PubMed

    Hao, Gang; Yu, Yunli; Gu, Bingren; Xing, Yiwen; Xue, Man

    2015-01-01

    1. The clinical use of doxorubicin, an effective anticancer drug, is severely hampered by its cardiotoxicity. Berberine, a botanical alkaloid, has been reported to possess cardioprotective and antitumor effects. In this study, we investigated the cardioprotective effect of berberine on doxorubicin-induced cardiotoxicity and the effect of berberine on the metabolism of doxorubicin. 2. Adult male Sprague-Dawley rats were administered doxorubicin in the presence or absence of berberine for 2 weeks. Administration of berberine effectively prevented doxorubicin-induced body weight reduction and mortality in rats. 3. Berberine reduced the activity of myocardial enzymes, including aspartate aminotransferase (AST), creatine kinase (CK), CK isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Echocardiographic examination further demonstrated that berberine effectively ameliorated cardiac dysfunction induced by doxorubicin. 4. Berberine inhibited the metabolism of doxorubicin in the cytoplasm of rat heart and reduced the accumulation of doxorubicinol (a secondary alcohol metabolite of doxorubicin) in heart. 5. These data showed that berberine alleviated the doxorubicin-induced cardiotoxicity in rats via inhibition of the metabolism of doxorubicin and reduced accumulation of doxorubicinol selectively in hearts.

  9. [Effects of ionic liquids on micellar microstructures and separation performance in micellar electrokinetic chromatography].

    PubMed

    Yu, Meijuan; Hang, Dong; Cao, Yuhua

    2011-02-01

    The effects of ionic liquids on micellar microstructures and separation performance in micellar electrokinetic chromatography (MEKC) were investigated. The experimental results showed that the addition of ionic liquids into micellar system would result in a decreased micellar surface charge density, an enlarged size of micelle and a slight enhancement of the polarity in the inner core of micelle. Prednisone, hydrocortisone and prednisolone were analyzed with MEKC to evaluate the separation performance. Hydrocortisone and prednisolone could not be separated in sodium lauryl sulfate (SDS) micellar system. However, the three analytes could be baseline separated in the mixed system of ionic liquids and SDS (20 mmol/L SDS-10 mmol/L 1-butyl-3-methyl imidazolium tetrafluoroborate-50 mmol/L borax, pH 8.4) within 17 min. Notably, the linearities of the three analytes ranged from 2 to 100 mg/L and the detection limits based on the ratio of signal to noise of 3 were 1.0, 1.1 and 1.0 mg/L for prednisone, hydrocortisone and prednisolone, respectively. The method has been used in the analysis of corticosteroids in cosmetic samples. The recoveries for the three analytes were between 95. 1% and 117%. This method has the advantages of simple pretreatment, high accuracy, good reproducibility, and can be applied to the quality control of cosmetics.

  10. Micellar Enzymology for Thermal, pH, and Solvent Stability.

    PubMed

    Minteer, Shelley D

    2017-01-01

    This chapter describes methods for enzyme stabilization using micellar solutions. Micellar solutions have been shown to increase the thermal stability, as well as the pH and solvent tolerance of enzymes. This field is traditionally referred to as micellar enzymology. This chapter details the use of ionic and nonionic micelles for the stabilization of polyphenol oxidase, lipase, and catalase, although this method could be used with any enzymatic system or enzyme cascade system.

  11. A study of micellar-enhanced ultrafiltration

    SciTech Connect

    Scamehorn, J.F.; Christian, S.D.

    1991-02-01

    Research on ultrafiltration continued. Progress is briefly reported in four basic categories: systematic studies of the phenomenon of solubilization of organics in micelles and the mechanism of removal of organics from aqueous streams, using micellar-enhanced ultrafiltration (MEUF); systematic studies and the development of theoretical models for the binding of ions by micelles and polyelectrolytes; development and demonstration of four new related separation processes for removing ions from water: ligand-modified micellar-enhanced ultrafiltration (LM-MEUF), polyelectrolyte-enhanced ultrafiltration (PEUF), ion-explusion ultrafiltration (IEUF), and a combined surfactant-polyelectrolyte ultrafiltration process; and investigation of downstream processing of the effluent streams from all five of the UF separation processes.

  12. Effect of micellar topology on shear rheology

    NASA Astrophysics Data System (ADS)

    Rogers, Simon; Calabrese, Michelle; Wagner, Norman

    2014-03-01

    Micellar topology affects the nonlinear shear rheology of self-assembled surfactant solutions. Segmental alignment of wormlike micelles (WLMs) exhibiting varying degrees of branching was investigated under shear in the flow-gradient and flow-vorticity planes using new small angle neutron scattering (SANS) sample environments. The degree of branching in mixed cationic/anionic surfactant (CTAT/SDBS) WLMs is controlled via the addition of the hydrotropic salt sodium tosylate. Shear-induced segmental alignment of the micelles is characterized by spatially-resolved flow-small angle neutron scattering (flow-SANS). Our ability to resolve structural projections in both planes provides insight to branch behavior and kinematics under shear flows. Local segmental orientation and alignment in the flow-gradient plane is a non-monotonic function of branching level and radial position. Alignment in the flow-gradient plane is significantly higher than that observed in the flow-vorticity plane, suggesting that branches may simultaneously migrate into the vorticity direction and inhibit spatially localized flows. Shear and normal stresses calculated from micellar alignment using the stress-SANS law are favorably compared with rheological measurements under identical conditions. The results provide evidence for the effects of micellar topology on the nonlinear shear rheology of WLM solutions.

  13. Cellular internalization of doxorubicin loaded star-shaped micelles with hydrophilic zwitterionic sulfobetaine segments.

    PubMed

    Cao, Jun; Xie, Xiaoxiong; Lu, Aijing; He, Bin; Chen, Yuanwei; Gu, Zhongwei; Luo, Xianglin

    2014-05-01

    Four arm star-shaped poly(ε-caprolactone)-b-poly((N,N-diethylaminoethyl methacrylate)-r-(N-(3-sulfopropyl)-N-methacryloxyethy-N,N-diethylammoniumbetaine)) (4sPCLDEAS) micelles were loaded with anticancer drug doxorubicin to track their endocytosis in Hela cancer cell line. The effects of mean diameters and surface charges of the drug loaded micelles on the cellular uptake were studied in details. The results demonstrated that the internalization of micelles was both time and energy dependent process. Endocytic pathways including clathrin-mediated endocytosis, caveolae-mediated endocytosis and macropinocytosis were all involved in the internalization; caveolae-mediated endocytosis was the main pathway for the internalization of 4sPCLDEAS micelles. The assays for cell apoptosis and growth inhibition of tumor spheroids identified that these doxorubicin loaded micelles could induce cell apoptosis and inhibit tumor spheroids growth efficiently, which was even equal to free DOX·HCl. This study provided a rational design strategy for fabricating diverse micellar drug delivery systems with high anticancer efficiency.

  14. Bone-Targeted Acid-Sensitive Doxorubicin Conjugate Micelles as Potential Osteosarcoma Therapeutics

    PubMed Central

    2015-01-01

    Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic d-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data. PMID:25291150

  15. Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics.

    PubMed

    Low, Stewart A; Yang, Jiyuan; Kopeček, Jindřich

    2014-11-19

    Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic D-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data.

  16. Monitoring subcellular biotransformation of N-L-leucyldoxorubicin by micellar electrokinetic capillary chromatography coupled to laser-induced fluorescence detection.

    PubMed

    Satori, Chad P; Meyer, Brandon; Arriaga, Edgar A

    2014-04-01

    Development of prodrugs is a promising alternative to address cytotoxicity and nonspecificity of common anticancer agents. N-L-leucyldoxorubicin (LeuDox) is a prodrug that is biotransformed to the anticancer drug doxorubicin (Dox) in the extracellular space; however, its biotransformation may also occur intracellularly in endocytic organelles. Such organelle-specific biotransformation is yet to be determined. In this study, magnetically enriched endocytic organelle fractions from human uterine sarcoma cells were treated with LeuDox. Micellar electrokinetic chromatography with laser-induced fluorescence detection (MEKC-LIF) was used to determine that 10% of LeuDox was biotransformed to Dox, accounting for ~43% of the biotransformation occurring in the post-nuclear fraction. This finding suggests that endocytic organelles also participate in the intracellular biotransformation of LeuDox to Dox.

  17. Reversible Interactions of Proteins with Mixed Shell Polymeric Micelles: Tuning the Surface Hydrophobic/Hydrophilic Balance toward Efficient Artificial Chaperones.

    PubMed

    Wang, Jianzu; Song, Yiqing; Sun, Pingchuan; An, Yingli; Zhang, Zhenkun; Shi, Linqi

    2016-03-22

    Molecular chaperones can elegantly fine-tune its hydrophobic/hydrophilic balance to assist a broad spectrum of nascent polypeptide chains to fold properly. Such precious property is difficult to be achieved by chaperone mimicking materials due to limited control of their surface characteristics that dictate interactions with unfolded protein intermediates. Mixed shell polymeric micelles (MSPMs), which consist of two kinds of dissimilar polymeric chains in the micellar shell, offer a convenient way to fine-tune surface properties of polymeric nanoparticles. In the current work, we have fabricated ca. 30 kinds of MSPMs with finely tunable hydrophilic/hydrophobic surface properties. We investigated the respective roles of thermosensitive and hydrophilic polymeric chains in the thermodenaturation protection of proteins down to the molecular structure. Although the three kinds of thermosensitive polymers investigated herein can form collapsed hydrophobic domains on the micellar surface, we found distinct capability to capture and release unfolded protein intermediates, due to their respective affinity for proteins. Meanwhile, in terms of the hydrophilic polymeric chains in the micellar shell, poly(ethylene glycol) (PEG) excels in assisting unfolded protein intermediates to refold properly via interacting with the refolding intermediates, resulting in enhanced chaperone efficiency. However, another hydrophilic polymer-poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) severely deteriorates the chaperone efficiency of MSPMs, due to its protein-resistant properties. Judicious combination of thermosensitive and hydrophilic chains in the micellar shell lead to MSPM-based artificial chaperones with optimal efficacy.

  18. pH-Responsive Triblock Copolymeric Micelles Decorated with a Cell-Penetrating Peptide Provide Efficient Doxorubicin Delivery

    NASA Astrophysics Data System (ADS)

    Ng, Khen Eng; Amin, Mohd Cairul Iqbal Mohd; Katas, Haliza; Amjad, Muhammad Wahab; Butt, Adeel Masood; Kesharwani, Prashant; Iyer, Arun K.

    2016-12-01

    This study developed novel triblock pH-responsive polymeric micelles (PMs) using cholic acid-polyethyleneimine-poly- l-arginine (CA-PEI-pArg) copolymers. PEI provided pH sensitivity, while the hydrophilic cell-penetrating pArg peptide promoted cellular PM internalization. The copolymers self-assembled into PMs in aqueous solution at above the critical micelle concentration (2.98 × 10-7 M) and encapsulated doxorubicin in the core region, with a 34.2% ( w/ w) entrapment efficiency. PMs showed pH-dependent swelling, increasing in size by almost sevenfold from pH 7.4 to 5.0. Doxorubicin release was pH-dependent, with about 65% released at pH 5.0, and 32% at pH 7.4. Cellular uptake, assessed by confocal microscopy and flow cytometry, was enhanced by using doxorubicin-loaded CA-PEI-pArg PMs, as compared to free doxorubicin and DOX-loaded CA-PEI PMs. Moreover, 24-h incubation of these PMs with a human breast cancer cell line produced greater cytotoxicity than free doxorubicin. These results indicate that pH-responsive CA-PEI-pArg micelles could provide a versatile delivery system for targeted cancer therapy using hydrophobic drugs.

  19. Calcium modulation of doxorubicin cytotoxicity in yeast and human cells.

    PubMed

    Nguyen, Thi Thuy Trang; Lim, Ying Jun; Fan, Melanie Hui Min; Jackson, Rebecca A; Lim, Kim Kiat; Ang, Wee Han; Ban, Kenneth Hon Kim; Chen, Ee Sin

    2016-03-01

    Doxorubicin is a widely used chemotherapeutic agent, but its utility is limited by cellular resistance and off-target effects. To understand the molecular mechanisms regulating chemotherapeutic responses to doxorubicin, we previously carried out a genomewide search of doxorubicin-resistance genes in Schizosaccharomyces pombe fission yeast and showed that these genes are organized into networks that counteract doxorubicin cytotoxicity. Here, we describe the identification of a subgroup of doxorubicin-resistance genes that, when disrupted, leads to reduced tolerance to exogenous calcium. Unexpectedly, we observed a suppressive effect of calcium on doxorubicin cytotoxicity, where concurrent calcium and doxorubicin treatment resulted in significantly higher cell survival compared with cells treated with doxorubicin alone. Conversely, inhibitors of voltage-gated calcium channels enhanced doxorubicin cytotoxicity in the mutants. Consistent with these observations in fission yeast, calcium also suppressed doxorubicin cytotoxicity in human breast cancer cells. Further epistasis analyses in yeast showed that this suppression of doxorubicin toxicity by calcium was synergistically dependent on Rav1 and Vph2, two regulators of vacuolar-ATPase assembly; this suggests potential modulation of the calcium-doxorubicin interaction by fluctuating proton concentrations within the cellular environment. Thus, the modulatory effects of drugs or diet on calcium concentrations should be considered in doxorubicin treatment regimes.

  20. Glassy states in attractive micellar systems

    NASA Astrophysics Data System (ADS)

    Mallamace, F.; Broccio, M.; Faraone, A.; Chen, W. R.; Chen, S.-H.

    2004-08-01

    Recent mode coupling theory (MCT) calculations show that in attractive colloids one may observe a new type of glass originating from clustering effects, as a result of the attractive interaction. This happens in addition to the known glass-forming mechanism due to cage effects in the hard sphere system. MCT also indicates that, within a certain volume fraction range, varying the external control parameter, the effective temperature, makes the glass-to-liquid-to-glass re-entrance and the glass-to-glass transitions possible. Here we present experimental evidence and details on this complex phase behavior in a three-block copolymer micellar system.

  1. SANS studies of micellar and magnetic fluids

    SciTech Connect

    Hayter, J.B,

    1985-08-01

    Small-angle neutron scattering (SANS) has proved to be an excellent technique for the study of complex fluids. This article introduces SANS from the viewpoint of such studies. The use of SANS to determine the structures of concentrated micellar fluids is then discussed within the framework of current one-component macrofluid (OCM) models, and experimental examples are taken from several contemporary studies. Finally, the discussion is extended to magnetic fluids (ferrofluids) in which the neutron magnetic interaction plays an important experimental role. 25 refs., 11 figs., 1 tab.

  2. Static Structure of Polydisperse Micellar Solutions.

    PubMed

    Mileva

    2000-12-15

    A model study of polydisperse micellar solutions formed by ionic amphiphiles in the presence of added salt is proposed. The structural peculiarities of the system are determined by effective potentials including the screened electrostatic and the hardcore interactions. A perturbation procedure is applied to expand the characteristic parameters of the system around a reference system. The basic result is a model size distribution curve that accounts not only for the inherent polydispersity of the system but also includes the interaggregate interactions and the space correlation of the aggregates. Copyright 2000 Academic Press.

  3. The role of macrocyclic ligands in the structure of LDS micellar solutions

    NASA Astrophysics Data System (ADS)

    Baglioni, P.; Gambi, C. M. C.; Giordano, R.; Teixeira, J.

    1995-02-01

    We have studied the effect of macrocyclic ligands on the aggregation behavior of lithium dodecyl sulfate (LDS) micellar solutions. Two different classes of macrocyclic compounds are investigated: crown-ethers and cryptands. We show that macrocyclic ligands solubilize at the micellar surface by decreasing the micellar surface charge and the micellar aggregation number and increasing the thickness of the micellar polar head group region. These effects are dependent on the shape and size of the macrocyclic ligand.

  4. Voltammetry as a tool for monitoring micellar structural evolution?

    PubMed

    Charlton; Doherty

    2000-02-15

    Self-assembled systems such as micelles and liquid crystals are currently of interest as templates for the controlled formation of nanoscale structures. Knowledge of the mesophase structure, structural evolution, and interparticle interaction is of great importance in understanding the behavior of such systems especially for applications such as nanoreactors. Here, we compare the use of cyclic voltammetry, chronoamperometry, and the rotating disk electrode (RDE) for the determination of micellar hydrodynamic radii and show that only the steady-state RDE yields values directly comparable with nonelectrochemical techniques. The RDE is applied for the determination of cetyltrimethylammonium chloride micellar structure and observing micellar structural evolution as well as evaluating the usual intermicellar interactions. The results clearly show (a) the collapse of the micellar shear plane toward the hard-sphere surface with increasing electrolyte concentration, (b) the electrolyte-dependent spherical expansion of the micellar hard-spheres due to increasing aggregation (N) number, (c) the structural transition from spherical to rodlike micelles, and (d) micellar elongation. As well as structural evolution, the evolutionary changes in interaction processes are also observed, i.e. the transition from Coulombic interactions to excluded volume interaction. This paper describes in detail the voltammetric measurement of these processes and explicates the necessary experimental conditions for successful observation of micellar structural evolution.

  5. Tailoring magnetic PLGA nanoparticles suitable for doxorubicin delivery

    NASA Astrophysics Data System (ADS)

    Tansık, Gülistan; Yakar, Arzu; Gündüz, Ufuk

    2014-01-01

    One of the main problems of current cancer chemotherapy is the lack of selectivity of anti-cancer drugs to tumor cells, which leads to systemic toxicity and adverse side effects. In order to overcome these limitations, researches on controlled drug delivery systems have gained much attention. Nanoscale-based drug delivery systems provide tumor targeting. Among many types of nanocarriers, superparamagnetic nanoparticles with their biocompatible polymer coatings can be targeted to an intented site by an external magnetic field. Thus, the drug can be carried to the targeted site safely. The aim of this study is to prepare poly( dl-lactic- co-glycolic acid) (PLGA)-coated magnetic nanoparticles and load anti-cancer drug, doxorubicin to them. For this purpose, magnetite (Fe3O4) iron oxide nanoparticles were synthesized as a magnetic core material (MNP) and then coated with oleic acid. Oleic acid-coated MNP (OA-MNP) was encapsulated into PLGA. Effects of different OA-MNP/PLGA ratios on magnetite entrapment efficiency were investigated. Doxorubicin-loaded magnetic polymeric nanoparticles (DOX-PLGA-MNP) were prepared. After the characterization of prepared nanoparticles, their cytotoxic effects on MCF-7 cell line were studied. PLGA-coated magnetic nanoparticles (PLGA-MNP) had a proper size and superparamagnetic character. The highest magnetite entrapment efficiency of PLGA-MNP was estimated as 63 % at 1:8 ratio. Cytotoxicity studies of PLGA-MNP did not indicate any notable cell death between the concentration ranges of 2 and 125 μg/ml. Drug loading efficiency was estimated as 32 %, and it was observed that DOX-PLGA-MNP showed significant cytotoxicity on MCF-7 cells compared to PLGA-MNP. The results showed that prepared nanoparticles have desired size and superparamagnetic characteristics without serious toxic effects on cells. These nanoparticles may be suitable for targeted drug delivery applications.

  6. Polymeric nanoparticles

    PubMed Central

    Bolhassani, Azam; Javanzad, Shabnam; Saleh, Tayebeh; Hashemi, Mehrdad; Aghasadeghi, Mohammad Reza; Sadat, Seyed Mehdi

    2014-01-01

    Nanocarriers with various compositions and biological properties have been extensively applied for in vitro/in vivo drug and gene delivery. The family of nanocarriers includes polymeric nanoparticles, lipid-based carriers (liposomes/micelles), dendrimers, carbon nanotubes, and gold nanoparticles (nanoshells/nanocages). Among different delivery systems, polymeric carriers have several properties such as: easy to synthesize, inexpensive, biocompatible, biodegradable, non-immunogenic, non-toxic, and water soluble. In addition, cationic polymers seem to produce more stable complexes led to a more protection during cellular trafficking than cationic lipids. Nanoparticles often show significant adjuvant effects in vaccine delivery since they may be easily taken up by antigen presenting cells (APCs). Natural polymers such as polysaccharides and synthetic polymers have demonstrated great potential to form vaccine nanoparticles. The development of new adjuvants or delivery systems for DNA and protein immunization is an expanding research field. This review describes polymeric carriers especially PLGA, chitosan, and PEI as vaccine delivery systems. PMID:24128651

  7. Evaluation of the El Dorado micellar-polymer demonstration project

    SciTech Connect

    Vanhorn, L.E.

    1983-01-01

    The El Dorado Micellar-Polymer Demonstration Project has been a cooperative venture between Cities Service Co. and the U.S. Department of Energy. The objective of the project was to determine if it was technically and economically feasible to produce commercial volumes of oil using a micellar-polymer process in the El Dorado field. The project was designed to allow a side-by-side comparison of 2 distinctly different micellar-polymer processes in the same field in order that the associated benefits and problems of each could be determined. These are described and evaluated.

  8. Evaluation of the El Dorado Micellar-Polymer Demonstration Project

    SciTech Connect

    VanHorn, L.E.

    1983-06-01

    The El Dorado Micellar-Polymer Demonstration Project has been a cooperative venture between Cities Service Company and the United States Department of Energy. The objective of the project was to determine if it was technically and economically feasible to produce commercial volumes of oil using a micellar-polymer process in the El Dorado field. The project was designed to allow a side-by-side comparison of two distinctly different micellar-polymer processes in the same field in order that the associated benefits and problems of each could be determined.

  9. Mechanisms of doxorubicin resistance in hepatocellular carcinoma

    PubMed Central

    Cox, Josiah; Weinman, Steven

    2015-01-01

    Hepatocellular carcinoma, one of the most common solid tumors worldwide, is poorly responsive to available chemotherapeutic approaches. While systemic chemotherapy is of limited benefit, intra-arterial delivery of doxorubicin to the tumor frequently produces tumor shrinkage. Its utility is limited, in part, by the frequent emergence of doxorubicin resistance. The mechanisms of this resistance include increased expression of multidrug resistance efflux pumps, alterations of the drug target, topoisomerase, and modulation of programmed cell death pathways. Many of these effects result from changes in miRNA expression and are particularly prominent in tumor cells with a stem cell phenotype. This review will summarize the current knowledge on the mechanisms of doxorubicin resistance of hepatocellular carcinoma and the potential for approaches toward therapeutic chemosensitization. PMID:26998221

  10. In vivo and in vitro anti-cancer activity of thermo-sensitive and photo-crosslinkable doxorubicin hydrogels composed of chitosan-doxorubicin conjugates.

    PubMed

    Cho, Young Il; Park, Shinyoung; Jeong, Seo Young; Yoo, Hyuk Sang

    2009-09-01

    Doxorubicin was chemically conjugated to acrylated chitosan in order to obtain sustained-release profiles of doxorubicin from thermo-responsive and photo-crosslinkable hydrogels. Chitooligosaccharide was acrylated with glycidyl methacrylate and subsequently conjugated to doxorubicin via an amide linkage. A mixture of doxorubicin-chitosan conjugates, acrylated Pluronic, and doxorubicin formed physical gels at 37 degrees C. Photo-irradiation was subsequently performed to chemically crosslink the physical hydrogel at 37 degrees C. Chitooligosaccharide-doxorubicin conjugates in the doxorubicin hydrogels significantly reduced burst release of free doxorubicin from doxorubicin hydrogels compared hydrogels without the conjugates. Upon incubating doxorubicin hydrogels at 37 degrees C, chitosan-doxorubicin conjugates were confirmed to be degraded into more hydrophilic oligomers by reversed-phase chromatography. In vitro cytotoxicity assay using released media from doxorubicin hydrogels showed that degraded chitosan-doxorubicin had cytotoxicity comparable to free doxorubicin. Athymic nude mice bearing human lung adenocarcinoma were subjected to intra-tumoral injections of physical hydrogels. After photo-crosslinking injected hydrogels using surgical catheters, tumor sizes, body weights, and survivals were measured for 1 month. Released media from doxorubicin hydrogels exerted similar cytotoxicities to free doxorubicin, and the tumor volume was significantly reduced for 1 month compared to other samples. Thus, doxorubicin hydrogels containing doxorubicin conjugates can be employed as a novel injectable anti-cancer drug aiming to achieve sustained release of doxorubicin for several weeks against solid tumors.

  11. Targeted Magnetic Liposomes Loaded with Doxorubicin.

    PubMed

    Pradhan, Pallab; Banerjee, Rinti; Bahadur, Dhirendra; Koch, Christian; Mykhaylyk, Olga; Plank, Christian

    2017-01-01

    Targeted delivery systems for anticancer drugs are urgently needed to achieve maximum therapeutic efficacy by site-specific accumulation and thereby minimizing adverse effects resulting from systemic distribution of many potent anticancer drugs. We have prepared folate receptor-targeted magnetic liposomes loaded with doxorubicin, which are designed for tumor targeting through a combination of magnetic and biological targeting. Furthermore, these liposomes are designed for hyperthermia-induced drug release to be mediated by an alternating magnetic field and to be traceable by magnetic resonance imaging (MRI). Here, detailed preparation and relevant characterization techniques of targeted magnetic liposomes encapsulating doxorubicin are described.

  12. Micellar nano-carriers for the delivery of STAT3 dimerization inhibitors to melanoma.

    PubMed

    Soleimani, Amir H; Garg, Shyam M; Paiva, Igor M; Vakili, Mohammad R; Alshareef, Abdulraheem; Huang, Yung-Hsing; Molavi, Ommoleila; Lai, Raymond; Lavasanifar, Afsaneh

    2017-03-13

    The objective of this research was to develop polymeric micellar formulations of inhibitors of signal transducer and activator of transcription 3 (STAT3) dimerization, i.e., S3I-1757 and S3I-201, and evaluate the activity of successful formulations in B16-F10 melanoma, a STAT3 hyperactive cancer model, in vitro and in vivo. STAT3 inhibitory agents were encapsulated in methoxy poly(ethylene oxide)-b-poly(ε-caprolactone) (PEO114-b-PCL22) and methoxy poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (PEO114-b-PBCL20) micelles using co-solvent evaporation. Polymeric micelles of S3I-1757 showed high encapsulation efficiency (>88%), slow release profile (<32% release in 24 h) under physiological conditions, and a desirable average diameter for tumor targeting (33-54 nm). The same formulations showed low encapsulation efficiencies and rapid drug release for S3I-201. Further studies evidenced the delivery of functional S3I-1757 by polymeric micelles to B16-F10 melanoma cells, leading to a dose-dependent inhibition of cell growth and vascular endothelial growth factor (VEGF) production comparable with that of free drug. Encapsulation of S3I-1757 in polymeric micelles significantly reduced its cytotoxicity in normal bone marrow-derived dendritic cells (DCs). Micelles of S3I-1757 were able to significantly improve the function of B16-F10 tumor-exposed immunosuppressed DCs in the production of IL-12, an indication for functionality in the induction of cell-mediated immune response. In a B16-F10 melanoma mouse model, S3I-1757 micelles inhibited tumor growth and enhanced the survival of tumor-bearing mice more than free S3I-1757. Our findings show that both PCL- and PBCL-based polymeric micelles have potential for the solubilization and delivery of S3I-1757, a potent STAT3 inhibitory agent.

  13. Surface-Adaptive, Antimicrobially Loaded, Micellar Nanocarriers with Enhanced Penetration and Killing Efficiency in Staphylococcal Biofilms.

    PubMed

    Liu, Yong; Busscher, Henk J; Zhao, Bingran; Li, Yuanfeng; Zhang, Zhenkun; van der Mei, Henny C; Ren, Yijin; Shi, Linqi

    2016-04-26

    Biofilms cause persistent bacterial infections and are extremely recalcitrant to antimicrobials, due in part to reduced penetration of antimicrobials into biofilms that allows bacteria residing in the depth of a biofilm to survive antimicrobial treatment. Here, we describe the preparation of surface-adaptive, Triclosan-loaded micellar nanocarriers showing (1) enhanced biofilm penetration and accumulation, (2) electrostatic targeting at acidic pH toward negatively charged bacterial cell surfaces in a biofilm, and (3) antimicrobial release due to degradation of the micelle core by bacterial lipases. First, it was established that mixed-shell-polymeric-micelles (MSPM) consisting of a hydrophilic poly(ethylene glycol) (PEG)-shell and pH-responsive poly(β-amino ester) become positively charged at pH 5.0, while being negatively charged at physiological pH. This is opposite to single-shell-polymeric-micelles (SSPM) possessing only a PEG-shell and remaining negatively charged at pH 5.0. The stealth properties of the PEG-shell combined with its surface-adaptive charge allow MSPMs to penetrate and accumulate in staphylococcal biofilms, as demonstrated for fluorescent Nile red loaded micelles using confocal-laser-scanning-microscopy. SSPMs, not adapting a positive charge at pH 5.0, could not be demonstrated to penetrate and accumulate in a biofilm. Once micellar nanocarriers are bound to a staphylococcal cell surface, bacterial enzymes degrade the MSPM core to release its antimicrobial content and kill bacteria over the depth of a biofilm. This constitutes a highly effective pathway to control blood-accessible staphylococcal biofilms using antimicrobials, bypassing biofilm recalcitrance to antimicrobial penetration.

  14. Doxorubicin-transferrin conjugate triggers pro-oxidative disorders in solid tumor cells.

    PubMed

    Szwed, Marzena; Wrona, Dominika; Kania, Katarzyna D; Koceva-Chyla, Aneta; Marczak, Agnieszka

    2016-03-01

    The formation of reactive oxygen species (ROS) is a widely accepted mechanism of doxorubicin (DOX) toxicity toward cancer cells. However, little is known about the potential of new systems, designed for more efficient and targeted doxorubicin delivery (i.e. protein conjugates, polymeric micelles, liposomes, monoclonal antibodies), to induce oxidative stress (OS) in tumors and hematological malignancies. Therefore, the objective of our study was to determine the relation between the toxicity of doxorubicin-transferring (DOX-TRF) conjugate and its capability to generate oxidative/nitrosative stress in solid tumor cells. Our research proves that DOX-TRF conjugate displays higher cytotoxicity towards lung adenocarcinoma epithelial (A549) and hepatocellular carcinoma (HepG2) cell lines than the reference free drug (DOX) and induces more extensive OS, characterized by a significant decrease in the total cellular antioxidant capacity, glutathione level and amount of -SH groups and an increase in hydroperoxide content. The intracellular redox imbalance was accompanied by changes in the transcription of genes encoding key antioxidant enzymes engaged in the sustaining of cellular redox homeostasis: superoxide dismutase (SOD), catalase (CAT), glutathione transferase (GST) and glutathione peroxidase (GP).

  15. QRAR models for cardiovascular system drugs using biopartitioning micellar chromatography.

    PubMed

    Wang, Sumin; Yang, Gengliang; Zhang, Hua; Liu, Haiyan; Li, Zhiwei

    2007-02-01

    The capability of biopartitioning micellar chromatography (BMC) to describe and estimate pharmacological parameters of cardiovascular system drugs has been studied. The retention of cardiovascular system drugs was studied using different pH of Brij-35 as micellar mobile phase in modified C(18) stationary phase. Quantitative retention-activity relationships (QRAR) in BMC were investigated for these compounds. An adequate correlation between the retention factors (log k) and the toxicity (LD(50)) of cardiovascular system drugs was obtained.

  16. Chitosan-Decorated Doxorubicin-Encapsulated Nanoparticle Targets and Eliminates Tumor Reinitiating Cancer Stem-like Cells.

    PubMed

    Rao, Wei; Wang, Hai; Han, Jianfeng; Zhao, Shuting; Dumbleton, Jenna; Agarwal, Pranay; Zhang, Wujie; Zhao, Gang; Yu, Jianhua; Zynger, Debra L; Lu, Xiongbin; He, Xiaoming

    2015-06-23

    Tumor reinitiating cancer stem-like cells are responsible for cancer recurrence associated with conventional chemotherapy. We developed a doxorubicin-encapsulated polymeric nanoparticle surface-decorated with chitosan that can specifically target the CD44 receptors of these cells. This nanoparticle system was engineered to release the doxorubicin in acidic environments, which occurs when the nanoparticles are localized in the acidic tumor microenvironment and when they are internalized and localized in the cellular endosomes/lysosomes. This nanoparticle design strategy increases the cytotoxicity of the doxorubicin by six times in comparison to the use of free doxorubicin for eliminating CD44(+) cancer stem-like cells residing in 3D mammary tumor spheroids (i.e., mammospheres). We further show these nanoparticles reduced the size of tumors in an orthotopic xenograft tumor model with no evident systemic toxicity. The development of nanoparticle system to target cancer stem-like cells with low systemic toxicity provides a new treatment arsenal for improving the survival of cancer patients.

  17. Nanoengineered mesoporous silica nanoparticles for smart delivery of doxorubicin

    NASA Astrophysics Data System (ADS)

    Mishra, Akhilesh Kumar; Pandey, Himanshu; Agarwal, Vishnu; Ramteke, Pramod W.; Pandey, Avinash C.

    2014-08-01

    The motive of the at hand exploration was to contrive a proficient innovative pH-responsive nanocarrier designed for an anti-neoplastic agent that not only owns competent loading capacity but also talented to liberate the drug at the specific site. pH sensitive hollow mesoporous silica nanoparticles ( MSN) have been synthesized by sequence of chemical reconstruction with an average particle size of 120 nm. MSN reveal noteworthy biocompatibility and efficient drug loading magnitude. Active molecules such as Doxorubicin (DOX) can be stocked and set free from the pore vacuities of MSN by tuning the pH of the medium. The loading extent of MSN was found up to 81.4 wt% at pH 7.8. At mild acidic pH, DOX is steadily released from the pores of MSN. Both, the nitrogen adsorption-desorption isotherms and X-ray diffraction patterns reflects that this system holds remarkable stable mesostructure. Additionally, the outcomes of cytotoxicity assessment further establish the potential of MSN as a relevant drug transporter which can be thought over an appealing choice to a polymeric delivery system.

  18. Doxorubicin-Nanocarriers Enhance Doxorubicin Uptake and Clathrin-Mediated Endocytosis in Drug-Resistant Ovarian Cancer Cells

    NASA Astrophysics Data System (ADS)

    Abdullah, Mohammed

    We tested Fe3O4 TiO2 metal oxide core-shell nanocomposites as carriers for doxorubicin and investigated the distribution of "doxorubicin-nanocarriers" and free doxorubicin in doxorubicin-sensitive and -resistant ovarian cancer cell lines. We hypothesized that doxorubicin-nanocarriers (DOX-NCs) would increase doxorubicin uptake in a drug-resistant cell line. Our expectation was that doxorubicin would bind to the TiO2 surface either by a labile monodentate link or through adsorption and subsequent disassociation from the nanocomposite carriers upon acidification in cell endosomes. Released doxorubicin could then traverse the intracellular milieu to enter the cell nucleus, overcoming the p-glycoprotein mediated doxorubicin resistance. Using a combination of confocal fluorescent microscopy, flow cytometry, and X-ray fluorescence microscopy we were able to evaluate the uptake and distribution of doxorubicin-nanocarriers in cells. Moreover, we found that nanocomposite treatment modulates the simultaneous uptake and distribution of fluorescent transferrin in ovarian cancer cell lines. This increased transferrin uptake still occurred by clathrin-mediated endocytosis; it appears that the nanocomposites and DOX-NCs alike may interfere with trans-Golgi apparatus function.

  19. Chain Reaction Polymerization.

    ERIC Educational Resources Information Center

    McGrath, James E.

    1981-01-01

    The salient features and importance of chain-reaction polymerization are discussed, including such topics as the thermodynamics of polymerization, free-radical polymerization kinetics, radical polymerization processes, copolymers, and free-radical chain, anionic, cationic, coordination, and ring-opening polymerizations. (JN)

  20. Biokompatible Polymere

    NASA Astrophysics Data System (ADS)

    Ha, Suk-Woo; Wintermantel, Erich; Maier, Gerhard

    Der klinische Einsatz von synthetischen Polymeren begann in den 60-er Jahren in Form von Einwegartikeln, wie beispielsweise Spritzen und Kathetern, vor allem aufgrund der Tatsache, dass Infektionen infolge nicht ausreichender Sterilität der wiederverwendbaren Artikel aus Glas und metallischen Werkstoffen durch den Einsatz von sterilen Einwegartikeln signifikant reduziert werden konnten [1]. Die Einführung der medizinischen Einwegartikel aus Polymeren erfolgte somit nicht nur aus ökonomischen, sondern auch aus hygienischen Gründen. Wegen der steigenden Anzahl synthetischer Polymere und dem zunehmenden Bedarf an ärztlicher Versorgung reicht die Anwendung von Polymeren in der Medizin von preisgünstigen Einwegartikeln, die nur kurzzeitig intrakorporal eingesetzt werden, bis hin zu Implantaten, welche über eine längere Zeit grossen Beanspruchungen im menschlichen Körper ausgesetzt sind. Die steigende Verbreitung von klinisch eingesetzten Polymeren ist auf ihre einfache und preisgünstige Verarbeitbarkeit in eine Vielzahl von Formen und Geometrien sowie auf ihr breites Eigenschaftsspektrum zurückzuführen. Polymere werden daher in fast allen medizinischen Bereichen eingesetzt.

  1. Flow-induced structured phase in nonionic micellar solutions.

    PubMed

    Cardiel, Joshua J; Tonggu, Lige; de la Iglesia, Pablo; Zhao, Ya; Pozzo, Danilo C; Wang, Liguo; Shen, Amy Q

    2013-12-17

    In this work, we consider the flow of a nonionic micellar solution (precursor) through an array of microposts, with focus on its microstructural and rheological evolution. The precursor contains polyoxyethylene(20) sorbitan monooleate (Tween-80) and cosurfactant monolaurin (ML). An irreversible flow-induced structured phase (NI-FISP) emerges after the nonionic precursor flows through the hexagonal micropost arrays, when subjected to strain rates ~10(4) s(-1) and strain ~10(3). NI-FISP consists of close-looped micellar bundles and multiconnected micellar networks as evidenced by transmission electron microscopy (TEM) and cryo-electron microscopy (cryo-EM). We also conduct small-angle neutron scattering (SANS) measurements in both precursor and NI-FISP to illustrate the structural transition. We propose a potential mechanism for the NI-FISP formation that relies on the micropost arrays and the flow kinematics in the microdevice to induce entropic fluctuations in the micellar solution. Finally, we show that the rheological variation from a viscous precursor solution to a viscoelastic micellar structured phase is associated with the structural evolution from the precursor to NI-FISP.

  2. Micellar effects on dediazoniation and on azo coupling reactions.

    PubMed

    Pazo-Llorente, Román; Rodriguez-Menacho, M A Carmen; González-Romero, Elisa; Bravo-Díaz, Carlos

    2002-04-01

    The effects of a sodium dodecyl sulfate, SDS, micellar solution on the coupling rates of two arenediazonium ions, ArN(2)(+), with the hydrophobic 1-naphthylamine, 1NA and N-(1-naphthyl) ethylenediamine, NED, coupling agents and with the hydrophilic Na salt of 2-naphthol-6-sulfonic acid, 2N6S, have been studied. First, we explored the micellar effects on the thermal decomposition of the arenediazonium ions. The observed rate constants are slightly depressed or increased, depending on the nature of ArN(2)(+), compared to those in pure water upon increasing [SDS]. Estimations of the corresponding association constant to the micelle indicate that a significant fraction of the arenediazonium ions are incorporated into the micelles even at low surfactant concentrations. The sulfonate group in 2N6S prevents its incorporation into the micellar aggregate due to the electrostatic barrier imposed by the micelles and, in consequence, the coupling reaction is inhibited. In contrast, when employing the naphthylamine derivatives, the observed rate constant increase rapidly up to a maximum at [SDS]micellar and aqueous pseudophases, the micellar-induced shift in the pK(a) of the amines, and the concentration/dilution effect exerted by the micelles.

  3. Principles of micellar electrokinetic capillary chromatography applied in pharmaceutical analysis.

    PubMed

    Hancu, Gabriel; Simon, Brigitta; Rusu, Aura; Mircia, Eleonora; Gyéresi, Arpád

    2013-01-01

    Since its introduction capillary electrophoresis has shown great potential in areas where electrophoretic techniques have rarely been used before, including here the analysis of pharmaceutical substances. The large majority of pharmaceutical substances are neutral from electrophoretic point of view, consequently separations by the classic capillary zone electrophoresis; where separation is based on the differences between the own electrophoretic mobilities of the analytes; are hard to achieve. Micellar electrokinetic capillary chromatography, a hybrid method that combines chromatographic and electrophoretic separation principles, extends the applicability of capillary electrophoretic methods to neutral analytes. In micellar electrokinetic capillary chromatography, surfactants are added to the buffer solution in concentration above their critical micellar concentrations, consequently micelles are formed; micelles that undergo electrophoretic migration like any other charged particle. The separation is based on the differential partitioning of an analyte between the two-phase system: the mobile aqueous phase and micellar pseudostationary phase. The present paper aims to summarize the basic aspects regarding separation principles and practical applications of micellar electrokinetic capillary chromatography, with particular attention to those relevant in pharmaceutical analysis.

  4. Self-crosslinkable and intracellularly decrosslinkable biodegradable micellar nanoparticles: A robust, simple and multifunctional nanoplatform for high-efficiency targeted cancer chemotherapy.

    PubMed

    Zou, Yan; Fang, Ya; Meng, Hao; Meng, Fenghua; Deng, Chao; Zhang, Jian; Zhong, Zhiyuan

    2016-12-28

    Nanomedicines based on biodegradable micelles offer a most promising treatment for malignant tumors. Their clinical effectiveness, however, remains to be improved. Here, we report that self-crosslinkable and intracellularly decrosslinkable micellar nanoparticles (SCID-Ms) self-assembled from novel amphiphilic biodegradable poly(ethylene glycol)-b-poly(dithiolane trimethylene carbonate) block copolymer achieve high-efficiency targeted cancer chemotherapy in vivo. Interestingly, doxorubicin (DOX)-loaded SCID-Ms showed favorable features of superb stability, minimal drug leakage, long circulation time, triggered drug release inside the tumor cells, and an unprecedented maximum-tolerated dose (MTD) of over 100mg DOX equiv./kg in mice, which was at least 10 times higher than free drug. The in vivo studies in malignant B16 melanoma-bearing C57BL/6 mice revealed that DOX-SCID-Ms at a dosage of 30mg DOX equiv./kg could effectively suppress tumor growth and prolong mice survival time without causing obvious systemic toxicity. Moreover, DOX-SCID-Ms could be readily decorated with a targeting ligand like cRGD peptide. The biodistribution studies showed that cRGD20/DOX-SCID-Ms had a high tumor accumulation of 6.13% ID/g at 6h post injection, which was ca. 3-fold higher than that for clinically used pegylated liposomal doxorubicin (DOX-LPs). Accordingly, cRGD20/DOX-SCID-Ms exhibited significantly better therapeutic efficacy and lower side effects than DOX-LPs in B16 melanoma-bearing mice. These self-regulating biodegradable micellar nanoparticles offer a robust, multifunctional and viable nanoplatform for targeted cancer chemotherapy.

  5. The effect of flavonoid derivatives on doxorubicin transport and metabolism.

    PubMed

    Václavíková, Radka; Kondrová, Eliska; Ehrlichová, Marie; Boumendjel, Ahcene; Kovár, Jan; Stopka, Pavel; Soucek, Pavel; Gut, Ivan

    2008-02-15

    This study investigated the effect of naturally occurring flavonoids and synthetic aurone derivatives on the formation of cardiotoxic doxorubicinol and transport of doxorubicin in breast cancer cells. Quercetin significantly inhibited the formation of doxorubicinol. Quercetin and aurones did not significantly affect transport of [14C]doxorubicin in human resistant breast cancer cells. In conclusion, quercetin should be further tested for its potency to decrease doxorubicin-mediated toxicity.

  6. Doxorubicin cardiomyopathy in children with left-sided Wilms tumor

    SciTech Connect

    Pinkel, D.; Camitta, B.; Kun, L.; Howarth, C.; Tang, T.

    1982-01-01

    Two children with Wilms tumor of the left kidney experienced severe anthracycline cardiomyopathy after irradiation to the tumor bed and conventional dosage of doxorubicin. The cardiomyopathy is attributed 1) to the fact that radiation fields for left Wilms tumor include the lower portion of the heart and 2) to the interaction of doxorubicin and irradiation on cardiac muscle. It is recommended that doxorubicin dosage be sharply restricted in children with Wilms tumor of the left kidney who receive postoperative irradiation.

  7. Counterion condensation and release in micellar solutions

    NASA Astrophysics Data System (ADS)

    Hsiao, Chin Chieh; Wang, Tzu-Yu; Tsao, Heng-Kwong

    2005-04-01

    Counterion condensation and release in micellar solutions are investigated by direct measurement of counterion concentration with ion-selective electrode. Monte Carlo simulations based on the cell model are also performed to analyze the experimental results. The degree of counterion condensation is indicated by the concentration ratio of counterions in the bulk to the total ionic surfactant added, α⩽1. The ionic surfactant is completely dissociated below the critical micelle concentration (cmc). However, as cmc is exceeded, the free counterion ratio α declines with increasing the surfactant concentration and approaches an asymptotic value owing to counterion condensation to the surface of the highly charged micelles. Micelle formation leads to much stronger electrostatic attraction between the counterion and the highly charged sphere in comparison to the attraction of single surfactant ion with its counterion. A simple model is developed to obtain the true degree of ionization, which agrees with our Monte Carlo results. Upon addition of neutral polymer or monovalent salts, some of the surfactant counterions are released to the bulk. The former is due to the decrease of the intrinsic charge (smaller aggregation number) and the degree of ionization is increased. The latter is attributed to competitive counterion condensation, which follows the Hefmeister series. This consequence indicates that the specific ion effect plays an important role next to the electrostatic attraction.

  8. Cardiac actomyosin ATPase activity after chronic doxorubicin treatment.

    PubMed

    Bergson, A; Inchiosa, M A

    1985-04-01

    Doxorubicin (Adriamycin), a potent antineoplastic drug, produces progressive cardiotoxicity which may lead to ultimate cardiac failure. The effects of chronic doxorubicin treatment on cardiac actomyosin ATPase were the principal focus of the present studies. This approach was based on the established correlation between cardiac contractility and contractile protein ATPase activity. Rabbits were injected intravenously with doxorubicin (4 mg/kg) at weekly intervals for 1-7 weeks. Body weight increase was attenuated in the treated animals; heart weight/body weight ratio was unchanged. Actomyosin and water contents of ventricular muscle were not different in doxorubicin-treated as compared with vehicle control animals. Cellular damage was detected histologically after one dose of doxorubicin (equivalent to a single clinical dose), and was extensive after 4-5 weeks of treatment. Animals which received 1-2 injections of doxorubicin demonstrated a 29% average increase in actomyosin ATPase activity as compared to vehicle controls; this difference was highly significant (p less than 0.001). Further treatment with doxorubicin tended to progressively decrease ATPase activity. It is suggested that the increased actomyosin ATPase activity seen with low total doses of doxorubicin may represent a compensatory mechanism for maintenance of contractility; this interpretation is supported by the clinical observation that the morphologic evidence of progressive doxorubicin toxicity is not associated with a parallel decrease in contractility, until severe cumulative toxicity has been induced.

  9. Biopartitioning micellar chromatography to predict mutagenicity of aromatic amines.

    PubMed

    Torres-Cartas, S; Martín-Biosca, Y; Villanueva-Camañas, R M; Sagrado, S; Medina-Hernández, M J

    2007-01-01

    Mutagenicity is a toxicity endpoint associated with the chronic exposure to chemicals. Aromatic amines have considerable industrial and environmental importance due to their widespread use in industry and their mutagenic capacity. Biopartitioning micellar chromatography (BMC), a mode of micellar liquid chromatography that uses micellar mobile phases of Brij35 in adequate experimental conditions, has demonstrated to be useful in mimicking the drug partitioning process into biological systems. In this paper, the usefulness of BMC for predicting mutagenicity of aromatic amines is demonstrated. A multiple linear regression (MLR) model based on BMC retention data is proposed and compared with other ones reported in bibliography. The proposed model present better or similar descriptive and predictive capability.

  10. El Dorado micellar-polymer project - a status report

    SciTech Connect

    Vanhorn, L.E.

    1981-01-01

    The El Dorado Micellar-Polymer Demonstration Project is a cooperative venture between Cities Service Co. and the U.S. Department of Energy. The primary objective of the project is to determine the economic feasibility of improved oil recovery using 2 micellar-polymer processes and to determine the associated benefits and problems of each process. The El Dorado Demonstration Project is designed to allow a side-by-side comparison of 2 distinct micellar-polymer processes in the same field so that the reservoir conditions for the 2 floods are as similar as possible. This report updates the status of the operation of the El Dorado Project from Jan. 1979 through Dec. 1980.

  11. Mechanistic studies of partial-filing micellar electrokinetic chromatography

    SciTech Connect

    Nelson, W.M.; Lee, C.S. |

    1996-09-15

    The need for coupling micellar electrokinetic chromatography (MEKC) with electrospray mass spectrometry initiates the development of partial-filling MEKC. In comparison with conventional MEKC, only a small portion of the capillary is filled with a micellar solution for performing the separation in partial-filling MEKC. Analytes first migrate into the micellar plug, where the separation occurs, and then into the leading electrophoresis buffer, which is free of surfactants. A theoretical model is proposed for predicting the separation behavior of triazine herbicides in partial-filling MEKC. The comparisons between conventional and partial-filling MEKC in terms of separation efficiency and resolution of triazine herbicides are presented and discussed. The optimization techniques, possible applications, and advantages of partial-filling MEKC are similarly addressed. 11 refs., 6 figs., 5 tabs.

  12. Micellar kinetics of a fluorosurfactant through stopped-flow NMR.

    PubMed

    Yushmanov, Pavel V; Furó, István; Stilbs, Peter

    2006-02-28

    19F NMR chemical shifts and transverse relaxation times T2 were measured as a function of time after quick stopped-flow dilution of aqueous solutions of sodium perfluorooctanoate (NaPFO) with water. Different initial concentrations of micellar solution and different proportions of mixing were tested. Previous stopped-flow studies by time-resolved small-angle X-ray scattering (TR-SAXS) detection indicated a slow (approximately 10 s) micellar relaxation kinetics in NaPFO solutions. In contrast, no evidence of any comparable slow (>100 ms) relaxation process was found in our NMR studies. Possible artifacts of stopped-flow experiments are discussed as well as differences between NMR and SAXS detection methods. Upper bounds on the relative weight of a slow relaxation process are given within existing kinetic theories of micellar dissolution.

  13. Development and application of a streamline micellar/polymer simulator

    SciTech Connect

    Wang, B.; Lake, L.W.; Pope, G.A.

    1981-01-01

    A large-scale, two-dimensional, multicomponent, multiphase, compositional simulator for micellar/polymer flooding has been developed and applied. It can be used to calculate the areal sweep with any well pattern and any irregular reservoir boundary. The model involves both streamline and finite-difference techniques. In order to demonstrate that this model is capable of handling large field problems, a large-scale simulation of the north lease of the Kansas' El Dorado micellar/polymer pilot test was made. The simulated final oil recovery and the production histories of each producer are illustrated. 28 refs.

  14. Adsorption Kinetics in Micellar Solutions of Nonionic Surfactants

    NASA Astrophysics Data System (ADS)

    Colegate, Daniel M.; Bain, Colin D.

    2005-11-01

    Standard models of the adsorption kinetics of surfactants at the air-water surface assume that micelles break down into monomers in the bulk solution and that only monomers adsorb. We show here that micelles of the nonionic surfactant C14E8 adsorb to the surface of a liquid jet at a diffusion-controlled rate. Micellar adsorption can be switched off by incorporation of a small amount of ionic surfactant into the micelle and switched on again by addition of salt. More sophisticated models of adsorption processes in micellar solutions are required that permit a kinetic flux of micelles to the air-water interface.

  15. Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression

    PubMed Central

    Dong, Qinghua; Chen, Long; Lu, Qunwei; Sharma, Sherven; Li, Lei; Morimoto, Sachio; Wang, Guanyu

    2014-01-01

    Background and Purpose Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin-induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi-1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin-mediated protection against doxorubicin-induced cardiotoxicity. Experimental Approach Effects of quercetin on doxorubicin-induced cardiotoxicity was evaluated using H9c2 cardiomyocytes and C57BL/6 mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2 cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre-treatment. Key Results In H9c2 cells, quercetin reduced doxorubicin-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double-strand breaks. The quercetin-mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53 and oxidase (p47 and Nox1) and by increased expression of Bcl-2 and Bmi-1. Bmi-1 siRNA abolished the protective effect of quercetin against doxorubicin-induced toxicity in H9c2 cells. Furthermore, quercetin protected mice from doxorubicin-induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi-1 and anti-oxidative superoxide dismutase. Conclusions and Implications Our results demonstrate that quercetin decreased doxorubicin-induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up-regulation of Bmi-1 expression. The findings presented in this study have potential applications in preventing doxorubicin-induced cardiomyopathy. PMID:24902966

  16. El Dorado micellar-polymer demonstration project

    SciTech Connect

    Rosenwald, G.W.

    1980-02-01

    The micellar fluid injection was completed in the north (Chesney) pattern, and injection of polymer soluttion was initiated. Polymer solution was injected into the south (Hegberg) pattern during the entire reporting period. The third step of the graded polymer injection design is nearing completion. Fluid movement at the observation wells has been monitored closely. Oil mobilization has been indicated by the detection of an oil bank moving past some of the observation wells in both patterns. No significant changes in fluid composition have occurred at the eight production wells during this reporting period. Three flow tests designed to define the optimal salinity for the north pattern polymer drive were made using El Dorado 650-ft Sandstone cores. Results of these tests indicated that a polymer drive with 1.0 wt %. NaCl in El Dorado lake water has the highest oil recovery efficiency. The pressures in the project monitoring wells were measured four times. Two sets of pressure transient tests were conducted to determine the extent of a hydraulic fracture of well MP-213; these tests also involved wells MP-226 and MP-227. An extensive discussion of the west-to-east pressure gradient observed in the field was presented last year. Data indicate the gradient still exists. Computations show that the gradient cannot be caused by the degree of reservoir heterogeneity thought to exist in the El Dorado reservoir. Although the cause of the gradient remains unexplained, its adverse impact on ultimate oil recovery could be significant and should be considered in future performance modeling. An estimate of recovery efficiency was made based on the updated calculations and the data taken for the one-foot interval at well MP-131. These preliminary results showed about 40% displacement efficiency.

  17. Comparison of doxorubicin-cyclophosphamide with doxorubicin-dacarbazine for the adjuvant treatment of canine hemangiosarcoma.

    PubMed

    Finotello, R; Stefanello, D; Zini, E; Marconato, L

    2017-03-01

    Canine hemangiosarcoma (HSA) is a neoplasm of vascular endothelial origin that has an aggressive biological behaviour, with less than 10% of dogs alive at 12-months postdiagnosis. Treatment of choice consists of surgery followed by adjuvant doxorubicin-based chemotherapy. We prospectively compared adjuvant doxorubicin and dacarbazine (ADTIC) to a traditional doxorubicin and cyclophosphamide (AC) treatment, aiming at determining safety and assessing whether this regimen prolongs survival and time to metastasis (TTM). Twenty-seven dogs were enrolled; following staging work-up, 18 were treated with AC and 9 with ADTIC. Median TTM and survival time were longer for dogs treated with ADTIC compared with those receiving AC (>550 versus 112 days, P = 0.021 and >550 versus 142 days, P = 0.011, respectively). Both protocols were well tolerated, without need for dose reduction or increased interval between treatments. A protocol consisting of combined doxorubicin and dacarbazine is safe in dogs with HSA and prolongs TTM and survival time.

  18. Dynamics of adsorption in micellar and non micellar solutions of derivatives of lysosomotropic substances.

    PubMed

    Dopierala, Katarzyna; Prochaska, Krystyna

    2010-04-22

    Dynamics of adsorption in micellar and non micellar solutions of derivatives of lysosomotropic substances was studied. The following compounds were considered in our research work: alkyl N,N-dimethyl-alaninates methobromides (DMALM-n), alkyl N,N-dimethylglycinates methobromides (DMGM-n), fatty acids N,N-dimethylaminoethylesters methobromides (DMM-n), fatty acids N,N-dimethylaminopropylesters methobromides (DMPM-n), fatty acids 1-dimethylamino-2-propyl methobromides (DMP(2)M-n), and derivatives of aminoesters with double alkyl chains (M(2)M-n). The examined compounds show interesting biological properties which can be useful, especially in medicine. The exact mechanism of interaction of such compounds with biological membrane is not fully known. However, it is supposed that the presence of micelles has an important role in biological systems. In this paper we show the results of dynamic surface tension measurements in solutions containing the investigated compounds at concentrations above and below cmc. Moreover, we analyzed the influence of the chemical structure of molecules on the diameters of the micelles formed in the solutions. It was found that adsorption dynamics for the studied compounds is strongly affected by the chemical structure of the considered derivatives, especially by the presence of the ester bond, linearity of the molecule, as well as its hydrophobicity. The obtained results show that the structure of the bromide M(2)M-n with two short hydrocarbon chains favors a faster and more efficient adsorption of the molecules at the air/water interface, compared with compounds having one long alkyl chain. Moreover, the double chained derivatives of the M(2)M-n type do not form typical spherical micelles but bilayer structures probably exist in these solutions. The micelles present in the solutions influence the dynamics of adsorption drastically. Moreover, the obtained results indicated that the compounds with especially high biological activity form

  19. Doxorubicin (Adriamycin) Cardiomyopathy—A Critical Review

    PubMed Central

    Saltiel, Emmanuel; McGuire, William

    1983-01-01

    Despite its vast utility in clinical oncology, the use of doxorubicin hydrochloride (Adriamycin) is limited by a potentially fatal cardiomyopathy. The following critical review, which examines the natural course, histopathologic effects, risk factors and monitoring indicators of this toxicity, also analyzes recent research of proposed mechanisms, including free radical formation with depletion of detoxifying enzymes, inhibition of vital enzyme systems and alterations in relative calcium concentrations. Prevention of the adverse reaction has been attempted by using such agents as α-tocopherol, selenium sulfide, coenzyme Q10, sulfhydryl donors, nucleosides and razoxane, and via liposomal carriage and alternative methods of administration. PMID:6356608

  20. MICELLAR ELECTROKINETIC CHROMATOGRAPHY-MASS SPECTROMETRY (R823292)

    EPA Science Inventory

    The combination of micellar electrokinetic chromatography (MEKC) with mass spectrometry (MS) is very attractive for the direct identification of analyte molecules, for the possibility of selectivity enhancement, and for the structure confirmation and analysis in a MS-MS mode. The...

  1. Use of a fluorosurfactant in micellar electrokinetic capillary chromatography.

    PubMed

    de Ridder, R; Damin, F; Reijenga, J; Chiari, M

    2001-05-04

    A fluorosurfactant, the anionic N-ethyl-N-[(heptadecafluorooctyl)sulfonyl]glycine potassium salt, trade name FC-129 [CAS 2991-51-7] was investigated for possible application in micellar electrokinetic capillary chromatography (MEKC). The surfactant was characterized with conductometric titration and test sample mixtures were investigated in MEKC systems, and compared with sodium dodecylsulphate. An increased efficiency and interesting selectivity differences were observed.

  2. Biopolymer based nanosystem for doxorubicin targeted delivery

    PubMed Central

    Csikós, Zsuzsanna; Kerekes, Krisztina; Fazekas, Erika; Kun, Sándor; Borbély, János

    2017-01-01

    This study describes formation of an actively and passively targeted, water-soluble drug delivery system (DDS) which contains doxorubicin (DOX). The system comprises two biocompatible and biodegradable polymers: poly-γ-glutamic acid (PGA) and chitosan (CH). Self-assembly of these biopolymers in aqueous medium results stable nanoparticles (NPs) with a hydrodynamic size of 80-150 nm and slightly negative surface charge. Folic acid (FA) was used as targeting agent bonded to the polyanion (PA) and also to the surface of the NPs. The NP’s physical stability, active targeting effect, cellular toxicity, release profile and in vivo anti-tumor efficacy were investigated. It was found that the targeted, self-assembled nanoparticles are stable at 4°C for several months, cause better in vitro toxicity effect on folate receptor (FR) positive cell lines than the doxorubicin or the non-targeted nanosystem and based on its release profile it is expected, that the nanosystem will remain stable during the circulation in the body. Pharmacodynamic studies demonstrated that the DOX-loaded nanoparticles can deliver greater tumor growth inhibition than the free drug molecules and the liposomal compound, with less general toxicity. It was observed that the overall survival is the main benefit of the biopolymer based drug delivery system.

  3. Imaging of doxorubicin release from theranostic macromolecular prodrugs via fluorescence resonance energy transfer.

    PubMed

    Krüger, Harald R; Schütz, Irene; Justies, Aileen; Licha, Kai; Welker, Pia; Haucke, Volker; Calderón, Marcelo

    2014-11-28

    Herein we present a FRET-based theranostic macromolecular prodrug (TMP) composed of (a) dendritic polyglycerol (PG) as polymeric nanocarrier, (b) doxorubicin (Dox) linked via a pH-sensitive hydrazone to (c) a tri-functional linker, and (d) an indodicarbocyanine dye (IDCC) attached in close proximity to Dox. The drug fluorescence is quenched via intramolecular FRET until the pH-sensitive hydrazone bond between the TMP and Dox is cleaved at acidic pH. By measuring its fluorescence, we characterized the TMP cleavage kinetics at different pH values in vitro. The intracellular release of Dox from the carrier was monitored in real time in intact cancer cells, giving more insight into the mode of action of a polymer drug conjugate.

  4. Biochemical characterization of the interactions between doxorubicin and lipidic GM1 micelles with or without paclitaxel loading

    PubMed Central

    Leonhard, Victoria; Alasino, Roxana V; Bianco, Ismael D; Garro, Ariel G; Heredia, Valeria; Beltramo, Dante M

    2015-01-01

    Doxorubicin (Dox) is an anthracycline anticancer drug with high water solubility, whose use is limited primarily due to significant side effects. In this study it is shown that Dox interacts with monosialoglycosphingolipid (GM1) ganglioside micelles primarily through hydrophobic interactions independent of pH and ionic strength. In addition, Dox can be incorporated even into GM1 micelles already containing highly hydrophobic paclitaxel (Ptx). However, it was not possible to incorporate Ptx into Dox-containing GM1 micelles, suggesting that Dox could be occupying a more external position in the micelles. This result is in agreement with a higher hydrolysis of Dox than of Ptx when micelles were incubated at alkaline pH. The loading of Dox into GM1 micelles was observed over a broad range of temperature (4°C–55°C). Furthermore, Dox-loaded micelles were stable in aqueous solutions exhibiting no aggregation or precipitation for up to 2 months when kept at 4°C–25°C and even after freeze–thawing cycles. Upon exposure to blood components, Dox-containing micelles were observed to interact with human serum albumin. However, the amount of human serum albumin that ended up being associated to the micelles was inversely related to the amount of Dox, suggesting that both could share their binding sites. In vitro studies on Hep2 cells showed that the cellular uptake and cytotoxic activity of Dox and Ptx from the micellar complexes were similar to those of the free form of these drugs, even when the micelle was covered with albumin. These results support the idea of the existence of different nano-domains in a single micelle and the fact that this micellar model could be used as a platform for loading and delivering hydrophobic and hydrophilic active pharmaceutical ingredients. PMID:26005348

  5. Hyperbaric Oxygen Preconditioning Provides Preliminary Protection Against Doxorubicin Cardiotoxicity

    PubMed Central

    Tezcan, Orhan; Karahan, Oguz; Alan, Mustafa; Ekinci, Cenap; Yavuz, Celal; Demirtas, Sinan; Ekinci, Aysun; Caliskan, Ahmet

    2017-01-01

    Background Doxorubicin (DOX) is generally recognized to have important cardiotoxic side effects. Studies are contradictory about the interaction between hyperbaric oxygen (HBO2) therapy and doxorubicin-induced cardiomyotoxicity. Recent data suggests that HBO2 therapy can lead to preconditioning of myocardium while generating oxidative stress. Herein we have investigated the effect of HBO2 therapy in a DOX-induced cardiomyocyte injury animal model. Methods Twenty-one rats were divided into three equal groups as follows: 1) Group 1 is a control group (without any intervention), used for evaluating the basal cardiac structures and determining the normal value of cardiacs and serum oxidative markers; 2) Group 2 is the doxorubicin group (single dose i.p. 20 mg/kg doxorubicin) for detecting the cardiotoxic and systemic effects of doxorubicin; 3) Group 3 is the doxorubicin and HBO2 group (100% oxygen at 2.5 atmospheric for 90 minutes, daily), for evaluating the effect of HBO2 in doxorubicin induced cardiotoxicity. At the end of the protocols, the hearts were harvested and blood samples (2 ml) were obtained. Results The doxorubicin treated animals (Group 2) had increased oxidative stress markers (both cardiac and serum) and severe cardiac injury as compared to the basal findings in the control group. Nevertheless, the highest cardiac oxidative stress index was detected in Group 3 (control vs. Group 3, p = 0.01). However, histological examination revealed that cardiac structures were well preserved in Group 3 when compared with Group 2. Conclusions Our results suggest that HBO2 preconditioning appears to be protective in the doxorubicin-induced cardiotoxicity model. Future studies are required to better elucidate the basis of this preconditioning effect of HBO2. PMID:28344418

  6. Febuxostat ameliorates doxorubicin-induced cardiotoxicity in rats.

    PubMed

    Krishnamurthy, Bhaskar; Rani, Neha; Bharti, Saurabh; Golechha, Mahaveer; Bhatia, Jagriti; Nag, Tapas Chandra; Ray, Ruma; Arava, Sudheer; Arya, Dharamvir Singh

    2015-07-25

    The clinical use of doxorubicin is associated with dose limiting cardiotoxicity. This is a manifestation of free radical production triggered by doxorubicin. Therefore, we evaluated the efficacy of febuxostat, a xanthine oxidase inhibitor and antioxidant, in blocking cardiotoxicity associated with doxorubicin in rats. Male albino Wistar rats were divided into four groups: control (normal saline 2.5mL/kg/dayi.p. on alternate days, a total of 6 doses); Doxorubicin (2.5mg/kg/dayi.p. on alternate days, a total of 6 doses), Doxorubicin+Febuxostat (10mg/kg/day oral) and Doxorubicin+Carvedilol (30mg/kg/day oral) for 14days. Febuxostat significantly ameliorated the doxorubicin-induced deranged cardiac functions as there was significant improvement in arterial pressures, left ventricular end diastolic pressure and inotropic and lusitropic states of the myocardium. These changes were well substantiated with biochemical findings, wherein febuxostat prevented the depletion of non-protein sulfhydryls level, with increased manganese superoxide dismutase level and reduced cardiac injury markers (creatine kinase-MB and B-type natriuretic peptide levels) and thiobarbituric acid reactive substances level. Febuxostat also exhibited significant anti-inflammatory (decreased expression of NF-κBp65, IKK-β and TNF-α) and anti-apoptotic effect (increased Bcl-2 expression and decreased Bax and caspase-3 expression and TUNEL positivity). Hematoxylin and Eosin, Masson Trichome, Picro Sirius Red and ultrastructural studies further corroborated with hemodynamic and biochemical findings showing that febuxostat mitigated doxorubicin-induced increases in inflammatory cells, edema, collagen deposition, interstitial fibrosis, perivascular fibrosis and mitochondrial damage and better preservation of myocardial architecture. In addition, all these changes were comparable to those produced by carvedilol. Thus, our results suggest that the antioxidant and anti-apoptotic effect of febuxostat

  7. Polymeric micellar nanoplatforms for Fenton reaction as a new class of antibacterial agents.

    PubMed

    Park, Seong-Cheol; Kim, Nam-Hong; Yang, Wonseok; Nah, Jae-Woon; Jang, Mi-Kyeong; Lee, Dongwon

    2016-01-10

    Reactive oxygen species (ROS) produced by host phagocytes exert antibacterial action against a variety of pathogens and ROS-induced oxidative stress is the governing mechanism for the antibacterial activity of major bactericidal antibiotics. In particular, hydroxyl radical is a strong and nonselective oxidant which can damage biomolecules such as DNA, proteins and lipids. Ferrous ion is known to convert mild oxidant hydrogen peroxide (H2O2) into highly reactive and toxic hydroxyl radicals, referred to as Fenton reaction. Herein, we report a new class of antibacterial agents based on Fenton reaction-performing nanostructures, composed of H2O2-generating polymer (PCAE) and iron-containing ferrocene. Amphiphilic PCAE was designed to incorporate H2O2-generating cinnamaldehyde through acid-cleavable linkages and self-assemble to form thermodynamically stable micelles which could encapsulate ferrocene in their hydrophobic core. All the experiments in vitro display that ferrocene-loaded PCAE micelles produce hydroxyl radicals to kill Escherichia coli and Pseudomonas aeruginosa through membrane damages. Intraperitoneally injected ferrocene-loaded PCAE micelles significantly reduced the lung damages and therefore increased the survival rate of mice infected with drug resistant P. aeruginosa. Given their potent antibacterial activity, ferrocene-loaded PCAE micelles hold great potential as a new class of ROS-manipulating antibacterial agents.

  8. Combinatorial effects of doxorubicin and retargeted tissue factor by intratumoral entrapment of doxorubicin and proapoptotic increase of tumor vascular infarction

    PubMed Central

    Brand, Caroline; Höltke, Carsten; Schliemann, Christoph; Kessler, Torsten; Schmidt, Lars Henning; Harrach, Saliha; Mantke, Verena; Hintelmann, Heike; Hartmann, Wolfgang; Wardelmann, Eva; Lenz, Georg; Wünsch, Bernhard; Müller-Tidow, Carsten; Mesters, Rolf M.; Schwöppe, Christian; Berdel, Wolfgang E.

    2016-01-01

    Truncated tissue factor (tTF), retargeted to tumor vasculature by GNGRAHA peptide (tTF-NGR), and doxorubicin have therapeutic activity against a variety of tumors. We report on combination experiments of both drugs using different schedules. We have tested fluorescence- and HPLC-based intratumoral pharmacokinetics of doxorubicin, flow cytometry for cellular phosphatidylserine (PS) expression, and tumor xenograft studies for showing in vivo apoptosis, proliferation decrease, and tumor shrinkage upon combination therapy with doxorubicin and induced tumor vascular infarction. tTF-NGR given before doxorubicin inhibits the uptake of the drug into human fibrosarcoma xenografts in vivo. Reverse sequence does not influence the uptake of doxorubicin into tumor, but significantly inhibits the late wash-out phase, thus entrapping doxorubicin in tumor tissue by vascular occlusion. Incubation of endothelial and tumor cells with doxorubicin in vitro increases PS concentrations in the outer layer of the cell membrane as a sign of early apoptosis. Cells expressing increased PS concentrations show comparatively higher procoagulatory efficacy on the basis of equimolar tTF-NGR present in the Factor X assay. Experiments using human M21 melanoma and HT1080 fibrosarcoma xenografts in athymic nude mice indeed show a combinatorial tumor growth inhibition applying doxorubicin and tTF-NGR in sequence over single drug treatment. Combination of cytotoxic drugs such as doxorubicin with tTF-NGR-induced tumor vessel infarction can improve pharmacodynamics of the drugs by new mechanisms, entrapping a cytotoxic molecule inside tumor tissue and reciprocally improving procoagulatory activity of tTF-NGR in the tumor vasculature via apoptosis induction in tumor endothelial and tumor cells. PMID:27738341

  9. Doxorubicin-loaded micelles based on multiarm star-shaped PLGA-PEG block copolymers: influence of arm numbers on drug delivery.

    PubMed

    Ma, Guilei; Zhang, Chao; Zhang, Linhua; Sun, Hongfan; Song, Cunxian; Wang, Chun; Kong, Deling

    2016-01-01

    Star-shaped block copolymers based on poly(D,L-lactide-co-glycolide) (PLGA) and poly(ethylene glycol) (PEG) (st-PLGA-PEG) were synthesized with structural variation on arm numbers in order to investigate the relationship between the arm numbers of st-PLGA-PEG copolymers and their micelle properties. st-PLGA-PEG copolymers with arm numbers 3, 4 and 6 were synthesized by using different cores such as trimethylolpropane, pentaerythritol and dipentaerythritol, and were characterized by nuclear magnetic resonance and gel permeation chromatography. The critical micelle concentration decreased with increasing arm numbers in st-PLGA-PEG copolymers. The doxorubicin-loaded st-PLGA-PEG micelles were prepared by a modified nanoprecipitation method. Micellar properties such as particle size, drug loading content and in vitro drug release behavior were investigated as a function of the number of arms and compared with each other. The doxorubicin-loaded 4-arm PLGA-PEG micelles were found to have the highest cellular uptake efficiency and cytotoxicity compared with 3-arm PLGA-PEG micelles and 6-arm PLGA-PEG micelles. The results suggest that structural tailoring of arm numbers from st-PLGA-PEG copolymers could provide a new strategy for designing drug carriers of high efficiency. Structural tailoring of arm numbers from star shaped-PLGA-PEG copolymers (3-arm/4-arm/6-arm-PLGA-PEG) could provide a new strategy for designing drug carriers of high efficiency.

  10. Polymerization of perfluorobutadiene

    NASA Technical Reports Server (NTRS)

    Newman, J.; Toy, M. S.

    1970-01-01

    Diisopropyl peroxydicarbonate dissolved in liquid perfluorobutadiene is conducted in a sealed vessel at the autogenous pressure of polymerization. Reaction temperature, ratio of catalyst to monomer, and amount of agitation determine degree of polymerization and product yield.

  11. Micellar and Structural Stability of Nanoscale Amphiphilic Polymers: Implications for Anti-atherosclerotic Bioactivity

    PubMed Central

    Zhang, Yingyue; Li, Qi; Welsh, William J.; Moghe, Prabhas V.; Uhrich, Kathryn E.

    2016-01-01

    Atherosclerosis, a leading cause of mortality in developed countries, is characterized by the buildup of oxidized low-density lipoprotein (oxLDL) within the vascular intima, unregulated oxLDL uptake by macrophages, and ensuing formation of arterial plaque. Amphiphilic polymers (AMPs) comprised of a branched hydrophobic domain and a hydrophilic poly(ethylene glycol) (PEG) tail have shown promising anti-atherogenic effects through direct inhibition of oxLDL uptake by macrophages. In this study, five AMPs with controlled variations were evaluated for their micellar and structural stability in the presence of serum and lipase, respectively, to develop underlying structure-atheroprotective activity relations. In parallel, molecular dynamics simulations were performed to explore the AMP conformational preferences within an aqueous environment. Notably, AMPs with ether linkages between the hydrophobic arms and sugar backbones demonstrated enhanced degradation stability and storage stability, and also elicited enhanced anti-atherogenic bioactivity. Additionally, AMPs with increased hydrophobicity elicited increased atheroprotective bioactivity in the presence of serum. These studies provide key insights for designing more serum-stable polymeric micelles as prospective cardiovascular nanotherapies. PMID:26828687

  12. Micellar and structural stability of nanoscale amphiphilic polymers: Implications for anti-atherosclerotic bioactivity.

    PubMed

    Zhang, Yingyue; Li, Qi; Welsh, William J; Moghe, Prabhas V; Uhrich, Kathryn E

    2016-04-01

    Atherosclerosis, a leading cause of mortality in developed countries, is characterized by the buildup of oxidized low-density lipoprotein (oxLDL) within the vascular intima, unregulated oxLDL uptake by macrophages, and ensuing formation of arterial plaque. Amphiphilic polymers (AMPs) comprised of a branched hydrophobic domain and a hydrophilic poly(ethylene glycol) (PEG) tail have shown promising anti-atherogenic effects through direct inhibition of oxLDL uptake by macrophages. In this study, five AMPs with controlled variations were evaluated for their micellar and structural stability in the presence of serum and lipase, respectively, to develop underlying structure-atheroprotective activity relations. In parallel, molecular dynamics simulations were performed to explore the AMP conformational preferences within an aqueous environment. Notably, AMPs with ether linkages between the hydrophobic arms and sugar backbones demonstrated enhanced degradation stability and storage stability, and also elicited enhanced anti-atherogenic bioactivity. Additionally, AMPs with increased hydrophobicity elicited increased atheroprotective bioactivity in the presence of serum. These studies provide key insights for designing more serum-stable polymeric micelles as prospective cardiovascular nanotherapies.

  13. Terahertz absorption spectroscopy of protein-containing reverse micellar solution

    NASA Astrophysics Data System (ADS)

    Murakami, H.; Toyota, Y.; Nishi, T.; Nashima, S.

    2012-01-01

    Terahertz time-domain spectroscopy has been carried out for AOT/isooctane reverse micellar solution with myoglobin at the water-to-surfactant molar ratios ( w0) of 0.2 and 4.4. The amplitude of the absorption spectrum increases with increasing the protein concentration at w0 = 0.2, whereas it decreases at w0 = 4.4. The molar extinction coefficients of the protein-filled reverse micelle, and the constituents, i.e., myoglobin, water, and AOT, have been derived by use of the structural parameters of the micellar solution. The experimental results are interpreted in terms of hydration onto the protein and surfactant in the reverse micelle.

  14. Photodegradation in Micellar Aqueous Solutions of Erythrosin Esters Derivatives.

    PubMed

    Herculano, Leandro Silva; Lukasievicz, Gustavo Vinicius Bassi; Sehn, Elizandra; Caetano, Wilker; Pellosi, Diogo Silva; Hioka, Noboru; Astrath, Nelson Guilherme Castelli; Malacarne, Luis Carlos

    2015-07-01

    Strong light absorption and high levels of singlet oxygen production indicate erythrosin B as a viable candidate as a photosensitizer in photodynamic therapy or photodynamic inactivation of microorganisms. Under light irradiation, erythrosin B undergoes a photobleaching process that can decrease the production of singlet oxygen. In this paper, we use thermal lens spectroscopy to investigate photobleaching in micellar solutions of erythrosin ester derivatives: methyl, butyl, and decyl esters in low concentrations of non-ionic micellar aqueous solutions. Using a previously developed thermal lens model, it was possible to determine the photobleaching rate and fluorescence quantum efficiency for dye-micelle solutions. The results suggest that photobleaching is related to the intensity of the dye-micelle interaction and demonstrate that the thermal lens technique can be used as a sensitive tool for quantitative measurement of photochemical properties in very diluted solutions.

  15. Resveratrol, a polyphenol phytoalexin, protects against doxorubicin-induced cardiotoxicity

    PubMed Central

    Gu, Jun; Hu, Wei; Zhang, Da-dong

    2015-01-01

    Doxorubicin is the mainstay of treatment for various haematological malignancies and solid tumours. However, its clinical application may be hampered by dose-dependent cardiotoxicity. The mechanism of doxorubicin-induced cardiotoxicity may involve various signalling pathways including free radical generation, peroxynitrite formation, calcium overloading, mitochondrial dysfunction and alteration in apoptosis and autophagy. Interestingly, the use of resveratrol in combination with doxorubicin has been reported to prevent cardiac toxicity as well as to exert a synergistic effect against tumour cells both in vivo and in vitro. Thus, the aim of this review is to summarize current knowledge and to elucidate the protective effect of resveratrol in doxorubicin-induced cardiotoxicity. PMID:26177159

  16. Polymerization Reactor Engineering.

    ERIC Educational Resources Information Center

    Skaates, J. Michael

    1987-01-01

    Describes a polymerization reactor engineering course offered at Michigan Technological University which focuses on the design and operation of industrial polymerization reactors to achieve a desired degree of polymerization and molecular weight distribution. Provides a list of the course topics and assigned readings. (TW)

  17. Polymeric mixed micelles as nanomedicines: Achievements and perspectives.

    PubMed

    Cagel, Maximiliano; Tesan, Fiorella C; Bernabeu, Ezequiel; Salgueiro, Maria J; Zubillaga, Marcela B; Moretton, Marcela A; Chiappetta, Diego A

    2017-04-01

    During the past few decades, polymeric micelles have raised special attention as novel nano-sized drug delivery systems for optimizing the treatment and diagnosis of numerous diseases. These nanocarriers exhibit several in vitro and in vivo advantages as well as increased stability and solubility to hydrophobic drugs. An interesting approach for optimizing these properties and overcoming some of their disadvantages is the combination of two or more polymers in order to assemble polymeric mixed micelles. This review article gives an overview on the current state of the art of several mixed micellar formulations as nanocarriers for drugs and imaging probes, evaluating their ongoing status (preclinical or clinical stage), with special emphasis on type of copolymers, physicochemical properties, in vivo progress achieved so far and toxicity profiles. Besides, the present article presents relevant research outcomes about polymeric mixed micelles as better drug delivery systems, when compared to polymeric pristine micelles. The reported data clearly illustrates the promise of these nanovehicles reaching clinical stages in the near future.

  18. Doxorubicin induced heart failure: Phenotype and molecular mechanisms

    PubMed Central

    Mitry, Maria A.; Edwards, John G.

    2016-01-01

    Long term survival of childhood cancers is now more than 70%. Anthracyclines, including doxorubicin, are some of the most efficacious anticancer drugs available. However, its use as a chemotherapeutic agent is severely hindered by its dose-limiting toxicities. Most notably observed is cardiotoxicity, but other organ systems are also degraded by doxorubicin use. Despite the years of its use and the amount of information written about this drug, an understanding of its cellular mechanisms is not fully appreciated. The mechanisms by which doxorubicin induces cytotoxicity in target cancer cells have given insight about how the drug damages cardiomyocytes. The major mechanisms of doxorubicin actions are thought to be as an oxidant generator and as an inhibitor of topoisomerase 2. However, other signaling pathways are also invoked with significant consequences for the cardiomyocyte. Further the interaction between oxidant generation and topoisomerase function has only recently been appreciated and the consequences of this interaction are still not fully understood. The unfortunate consequences of doxorubicin within cardiomyocytes have promoted the search for new drugs and methods that can prevent or reverse the damage caused to the heart after treatment in cancer patients. Alternative protocols have lessened the impact on newly diagnosed cancer patients. However the years of doxorubicin use have generated a need for monitoring the onset of cardiotoxicity as well as understanding its potential long-term consequences. Although a fairly clear understanding of the short-term pathologic mechanisms of doxorubicin actions has been achieved, the long-term mechanisms of doxorubicin induced heart failure remain to be carefully delineated. PMID:27213178

  19. Distinct biodistribution of doxorubicin and the altered dispositions mediated by different liposomal formulations.

    PubMed

    Luo, Ruijuan; Li, Yan; He, Miao; Zhang, Huixia; Yuan, Hebao; Johnson, Mark; Palmisano, Maria; Zhou, Simon; Sun, Duxin

    2017-03-15

    The liposomal formulations of doxorubicin produced distinct efficacy and toxicity profiles compared to doxorubicin solution in cancer patients. This study aims to investigate the drug tissue distribution and the driving force for tissue distribution from doxorubicin solution and two liposomal delivery systems, Doxil and Myocet. These three formulations were intravenously administered to mice at a single dose of 5mg/kg. Eleven organs, plasma and blood were collected at different time points. Total doxorubicin concentrations in each specimen were measured with LC-MS/MS. Compared to doxorubicin solution, both Doxil and Myocet produced distinct doxorubicin tissue exposure in all 11 tissues. Interestingly, the tissue exposure by Myocet was drastically different from that of Doxil and showed a formulation-dependent pattern. Cmax of doxorubicin in heart tissue by Doxil and Myocet was approximately 60% and 50% respectively of that by doxorubicin solution. The predominant driving force for doxorubicin tissue distribution is liposomal-doxorubicin deposition for Doxil and free drug concentration for doxorubicin solution. For Myocet, the driving force for tissue distribution is predominately liposomal-doxorubicin deposition into tissues within the first 4h; as the non-PEGylated doxorubicin liposomal decomposes, the driving force for tissue distribution is gradually switched to the released free doxorubicin. Unique tissue distributions are correlated with their toxicity profiles.

  20. Phosphatidylcholine embedded micellar systems: enhanced permeability through rat skin.

    PubMed

    Spernath, Aviram; Aserin, Abraham; Sintov, Amnon C; Garti, Nissim

    2008-02-15

    Micellar and microemulsion systems are excellent potential vehicles for delivery of drugs because of their high solubilization capacity and improved transmembrane bioavailability. Mixtures of propylene glycol (PG) and nonionic surfactants with sodium diclofenac (DFC) were prepared in the presence of phosphatidylcholine (PC) as transmembrane transport enhancers. Fully dilutable systems with maximum DFC solubilization capacity (SC) at pH 7 are presented. It was demonstrated that the concentrates underwent phase transitions from reverse micelles to swollen reverse micelles and, via the bicontinuous transitional mesophase, into inverted O/W microstructures. The SC decreases as a function of dilution. DFC transdermal penetration using rat skin in vitro correlated with SC, water content, effect of phospholipid content, presence of an oil phase, and ethanol. Skin penetration from the inverted bicontinuous mesophase and the skin penetration from the O/W-like microstructure were higher than that measured from the W/O-like droplets, especially when the micellar system containing the nonionic surfactant, sugar ester L-1695, and hexaglycerol laurate. PC embedded within the micelle interface significantly increased the penetration flux across the skin compared to micellar systems without the embedded PC at their interface. Moreover, the combination of PC with HECO40 improved the permeation rate (P) and shortened the lag-time (T(L)).

  1. Quantitative treatment of micellar effects upon deprotonation equilibria

    SciTech Connect

    Bunton, C.A.; Romsted, L.S.; Sepulveda, L.

    1980-10-02

    The apparent base dissociation constants, KB, for deprotonation of benzimidazole in dilute NaOh go through minima with increasing concentration of cetyltrimethylammonium ion surfactants (CTAX, X = Cl, Br, NO/sub 3/) at concentrations of surfactant counterions is maintained at 0.1 mole. In both cases the micellar effect on KB follows the sequence CTaCl > CTaBr > CTaNO/sub 3/. These observations are consistent with a pseudophase ion-exchange model in which the micelle binds OH/sup -/ and both forms of the indicator, increasing deprotonation and decreasing KB, but the counterion of the surfactant displaces OH/sup -/ from the micellar surface so that KB goes through a minimum with increasing (CTAX). This model leads to a simple quantitative treatment which fits the data for (CTAX) > 0.01 mole. A similar pattern of behavior has been found for deprotonation of phenols and oximes in CTABr in the presence of borate buffer. Intrinsic basicity constants in the micellar pseudophase can be estimated which are larger than those in water by approximately one order of magnitude. 39 references.

  2. Flow-induced gelation of living (micellar) polymers

    NASA Technical Reports Server (NTRS)

    Bruinsma, Robijn; Gelbart, William M.; Ben-Shaul, Avinoam

    1992-01-01

    The effect of shear velocity gradients on the size (L) of rodlike micelles in dilute and semidilute solution is considered. A kinetic equation is introduced for the time-dependent concentration of aggregates of length L, consisting of 'bimolecular' combination processes L + L-prime yield (L + L-prime) and unimolecular fragmentations L yield L + (L - L-prime). The former are described by a generalization (from spheres to rods) of the Smoluchowski mechanism for shear-induced coalesence of emulsions, and the latter by incorporating the tension-deformation effects due to flow. Steady-state solutions to the kinetic equation are obtained, with the corresponding mean micellar size evaluated as a function of the Peclet number P (i.e., the dimensionless ratio of the flow rate and the rotational diffusion coefficient). For sufficiently dilute solutions, only a weak dependence of the micellar size on P is found. In the semidilute regime, however, an apparent divergence in the micellar size at P of about 1 suggests a flow-induced first-order gelation phenomenon.

  3. Injectable micellar supramolecular hydrogel for delivery of hydrophobic anticancer drugs.

    PubMed

    Fu, CuiXiang; Lin, XiaoXiao; Wang, Jun; Zheng, XiaoQun; Li, XingYi; Lin, ZhengFeng; Lin, GuangYong

    2016-04-01

    In this paper, an injectable micellar supramolecular hydrogel composed of α-cyclodextrin (α-CD) and monomethoxy poly(ethylene glycol)-b-poly(ε-caplactone) (MPEG5000-PCL5000) micelles was developed by a simple method for hydrophobic anticancer drug delivery. By mixing α-CD aqueous solution and MPEG5000-PCL5000 micelles, an injectable micellar supramolecular hydrogel could be formed under mild condition due to the inclusion complexation between α-CD and MPEG segment of MPEG5000-PCL5000 micelles. The resultant supramolecular hydrogel was thereafter characterized by X-ray diffraction (XRD) and Scanning electron microscopy (SEM). The effect of α-CD amount on the gelation time, mechanical strength and thixotropic property was studied by a rheometer. Payload of hydrophobic paclitaxel (PTX) to supramolecular hydrogel was achieved by encapsulation of PTX into MPEG5000-PCL5000 micelles prior mixing with α-CD aqueous solution. In vitro release study showed that the release behavior of PTX from hydrogel could be modulated by change the α-CD amount in hydrogel. Furthermore, such supramolecular hydrogel could enhance the biological activity of encapsulated PTX compared to free PTX, as indicated by in vitro cytotoxicity assay. All these results indicated that the developed micellar supramolecular hydrogel might be a promising injectable drug delivery system for anticancer therapy.

  4. Bioadhesive chitosan-coated cyclodextrin-based superamolecular nanomicelles to enhance the oral bioavailability of doxorubicin

    NASA Astrophysics Data System (ADS)

    Liu, Yuhai; Zhai, Yinglei; Han, Xiaopeng; Liu, Xiaohong; Liu, Wanjun; Wu, Chunnuan; Li, Lin; Du, Yuqian; Lian, He; Wang, Yongjun; He, Zhonggui; Sun, Jin

    2014-10-01

    In order to improve the oral bioavailability of doxorubicin (Dox), a novel bioadhesive nanomicelle based on host-guest interaction was developed in this study. Hyaluronic acid-linked β-cyclodextrin (HA-CD) was synthesized. The primary nanomicelles were formed through the self-assemble of HA-CD and retinoic acid (RA) which was included as the hydrophobic core to anchor CD cavity by host-guest interaction. Chitosan (CS) was then coated on the surface of primary nanomicelles by ionic interaction with the negatively charged HA. The critical micellar concentration of HA-CD-RA was as low as 22.5 μg/mL. Dox was successfully encapsulated into the hydrophobic core of CS-coated HA-CD-RA nanomicelles (CS/HA-CD-RA-Dox), with encapsulation efficiency as high as 89.2 %. The CS/HA-CD-RA-Dox particle size was 234 nm and was stable over 30 days. In vitro Dox release showed that CS/HA-CD-RA nanomicelles were more sustained than HA-CD-RA nanomicelles, and Dox encapsulated into CS-coated nanomicelles was stable at low pH. The in situ single pass intestinal perfusion revealed that encapsulation of Dox into CS/HA-CD-RA nanomicelles could significantly improve the intestinal permeability of Dox. The mucoadhesion results indicated that the retention percentage of CS/HA-CD-RA nanomicelles was significantly higher than that of HA-CD-RA nanomicelles in gastrointestinal tract. In vivo pharmacokinetic study revealed that AUC(0-∞) of CS/HA-CD-RA nanomicelles was about fourfold higher than that of Dox solution. The present study suggested that CS/HA-CD-RA nanomicelles as biodegradable, biocompatible, and bioadhesive nanostructure can be a promising nanocarrier in improving the bioavailability of anticancer drugs to facilitate the oral chemotherapy.

  5. Cardioprotective effect of cannabidiol in rats exposed to doxorubicin toxicity.

    PubMed

    Fouad, Amr A; Albuali, Waleed H; Al-Mulhim, Abdulruhman S; Jresat, Iyad

    2013-09-01

    The potential protective effect of cannabidiol, the major non-psychotropic Cannabis constituent, was investigated against doxorubicin cardiotoxicity in rats. Cardiotoxicity was induced by six equal doses of doxorubicin (2.5mgkg(-1) i.p., each) given at 48h intervals over two weeks to achieve a total dose of 15mgkg(-1). Cannabidiol treatment (5mgkg(-1)/day, i.p.) was started on the same day of doxorubicin administration and continued for four weeks. Cannabidiol significantly reduced the elevations of serum creatine kinase-MB and troponin T, and cardiac malondialdehyde, tumor necrosis factor-α, nitric oxide and calcium ion levels, and attenuated the decreases in cardiac reduced glutathione, selenium and zinc ions. Histopathological examination showed that cannabidiol ameliorated doxorubicin-induced cardiac injury. Immunohistochemical analysis revealed that cannabidiol significantly reduced the expression of inducible nitric oxide synthase, nuclear factor-κB, Fas ligand and caspase-3, and increased the expression of survivin in cardiac tissue of doxorubicin-treated rats. These results indicate that cannabidiol represents a potential protective agent against doxorubicin cardiac injury.

  6. c(RGDfK) decorated micellar drug delivery system for intravesical instilled chemotherapy of superficial bladder cancer.

    PubMed

    Zhou, Danhua; Zhang, Guan; Gan, Zhihua

    2013-08-10

    The aim of this work was to develop a targeted drug delivery system with potentials for intravesical instilled chemotherapy of superficial bladder cancer. The amphiphilic diblock copolymer poly(ε-caprolactone)-b-poly(ethylene oxide) (PCL-b-PEO) was first conjugated with the cyclic (Arginine-Glycine-Aspartic acid-d-Phenylalanine-Lysine) (c(RGDfK)) and fluorescein isothiocyannate (FITC) via the functional terminal groups of hydrophilic block, and then assembled into micelles. The interaction between micelles and various model cells was well studied by means of confocal laser scanning microscopy and flow cytometry. The c(RGDfK) on the surface of the micelle was confirmed by (1)H NMR analysis and cell affinity with human glioblastoma-astrocytoma cells (U87MG). The cell viability of bladder cancer cells (T-24 cells) after incubation with doxorubicin (DOX) loaded polymeric micelles was evaluated by in vitro cytotoxicity assay. The results revealed that c(RGDfK) modified micelles showed strong affinity to T-24 cells and strong inhibitory effect on the proliferation of T-24 cells when doxorubicin drug was loaded, indicating the high affinity of c(RGDfK) to bladder cancer cells. The c(RGDfK) modified micelles assembled from PCL-b-PEO diblock copolymers developed in this study are of great potentials as nano-scaled drug delivery system for intravesical instilled chemotherapy of superficial bladder cancer.

  7. A comparison of the effect of doxorubicin and phenol on the skeletal muscle. May doxorubicin be a new alternative treatment agent for spasticity?

    PubMed

    Cullu, Emre; Ozkan, Ilhan; Culhaci, Nil; Alparslan, Bulent

    2005-03-01

    Since spasticity is still an unsolved problem for orthopaedic surgeons, different chemical agents are tried before surgery. Phenol is a chemical agent which has been used for spasticity treatment for a long time. Doxorubicin is an antitumoral agent that has recently been used for chemomyectomy. The intramuscular effects of phenol and two different dose of doxorubicin were compared in that experimental study. In the first group 0.5 mg/0.5 cm3 doxorubicin, in the second group 1 mg/0.5 doxorubicin and in the third group 5% aqueous solution of fenol/0.5 injection were applied into left quadriceps muscle of rats. Degeneration areas were wider in the high dose doxorubicin group (29.9%; 8.5-61), in comparison with the low dose doxorubicin group (6.4%; 3.1-12) and phenol group (4%; 0-14) after 6 weeks. Differences in degeneration area among three groups were statistically significant (P<0.001). The difference was significant between the high dose doxorubicin group and the phenol group (P=0.001) and also between the high dose doxorubicin group and the low dose doxorubicin group (P<0.001). The results of this study suggested that doxorubicin could provide an alternative treatment modality for neuromuscular disease causing spasticity and it has a dose-dependent effect. Further studies are needed for long-term comparison and clinical use of doxorubicin for spasticity treatment.

  8. Transferrin receptor-targeted pH-sensitive micellar system for diminution of drug resistance and targetable delivery in multidrug-resistant breast cancer

    PubMed Central

    Gao, Wei; Ye, Guihua; Duan, Xiaochuan; Yang, Xiaoying; Yang, Victor C

    2017-01-01

    The emergence of drug resistance is partially associated with overproduction of transferrin receptor (TfR). To overcome multidrug resistance (MDR) and achieve tumor target delivery, we designed a novel biodegradable pH-sensitive micellar system modified with HAIYPRH, a TfR ligand (7pep). First, the polymers poly(l-histidine)-coupled polyethylene glycol-2000 (PHIS-PEG2000) and 7pep-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000 (7pep-DSPE-PEG2000) were synthesized, and the mixed micelles were prepared by blending of PHIS-PEG2000 and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000 (DSPE-PEG2000) or 7pep-DSPE-PEG2000 (7-pep HD micelles). The micelles exhibited good size uniformity, high encapsulation efficiency, and a low critical micelle concentration. By changing the polymer ratio in the micellar formulation, the pH response range was specially tailored to pH ~6.0. When loaded with antitumor drug doxorubicin (DOX), the micelle showed an acid pH-triggering drug release profile. The cellular uptake and cytotoxicity study demonstrated that 7-pep HD micelles could significantly enhance the intracellular level and antitumor efficacy of DOX in multidrug-resistant cells (MCF-7/Adr), which attributed to the synergistic effect of poly(l-histidine)-triggered endolysosom escape and TfR-mediated endocytosis. Most importantly, the in vivo imaging study confirmed the target-ability of 7-pep HD micelles to MDR tumor. These findings indicated that 7-pep HD micelles would be a promising drug delivery system in the treatment of drug-resistant tumors. PMID:28223798

  9. Cardiomyocyte death in doxorubicin-induced cardiotoxicity

    PubMed Central

    Zhang, Yi-Wei; Shi, Jianjian; Li, Yuan-Jian; Wei, Lei

    2009-01-01

    SUMMARY Doxorubicin (DOX) is one of the most widely used and successful antitumor drugs, but its cumulative and dose-dependent cardiac toxicity has been the major concern of oncologists in cancer therapeutic practice for decades. With the increasing population of cancer survivals, there is a growing need to develop preventive strategies and effective therapies against DOX-induced cardiotoxicity, in particular, the late onset cardiomyopathy. Although intensive investigations on the DOX-induced cardiotoxicity have been continued for decades, the underlying mechanisms responsible for DOX-induced cardiotoxicity have not been completely elucidated. A rapidly expanding body of evidence supports that cardiomyocyte death by apoptosis and necrosis is a primary mechanism of DOX-induced cardiomyopathy and other types of cell death, such as autophagy and senescence/aging, may participate in this process. In this review, we will focus on the current understanding of molecular mechanisms underlying DOX-induced cardiomyocyte death, including the major primary mechanism of excess production of reactive oxygen species (ROS) and other recently discovered ROS-independent mechanisms. Different sensitivity to DOX-induced cell death signals between adult and young cardiomyocytes will also be discussed. PMID:19866340

  10. UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity.

    PubMed

    An, Lin; Hu, Xiao-Wen; Zhang, Shasha; Hu, Xiaowen; Song, Zongpei; Naz, Amber; Zi, Zhenguo; Wu, Jian; Li, Can; Zou, Yunzeng; He, Lin; Zhu, Hongxin

    2017-02-22

    Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity.

  11. UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity

    PubMed Central

    An, Lin; Hu, Xiao-wen; Zhang, Shasha; Hu, Xiaowen; Song, Zongpei; Naz, Amber; Zi, Zhenguo; Wu, Jian; Li, Can; Zou, Yunzeng; He, Lin; Zhu, Hongxin

    2017-01-01

    Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity. PMID:28225086

  12. Polymerization in emulsion microdroplet reactors

    NASA Astrophysics Data System (ADS)

    Carroll, Nick J.

    The goal of this research project is to utilize emulsion droplets as chemical reactors for execution of complex polymerization chemistries to develop unique and functional particle materials. Emulsions are dispersions of immiscible fluids where one fluid usually exists in the form of drops. Not surprisingly, if a liquid-to-solid chemical reaction proceeds to completion within these drops, the resultant solid particles will possess the shape and relative size distribution of the drops. The two immiscible liquid phases required for emulsion polymerization provide unique and complex chemical and physical environments suitable for the engineering of novel materials. The development of novel non-ionic fluorosurfactants allows fluorocarbon oils to be used as the continuous phase in a water-free emulsion. Such emulsions enable the encapsulation of almost any hydrocarbon compound in droplets that may be used as separate compartments for water-sensitive syntheses. Here, we exemplify the promise of this approach by suspension polymerization of polyurethanes (PU), in which the liquid precursor is emulsified into droplets that are then converted 1:1 into polymer particles. The stability of the droplets against coalescence upon removal of the continuous phase by evaporation confirms the formation of solid PU particles. These results prove that the water-free environment of fluorocarbon based emulsions enables high conversion. We produce monodisperse, cross-linked, and fluorescently labeled PU-latexes with controllable mesh size through microfluidic emulsification in a simple one-step process. A novel method for the fabrication of monodisperse mesoporous silica particles is presented. It is based on the formation of well-defined equally sized emulsion droplets using a microfluidic approach. The droplets contain the silica precursor/surfactant solution and are suspended in hexadecane as the continuous oil phase. The solvent is then expelled from the droplets, leading to

  13. Berberine attenuates doxorubicin-induced cardiotoxicity in mice.

    PubMed

    Zhao, X; Zhang, J; Tong, N; Liao, X; Wang, E; Li, Z; Luo, Y; Zuo, H

    2011-01-01

    This study investigated the effects of berberine, a natural alkaloid, on doxorubicin-induced cardiotoxicity in mice. Mice were injected intraperitoneally with saline 10 ml/kg (n = 10), doxorubicin 2.5 mg/kg (n = 10), 60 mg/kg berberine 1 h before doxorubicin 2.5 mg/kg (n = 10), or 60 mg/kg berberine alone (n = 10) every other day for 14 days. Body weight, general condition and mortality were recorded over the 14-day study period. Electro cardiography was performed before the start of treatment and after 14 days and plasma lactate dehydrogenase (LDH) activity was measured after 14 days. At the end of the study period the heart was excised and examined histologically. An increase in mortality, an initial decrease in body weight, increased LDH activity, prolongation of QRS duration and increased myocardial injury were seen in the doxorubicin-treated group compared with the saline control group. These changes were significantly attenuated by pretreatment with berberine. The study suggests that berberine may have a potential protective role against doxorubicin-induced cardiotoxicity in mice.

  14. Trichostatin A accentuates doxorubicin-induced hypertrophy in cardiac myocytes

    PubMed Central

    Karagiannis, Tom C; Lin, Ann JE; Ververis, Katherine; Chang, Lisa; Tang, Michelle M; Okabe, Jun; El-Osta, Assam

    2010-01-01

    Histone deacetylase inhibitors represent a new class of anticancer therapeutics and the expectation is that they will be most effective when used in combination with conventional cancer therapies, such as the anthracycline, doxorubicin. The dose-limiting side effect of doxorubicin is severe cardiotoxicity and evaluation of the effects of combinations of the anthracycline with histone deacetylase inhibitors in relevant models is important. We used a well-established in vitro model of doxorubicin-induced hypertrophy to examine the effects of the prototypical histone deacetylase inhibitor, Trichostatin A. Our findings indicate that doxorubicin modulates the expression of the hypertrophy-associated genes, ventricular myosin light chain-2, the alpha isoform of myosin heavy chain and atrial natriuretic peptide, an effect which is augmented by Trichostatin A. Furthermore, we show that Trichostatin A amplifies doxorubicin-induced DNA double strand breaks, as assessed by γH2AX formation. More generally, our findings highlight the importance of investigating potential side effects that may be associated with emerging combination therapies for cancer. PMID:20930262

  15. Assembling techniques for micellar dispersed carbon single-walled nanotubes

    NASA Astrophysics Data System (ADS)

    Burghard, M.; Muster, J.; Duesberg, G.; Philipp, G.; Krstic, V.; Roth, S.

    1998-08-01

    Surfactant-stabilised aqueous dispersions of carbon single-walled nanotubes (SWNTs) provide attractive possibilities for different types of assembling processes. The adsorption behaviour of chromatographically purified, micellar suspended SWNTs on silica substrates and metal electrodes is presented. Chemical modifications of the substrate surface allow to control the adsorption kinetics and the fraction between adsorbed individual SWNTs and bundles of SWNTs. Tube alignment occurs presumably due to flow effects upon removal of the surfactant. As a second assembling technique, we describe the preparation of Langmuir-Blodgett films consisting of SWNTs embedded in a surfactant matrix.

  16. Improved Efficacy of Liposomal Doxorubicin Treatment of Superficial Tumors by Thermotherapy.

    PubMed

    Ping, Xiong; Angang, Ding; Xia, Gong; Yinzhu, Zhao; Jia, Li; Guofeng, Shen; Yazhu, Chen

    2016-04-01

    Our study aimed to investigate the effect of ultrasonic thermotherapy on the targeted delivery of liposomal doxorubicin to superficial tumors, local drug concentrations in tumor tissue, and the curative effect of chemotherapy. Twenty rabbits with VX2 tumors transplanted into the superficial muscle of the hind limb were randomly assigned to the following 4 treatment groups: (1) free doxorubicin, (2) liposomal doxorubicin hydrochloride, (3) liposomal doxorubicin hydrochloride plus 41 °C thermotherapy, and (4) liposomal doxorubicin hydrochloride plus 43 °C thermotherapy. Ultrasonic thermotherapy was delivered at 41 °C to 43 °C. Plasma, tumor, and organ/tissue homogenates were analyzed by high-pressure liquid chromatography to determine doxorubicin concentrations. The drug concentration in plasma and tumor tissue was significantly higher in the liposomal doxorubicin hydrochloride plus thermotherapy group than in the liposomal doxorubicin hydrochloride and free doxorubicin groups, but there were no significant differences among the 4 groups in the concentration in heart or kidney tissue. Combining thermotherapy with liposomal doxorubicin hydrochloride chemotherapy significantly increased the concentration of the drug in tumor tissue. The doxorubicin concentration was significantly higher in the liposomal doxorubicin hydrochloride plus 41 °C thermotherapy group.

  17. Reversible derivatization to enhance enzymatic synthesis: Chemoenzymatic synthesis of Doxorubicin-14-O-Esters

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An efficient three-step, chemoenzymatic synthesis of unprotected doxorubicin-14-O-esters from doxorubicin hydrochloride salt is described. The key step is a lipase-catalyzed regioselective transesterification/esterification using commercially-available acyl donors and doxorubicin reversibly derivat...

  18. Comparison of active and passive targeting of doxorubicin for somatostatin receptor 2 positive tumor models by octreotide-modified HPMA copolymer-doxorubicin conjugates.

    PubMed

    He, Shuang; Zhou, Zhou; Li, Lian; Yang, Qingqing; Yang, Yang; Guan, Shan; Zhang, Jian; Zhu, Xi; Jin, Yun; Huang, Yuan

    2016-01-01

    Somatostatin receptor 2 (SSTR2), specifically over-expressed on many tumor cells, is a potential receipt for active targeting in cancer therapy. In the present study, octreotide (Oct), which had high affinity to SSTR2, was attached to N-(2-hydroxypropyl) methacrylamide (HPMA) polymeric system to enhance the antitumor efficiency of the anticancer drug doxorubicin (DOX). Two kinds of cell lines (HepG2 and A549), which overexpress SSTR2, were chosen as cell models. Compared with non-modified conjugates, Oct-modified conjugates exhibited superior cytotoxicity and intracellular uptake on both HepG2 and A549 cell lines. This might be due to the mechanism of receptor-mediated endocytosis. Subsequently, the in vivo biodistribution and antitumor activity evaluations showed that Oct modification significantly improved the tumor accumulation and antitumor efficacy of HPMA copolymer conjugates in SSTR2 over-expressed Kunming mice bearing H22 tumor xenografts. In summary, Oct-modified HPMA polymer-DOX conjugates might be a promising system for the treatment of SSTR2 over-expressed cancers.

  19. Synthesis of long-circulating, backbone degradable HPMA copolymer-doxorubicin conjugates and evaluation of molecular-weight-dependent antitumor efficacy.

    PubMed

    Pan, Huaizhong; Sima, Monika; Yang, Jiyuan; Kopeček, Jindřich

    2013-02-01

    Backbone degradable, linear, multiblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (DOX) conjugates are synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization followed by chain extension via thiol-ene click reaction. The examination of molecular-weight-dependent antitumor activity toward human ovarian A2780/AD carcinoma in nude mice reveals enhanced activity of multiblock, second-generation, higher molecular weight conjugates when compared with traditional HPMA copolymer-DOX conjugates. The examination of body weight changes during treatment indicates the absence of non-specific adverse effects.

  20. Step-Growth Polymerization.

    ERIC Educational Resources Information Center

    Stille, J. K.

    1981-01-01

    Following a comparison of chain-growth and step-growth polymerization, focuses on the latter process by describing requirements for high molecular weight, step-growth polymerization kinetics, synthesis and molecular weight distribution of some linear step-growth polymers, and three-dimensional network step-growth polymers. (JN)

  1. Making Polymeric Microspheres

    NASA Technical Reports Server (NTRS)

    Rhim, Won-Kyu; Hyson, Michael T.; Chung, Sang-Kun; Colvin, Michael S.; Chang, Manchium

    1989-01-01

    Combination of advanced techniques yields uniform particles for biomedical applications. Process combines ink-jet and irradiation/freeze-polymerization techniques to make polymeric microspheres of uniform size in diameters from 100 to 400 micrometer. Microspheres used in chromatography, cell sorting, cell labeling, and manufacture of pharmaceutical materials.

  2. Solute-solvent interactions in micellar electrokinetic chromatography. Selectivity of lithium dodecyl sulfate-lithium perfluorooctanesulfonate mixed-micellar buffers.

    PubMed

    Fuguet, E; Ràfols, C; Bosch, E; Rosés, M; Abraham, M H

    2001-01-12

    The solvation parameter model has been applied to the characterization of micellar electrokinetic chromatographic (MEKC) systems with mixtures of lithium dodecyl sulfate and lithium perfluorooctanesulfonate as surfactant. The variation in MEKC surfactant composition results in changes in the coefficients of the correlation equation, which in turns leads to information on solute-solvent and solute-micelle interactions. Lithium perfluorooctanesulfonate is more dipolar and hydrogen bond acidic but less polarizable and hydrogen bond basic than lithium dodecyl sulfate. Therefore mixtures of lithium dodecyl sulfate and lithium perfluorooctanesulfonate cover a very wide range of polarity and hydrogen bond properties, which in turn results in important selectivity changes for analytes with different solute properties.

  3. Cyclophosphamide and Doxorubicin Induced Melanonychia: A Case Report

    PubMed Central

    Prajapati, Vivek Bhanubhai; Acharya, Raviraj; Gopalaswamy, Vinaya; Doddamani, Akhila

    2017-01-01

    Chemotherapeutic agents may rarely cause discoloration and hyperpigmentation of the nails. We present a patient who developed blackish discoloration of nails also referred as melanonychia during six cycles of R-CHOP chemotherapy regimen (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) for the treatment of Non Hodgkin Lymphoma (NHL) follicular type. The patient developed blackish brown discoloration in all the nails. As suggested by previous literature evidence the melanonychia could be associated with cyclophosphamide and doxorubicin. According to the Naranjo causality assessment scale, we established that there was a ‘probable’ association of nail discoloration with the drug. PMID:28273993

  4. Polymeric Carbon Dioxide

    SciTech Connect

    Yoo, C-S.

    1999-11-02

    Synthesis of polymeric carbon dioxide has long been of interest to many chemists and materials scientists. Very recently we discovered the polymeric phase of carbon dioxide (called CO{sub 2}-V) at high pressures and temperatures. Our optical and x-ray results indicate that CO{sub 2}-V is optically non-linear, generating the second harmonic of Nd: YLF laser at 527 nm and is also likely superhard similar to cubic-boron nitride or diamond. CO{sub 2}-V is made of CO{sub 4} tetrahedra, analogous to SiO{sub 2} polymorphs, and is quenchable at ambient temperature at pressures above 1 GPa. In this paper, we describe the pressure-induced polymerization of carbon dioxide together with the stability, structure, and mechanical and optical properties of polymeric CO{sub 2}-V. We also present some implications of polymeric CO{sub 2} for high-pressure chemistry and new materials synthesis.

  5. Non-Isocyanate Polyurethane Soft Nanoparticles Obtained by Surfactant-Assisted Interfacial Polymerization.

    PubMed

    Bossion, Amaury; Jones, Gavin O; Taton, Daniel; Mecerreyes, David; Hedrick, James L; Ong, Zhan Yuin; Yang, Yi Yan; Sardon, Haritz

    2017-02-28

    Polyurethanes (PUs) are considered ideal candidates for drug delivery applications due to their easy synthesis, excellent mechanical properties, and biodegradability. Unfortunately, methods for preparing well-defined PU nanoparticles required miniemulsion polymerization techniques with a nontrivial control of the polymerization conditions due to the inherent incompatibility of isocyanate-containing monomers and water. In this work, we report the preparation of soft PU nanoparticles in a one-pot process using interfacial polymerization that employs a non-isocyanate polymerization route that minimizes side reactions with water. Activated pentafluorophenyl dicarbonates were polymerized with diamines and/or triamines by interfacial polymerization in the presence of an anionic emulsifier, which afforded non-isocyanate polyurethane (NIPU) nanoparticles with sizes in the range of 200-300 nm. Notably, 5 wt % of emulsifier was required in combination with a trifunctional amine to achieve stable PU dispersions and avoid particle aggregation. The versatility of this polymerization process allows for incorporation of functional groups into the PU nanoparticles, such as carboxylic acids, which can encapsulate the chemotherapeutic doxorubicin through ionic interactions. Altogether, this waterborne synthetic method for functionalized NIPU soft nanoparticles holds great promise for the preparation of drug delivery nanocarriers.

  6. The use of micellar solutions for novel separation techniques

    SciTech Connect

    Roberts, B.L.

    1993-12-31

    Surfactant based separation techniques based on the solubilization of organic compounds into the nonpolar interior of a micelle or electrostatic attraction of ionized metals and metal complexes to the charged surface of a micelle were studied in this work. Micellar solutions were used to recover two model volatile organic compounds emitted by the printing and painting industries (toluene and amyl acetate) and to investigate the effect of the most important variables in the surfactant enhanced carbon regeneration (SECR) process. SECR for liquid phase applications was also investigated in which the equilibrium adsorption of cetyl pyridinium chloride (CPC) and sodium dodecyl sulfate (SDS) on activated carbon were measured. Micellar-enhanced ultrafiltration (MEUF) was investigated using spiral wound membranes for the simultaneous removal of organic compounds, metals and metal complexes dissolved in water, with emphasis on pollution control applications. Investigations of MEUF to remove 99+ per cent of trichloroethylene (TCE) from contaminated groundwater using criteria such as: membrane flux, solubilization equilibrium constant, surfactant molecular weight, and Krafft temperature led to the selection of an anionic disulfonate with a molecular weight of 642 (DOWFAX 8390). These data and results from supporting experiments were used to design a system which could clean-up water in a 100,000 gallon/day operation. A four stage process was found to be an effective design and estimated cost for such an operation were found to be in the range of the cost of mature competitive technologies.

  7. Univalent salts as modifiers in micellar capillary electrophoresis.

    PubMed

    McLaren, David G; Boulat, Olivier; Chen, David D Y

    2002-06-01

    The influence of three univalent salts (LiCl, NaCl and RbCl) on the separation of amino acids labelled with 3-(4-carboxybenzoyl)-quinoline-2-carboxaldehyde (CBQCA) in micellar capillary electrophoresis has been studied. Capacity factors for a series of eight CBQCA-labelled amino acids in a sodium dodecyl sulfate (SDS) micellar system containing different concentrations of salt were measured and were found to be related to both the hydrodynamic radius of the salt counter-ion (Li(+), Na(+), Rb(+)) and the relative hydrophobicity of the amino acid. Affinities of the analytes for the micelles were generally observed to decrease as the salt concentration in the background electrolyte was increased from 10 to 50 mM. This decrease in affinity was greatest in the presence of the salt counter-ion with the smallest hydrodynamic radius and is primarily due to an increased resistance to mass transfer. Furthermore, interaction of hydrophobic analytes with the micelles is greater than that of hydrophilic analytes at all salt concentrations due to the greater strength of the hydrophobic interactions and this effect is also enhanced in the presence of a smaller counter-ion. No negative effects due to Joule heating or electromigrative dispersion were observed for low to moderate concentrations of salt, which suggests that the use of simple univalent salts to modify analyte/micelle affinities can be a practical method for improving the separation of complex mixtures.

  8. Worming Their Way into Shape: Toroidal Formations in Micellar Solutions

    SciTech Connect

    Cardiel Rivera, Joshua J.; Tonggu, Lige; Dohnalkova, Alice; de la Iglesia, Pablo; Pozzo, Danilo C.; Shen, Amy

    2013-11-01

    We report the formation of nanostructured toroidal micellar bundles (nTMB) from a semidilute wormlike micellar solution, evidenced by both cryogenicelectron microscopy and transmission electron microscopy images. Our strategy for creating nTMB involves a two-step protocol consisting of a simple prestraining process followed by flow through a microfluidic device containing an array of microposts, producing strain rates in the wormlike micelles on the order of 105 s^1. In combination with microfluidic confinement, these unusually large strain rates allow for the formation of stable nTMB. Electron microscopy images reveal a variety of nTMB morphologies and provide the size distribution of the nTMB. Small-angle neutron scattering indicates the underlying microstructural transition from wormlike micelles to nTMB. We also show that other flow-induced approaches such as sonication can induce and control the emergence of onion-like and nTMB structures, which may provide a useful tool for nanotemplating.

  9. Overview of the El Dorado Micellar-Polymer Project

    SciTech Connect

    Vanhorn, L.E.

    1981-01-01

    The primary objective of the El-Dorado Micellar-Polymer Demonstration Project is to determine the economic feasibility of improved oil recovery using 2 micellar-polymer processes and to determine the associated benefits and problems of each process. The project, located in the El Dorado field, is being conducted in the 650-ft shallow sand of the Admire Group in the base of the Permian section. Sand thicknesses vary upward to 30 ft in association with numerous mini-structures. The 650-ft sand has been described as a deltaic environment with intermixing swamps, bay, and distributary channel deposits. The average porosity is 24% with permeabilities averaging 230 md. The total areal extent of the 650-ft sand reservoir is in excess of 6200 acres. Original oil-in-place was estimated at approximately 108 million bbl. Primary, air-drive, and waterflood operations have recovered 36.5 million bbl of oil, leaving an estimated 71.5 million bbl of oil in place. Water injection was terminated in February 1971, and essentially all wells in the 650-ft sand were plugged prior to initiation of the project. The primary objectives of the demonstration test are given.

  10. Percolation and Critical Phenomena of AN Attractive Micellar System

    NASA Astrophysics Data System (ADS)

    Mallamace, F.; Chen, S. H.; Gambadauro, P.; Lombardo, D.; Faraone, A.; Tartaglia, P.

    In this work we study an attractive micellar system for which the percolation curve terminates near the critical point. We have studied such an intriguing situation by means of scattering (elastic and dynamical) and viscoelasticity experiments. Obtained data are accounted by considering in a proper way the fractal clustering processes typical of percolating systems and the related scaling concepts. We observe that the main role in the system structure and dynamics it is played by the cluster's partial screening of hydrodynamic interaction. This behaves on approaching the percolation threshold dramatic effects on the system rheological properties and on the density decay relaxations. The measured correlation functions assume a stretched exponential form and the system becomes strongly viscoelastic. The overall behavior of the measured dynamical and structural parameters indicates, that in the present micellar system, the clustering process originates dilute, poly-disperse and swelling structures. Finally, this originates an interesting situation observed in the present experiment. As it has been previously, proposed by A. Coniglio et al., percolation clusters can be considered to be "Ising clusters" with the same properties as the Fisher's critical droplets. Therefore at the critical point the percolation connectedness length (ξp) can be assumed as the diverging correlation length (ξp ≡ ξ) and the mean cluster size diverges as the susceptibility.

  11. Synthesis and characterization of smart N-isopropylacrylamide-based magnetic nanocomposites containing doxorubicin anti-cancer drug.

    PubMed

    Motaali, Soheila; Pashaeiasl, Maryam; Akbarzadeh, Abolfazl; Davaran, Soodabeh

    2017-05-01

    In the present study, magnetic and thermo/pH-sensitive (multiresponsive) nanocomposites based on N-isopropylacrylamide (NIPAAM) were synthesized and characterized. Nanocomposites were synthesized by free radical emulsion polymerization of NIPAAM as thermosensitive monomer and N,N-dimethyl-aminoethyl methacrylate (DMAEMA) as pH-sensitive monomer in the presence of methylene-bis-acrylamide as cross-linking agent. Doxorubicin, an anti-cancer drug, was loaded into these nanocomposites via equilibrium swelling method. Thermo/pH-sensitive cross-linked poly (NIPAAM-DMAEMA)-Fe3O4 nanocomposites were characterized by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and vibrating sample magnetometer (VSM). The volume of the loaded drug and drug release amount was determined by UV measurements. The results showed that this thermo/pH-sensitive magnetic nanocomposite has a high drug-loading efficiency. Doxorubicin was released at 40 °C and pH 5.8 more than the 37 °C and pH 7.4.

  12. Cryomilling for the fabrication of doxorubicin-containing silica-nanoparticle/polycaprolactone nanocomposite films

    NASA Astrophysics Data System (ADS)

    Gao, Yu; Lim, Jing; Han, Yiyuan; Wang, Lifeng; Chong, Mark Seow Khoon; Teoh, Swee-Hin; Xu, Chenjie

    2016-01-01

    Bionanocomposites need to have a homogeneous distribution of nanomaterials in the polymeric matrix to achieve consistent mechanical and biological functions. However, a significant challenge lies in achieving the homogeneous distribution of nanomaterials, particularly through a solvent-free approach. This report introduces a technology to address this need. Specifically, cryomilling, a solvent-free, low-temperature processing method, was applied to generate a bionanocomposite film with well-dispersed nanoparticles. As a proof-of-concept, polycaprolactone (PCL) and doxorubicin-containing silica nanoparticles (Si-Dox) were processed through cryomilling and subsequently heat pressed to form the PCL/Si-Dox (cPCL/Si-Dox) film. Homogeneous distribution of Si-Dox was observed under both confocal imaging and atomic force microscopy imaging. The mechanical properties of cPCL/Si-Dox were comparable to those of the pure PCL film. Subsequent in vitro release profiles suggested that sustained release of Dox from the cPCL/Si-Dox film was achievable over 50 days. When human cervical cancer cells were seeded directly on these films, uptake of Dox was observed as early as day 1 and significant inhibition of cell growth was recorded on day 5.Bionanocomposites need to have a homogeneous distribution of nanomaterials in the polymeric matrix to achieve consistent mechanical and biological functions. However, a significant challenge lies in achieving the homogeneous distribution of nanomaterials, particularly through a solvent-free approach. This report introduces a technology to address this need. Specifically, cryomilling, a solvent-free, low-temperature processing method, was applied to generate a bionanocomposite film with well-dispersed nanoparticles. As a proof-of-concept, polycaprolactone (PCL) and doxorubicin-containing silica nanoparticles (Si-Dox) were processed through cryomilling and subsequently heat pressed to form the PCL/Si-Dox (cPCL/Si-Dox) film. Homogeneous

  13. Hepatic Arterial Embolization with Doxorubicin-Loaded Superabsorbent Polymer Microspheres in a Rabbit Liver Tumor Model

    SciTech Connect

    Gupta, Sanjay Wright, Kenneth C.; Ensor, Joe; Van Pelt, Carolyn S.; Dixon, Katherine A.; Kundra, Vikas

    2011-10-15

    Objectives: The pharmacokinetic profile after hepatic arterial embolization with superabsorbent microspheres (QuadraSpheres) loaded with doxorubicin was studied. Methods: Rabbits with hepatic VX2 tumors were treated with intra-arterial administration of QuadraSpheres loaded with doxorubicin, or transarterial chemoembolization (TACE) using doxorubicin, Lipiodol and Embospheres, or hepatic arterial infusion (HAI) of doxorubicin. Tumor specimens were evaluated by fluorescence microscopy, and plasma and tumor concentrations of doxorubicin were measured. Results: The peak plasma concentration of doxorubicin was lower in the QuadraSphere group (309.9 ng/ml) than in the HAI (673.4 ng/ml) or TACE (360.5 ng/ml) groups, suggesting higher tumor retention in the QuadraSphere group. Intratumoral doxorubicin levels declined to negligible levels at 1 and 3 days after treatment, respectively, in the HAI and TACE groups. In the QuadraSphere groups, intratumoral doxorubicin level declined after day 1, but was still detectable at 14 days after treatment and was higher than that in the other groups at 1, 3, and 7 days. Intratumoral doxorubicin fluorescence was detected at all time points in the QuadraSphere group, but only at 1 day after treatment in the TACE group. Conclusions: Hepatic arterial administration of doxorubicin-loaded QuadraSpheres enables the sustained release of doxorubicin to hepatic tumors.

  14. Pentoxifylline as a modulator of anticancer drug doxorubicin. Part II: Reduction of doxorubicin DNA binding and alleviation of its biological effects.

    PubMed

    Gołuński, Grzegorz; Borowik, Agnieszka; Derewońko, Natalia; Kawiak, Anna; Rychłowski, Michał; Woziwodzka, Anna; Piosik, Jacek

    2016-04-01

    Anticancer drug doxorubicin is commonly used in cancer treatment. However, drug's severe side effects make toxicity reduction important matter. Another biologically active aromatic compound, pentoxifylline, can sequester aromatic compounds in stacking complexes reducing their bioactivity. This work deals with the problem of alleviating doxorubicin side effects by pentoxifylline. We employed a wide spectrum of prokaryotic and eukaryotic cellular assays. In addition, we used the doxorubicin-pentoxifylline mixed association constant to quantitatively assess pentoxifylline influence on the doxorubicin mutagenic activity. Obtained results indicate strong protective effects of pentoxifylline towards doxorubicin, observed on bacteria and human keratinocytes with no such effects observed on the cancer cells. It may be hypothesized that, considering much shorter half-life of pentoxifylline than doxorubicin, simultaneous administration of doxorubicin and pentoxifylline will lead to gradual release of doxorubicin from complexes with pentoxifylline to reach desired therapeutic concentration. Proposed results shed light on the possible doxorubicin chemotherapy modification and its side effects reduction without the loss of its therapeutic potential.

  15. Utilization of micellar electrokinetic chromatography-tandem mass spectrometry employed volatile micellar phase in the analysis of cathinone designer drugs.

    PubMed

    Švidrnoch, Martin; Lněníčková, Ludmila; Válka, Ivo; Ondra, Peter; Maier, Vítězslav

    2014-08-22

    A micellar electrokinetic chromatography method with tandem mass spectrometry has been developed for the selective separation, identification and determination of twelve new designer drugs from the group of synthetic cathinones. Ammonium salt of perfluorooctanoic acid at various concentrations as a volatile background electrolyte (BGE) to create micellar phase was studied for separation of selected synthetic cathinones with direct tandem mass spectrometry without significant loss of detection sensitivity. The optimized BGE contained 100 mM perfluorooctanoic acid with 200 mM ammonium hydroxide providing acceptable resolution of studied drugs in the MEKC step. In order to minimize interferences with matrix components and to preconcentrate target analytes, solid phase extraction was introduced as a clean-up step. The method was linear in the concentration range of 10-5000 ng mL(-1) and the limits of detection were in the range of 10-78 ng mL(-1). The method was demonstrated to be specific, sensitive, and reliable for the systematic toxicological analysis of these derivatives in urine samples.

  16. Grape seed and skin extract protects kidney from doxorubicin-induced oxidative injury.

    PubMed

    Mokni, Meherzia; Hamlaoui, Sonia; Kadri, Safwen; Limam, Ferid; Amri, Mohamed; Marzouki, Lamjed; Aouani, Ezzedine

    2016-05-01

    The study investigated the protective effect of grape seed and skin extract (GSSE) against doxorubicin-induced renal toxicity in healthy rats. Animals were treated with GSSE or not (control), for 8 days, administered with doxorubicin (20mg/kg) in the 4th day, and renal function as well as oxidative stress parameters were evaluated. Data showed that doxorubicin induced renal toxicity by affecting renal architecture and plasma creatinine. Doxorubicin also induced an oxidative stress characterized by an increase in malondialdehyde (MDA), calcium and H(2)O(2) and a decrease in catalase (CAT) and superoxide dismutase (SOD). Unexpectedly doxorubicin increased peroxidase (POD) and decreased carbonyl protein and plasma urea. Treatment with GSSE counteracted almost all adverse effects induced by doxorubicin. Data suggest that doxorubicin induced an oxidative stress into rat kidney and GSSE exerted antioxidant properties, which seem to be mediated by the modulation of intracellular calcium.

  17. Exercise preconditioning modulates genotoxicity induced by doxorubicin in multiple organs of rats.

    PubMed

    Martins, Renato Almeida; Minari, André Luis; Chaves, Marcelo Donizetti; dos Santos, Ronaldo Wagner Thomatieli; Barbisan, Luis Fernando; Ribeiro, Daniel Araki

    2012-06-01

    The aim of this study was to investigate the effects of exercise in multiple organs of rats treated with doxorubicin. Male adult Wistar rats were distributed into the following groups: sedentary + NaCl; exercise + NaCl; sedentary + doxorubicin; and exercise + doxorubicin. Animals were sacrificed 2 days following injections. Central fragments from heart, liver, and kidney were collected and minced in 0.9% NaCl being cellular suspensions used for the single-cell gel (comet) assay. The results showed that exercise was able to prevent genotoxicity induced by doxorubicin in heart cells. By contrast, exercise was not able to prevent genotoxicity induced by doxorubicin in liver cells. The same occurred to kidney cells, i.e. no statistically significant differences (p > 0.05) were found when compared with groups not exposed to doxorubicin. Taken together, our results support the idea that exercise could contribute to the protective effect against genotoxicity induced by doxorubicin in heart cells.

  18. Liposomal Coencapsulation of Doxorubicin with Listeriolysin O Increases Potency via Subcellular Targeting.

    PubMed

    Walls, Zachary F; Gong, Henry; Wilson, Rebecca J

    2016-03-07

    Liposomal doxorubicin is a clinically important drug formulation indicated for the treatment of several different forms of cancer. For doxorubicin to exert a therapeutic effect, it must gain access to the nucleus. However, a large proportion of the liposomal doxorubicin dose fails to work because it is sequestered within endolysosomal organelles following endocytosis of the liposomes due to the phenomenon of ion trapping. Listeriolysin O (LLO) is a pore-forming protein that can provide a mechanism for endosomal escape. The present study demonstrates that liposomal coencapsulation of doxorubicin with LLO enables a significantly larger percentage of the dose to colocalize with the nucleus compared to liposomes containing doxorubicin alone. The change in intracellular distribution resulted in a significantly more potent formulation of liposomal doxorubicin as demonstrated in both the ovarian carcinoma cell line A2780 and its doxorubicin-resistant derivative A2780ADR.

  19. Phase I trial of cremophor EL with bolus doxorubicin.

    PubMed

    Millward, M J; Webster, L K; Rischin, D; Stokes, K H; Toner, G C; Bishop, J F; Olver, I N; Linahan, B M; Linsenmeyer, M E; Woodcock, D M

    1998-10-01

    Cremophor EL (cremophor), a component of the paclitaxel formulation, can potentially reverse P-glycoprotein-associated multidrug resistance. A Phase I trial of cremophor as a 6-h infusion every 3 weeks was performed with bolus doxorubicin (50 mg/m2). The cremophor dose was escalated from 1 to 60 ml/m2. A standard paclitaxel premedication was given before cremophor. Using a bioassay, potentially active cremophor levels (> or = 1 microl/ml) were measured in plasma from patients receiving cremophor doses of 30, 45, and 60 ml/m2. A cross-over design was used to assess the influence of cremophor 30 ml/m2 on the pharmacokinetics of doxorubicin and doxorubicinol. The plasma area under the concentration versus time curve (AUC) of doxorubicin increased from 1448 +/- 350 to 1786 +/- 264 ng/ml x h (P = 0.02) in the presence of cremophor, whereas the AUC of doxorubicinol increased from 252 +/- 104 to 486 +/- 107 ng/ml x h (P = 0.02). This pharmacokinetic interaction was associated with significantly increased neutropenia. With reduction of the doxorubicin dose to 35 mg/m2, the cremophor dose was increased to 60 ml/m2. Dose-limiting toxicities occurred in two of six patients after 45 ml/m2 and two of four patients after 60 ml/m2, which included febrile neutropenia and grade III cremophor-related toxicities of rash, pruritus, headache, and hypotension. All patients who received 45 ml/m2 cremophor reached plasma levels > or = 1.5 microl/ml, but at 60 ml/m2, only two of four reached this level, and the calculated plasma clearance of cremophor was significantly faster at this dose. One patient with hepatoma resistant to epirubicin achieved a near-complete response. Cremophor 45 ml/m2 over 6 h with 35 mg/m2 doxorubicin is recommended for further studies. The pharmacokinetic interaction between cremophor and doxorubicin is quantitatively similar to that described in trials of paclitaxel with doxorubicin and suggests that the cremophor in the paclitaxel formulation is responsible.

  20. Injectable small molecule hydrogel as a potential nanocarrier for localized and sustained in vivo delivery of doxorubicin

    NASA Astrophysics Data System (ADS)

    Singh, Manish; Kundu, Somanath; Reddy M, Amarendar; Sreekanth, Vedagopuram; Motiani, Rajender K.; Sengupta, Sagar; Srivastava, Aasheesh; Bajaj, Avinash

    2014-10-01

    The majority of the localized drug delivery systems are based on polymeric or polypeptide scaffolds, as weak intermolecular interactions of low molecular weight hydrogelators (LMHGs, Mw <500 Da) are significantly perturbed in the presence of anticancer drugs. Here, we present l-alanine derived low molecular weight hydrogelators (LMHGs) that remain injectable even after entrapping the anticancer drug doxorubicin (DOX). These DOX containing nanoassemblies (DOX-Gel) showed promising anticancer activity in mice models. Subcutaneous injection of DOX-Gel near the tumor achieved a greater decrease in tumour load than by intravenous injection of DOX (DOX-IV), and local injection of DOX alone (DOX-Local) at the tumor site. We noticed that DOX-Gel nanocarriers are especially effective when injected during the early stage of tumor progression, and achieve a substantial decrease in tumor load in the long term.The majority of the localized drug delivery systems are based on polymeric or polypeptide scaffolds, as weak intermolecular interactions of low molecular weight hydrogelators (LMHGs, Mw <500 Da) are significantly perturbed in the presence of anticancer drugs. Here, we present l-alanine derived low molecular weight hydrogelators (LMHGs) that remain injectable even after entrapping the anticancer drug doxorubicin (DOX). These DOX containing nanoassemblies (DOX-Gel) showed promising anticancer activity in mice models. Subcutaneous injection of DOX-Gel near the tumor achieved a greater decrease in tumour load than by intravenous injection of DOX (DOX-IV), and local injection of DOX alone (DOX-Local) at the tumor site. We noticed that DOX-Gel nanocarriers are especially effective when injected during the early stage of tumor progression, and achieve a substantial decrease in tumor load in the long term. Electronic supplementary information (ESI) available: Scheme 1, Fig. S1-S6, synthesis of hydrogels; experimental section for gelation, rheology, MALDI, microscopy and

  1. HPLC-MS/MS determination of a peptide conjugate prodrug of doxorubicin, and its active metabolites, leucine-doxorubicin and doxorubicin, in dog and rat plasma.

    PubMed

    Mazuel, Claude; Grove, Jeffrey; Gerin, Geneviève; Keenan, Kevin P

    2003-12-04

    A HPLC-MS/MS Electrospray (ESI) method was developed and validated to quantify a peptide conjugate prodrug of doxorubicin (Dox-Con) and its active metabolites leucine-doxorubicin (Leu-Dox) and doxorubicin (Dox) in dog and rat plasma. The analytes were extracted from plasma by solid-phase extraction on a Bond Elut C8 cartridge and eluted with chloroform-methanol (2:1). Eluates were evaporated and reconstituted in acetonitrile-5 microM sodium trifluoroacetate in 0.1% aqueous formic acid (20:80) and injected onto a Waters Oasis HLB column. Analytes were eluted from the column with a solvent gradient into the mass analyzer. The ions were quantified in the selected reaction-monitoring mode (SRM), using positive ions, on a triple quadrupole mass spectrometer. The lower limits of quantification for Dox-Con, Leu-Dox, and Dox in plasma, were approximately 5, 1 (dog)/6 (rat), and 0.5 ng/ml, respectively. Intra- and inter-assay accuracy (% of nominal concentration) and precision (%CV) for all analytes were within 15 and 16%, respectively.

  2. Elasticity and Dynamic Properties of Ionic Micellar Nematics

    NASA Astrophysics Data System (ADS)

    Plumley, Sulakshana Sathi

    1990-01-01

    Micellar liquid crystals are formed in aqueous solutions of surfactants. Three ionic surfactant systems were used in this dissertation research: Potassium laurate system (KL/1-dec/D_2O), Sodium decyl sulfate system (SDS/1-dec/D_2O) and Cesium perfluorooctanoate system (CsPFO/H_2 O). The KL and SDS systems show three nematic phases: two uniaxial nematic and an intervening biaxial nematic phase. The nematic-nematic transitions are all second order. The aim of this research is to study the similarities and dissimilarities in physical properties of the different systems. In the CsPFO system, the birefringence and density were studied over the N-S transition which shows an unusual hysteresis. Rotational viscosities of micellar nematics were measured by monitoring the relaxation of the optical axes as a function of time in the presence of magnetic field. The KL and SDS systems show significant differences in viscosities and elastic constants. The elastic constants in KL and SDS systems were measured to be of the order of 10^{ -7}-10^{-8} dynes which is an order smaller than for thermotropic systems. The viscosity measured in the middle of N_{ rm C} phase is about 60 poise in SDS system while it is about 10 poise in the KL system. In the SDS system, a strong pretransitional effect is seen at the N_{rm BX} -N_{rm C} transition resulting in a decrease in viscosity. It is probably due to a change in short range interaction of the micelles. Birefringence measurements were taken for CsPFO system over the N-S transition to study the hysteresis at N-S transition. Density measurements were also done for the same purpose. Measurements taken at the different scan rate showed that there was still a small hysteresis even at rates as slow as 1mk/min. It is remarkable that in the SDS and CsPFO systems the density change at N-I transition is negative while the density change is positive at N-S transition. It indicates that there are different changes in the micellar structure. An

  3. Control of doxorubicin release from magnetic Poly( dl-lactide-co-glycolide) nanoparticles by application of a non-permanent magnetic field

    NASA Astrophysics Data System (ADS)

    Peça, Inês N.; Bicho, A.; Gardner, Rui; Cardoso, M. Margarida

    2015-11-01

    This work studied the effect of the application time of a non-permanent magnetic field on the rate of drug release from iron oxide polymeric nanoparticles. Magnetically responsive doxorubicin loaded poly( d-lactide-co-glycolide) (PLGA) nanoparticles were synthetized by the o/w solvent extraction/evaporation method and characterized. The produced particles show spherical shapes exhibiting a size between 200 and 400 nm, a drug loading of 3.6 % (w/w) and an iron concentration of 20.7 % (w/w). Cell cytotoxicity tests showed that unloaded magnetic PLGA nanoparticles were nontoxic. Concerning the therapeutic activity, doxorubicin-loaded magnetic particles cause a remarkable enhancement of the cell inhibition rates compared to their non-magnetic counterparts (40 against 7 % of dead cells). In vitro drug release studies performed under a non-permanent magnetic field show that the application time and the on/off cycle duration have a great influence with respect to the final amount and to the rate of drug release. The final amount and the rate of doxorubicin released increase with the time of field application reaching higher values for a higher number of pulses with a lower duration. Doxorubicin release mechanism has shown to be governed by Fickian diffusion in the absence of a magnetic field while in the presence of a magnetic field some controlled relaxation polymer chains might also be present. The results show that the drug release rate from magnetic PLGA nanoparticles can be modulated through the application time and the on/off cycles duration of a non-permanent magnetic field.

  4. SOLUBILIZATION OF DODECANE, TETRACHLOROETHYLENE, AND 1,2-DICHLOROBENZENE IN MICELLAR SOLUTIONS OF ETHOXYLATED NONIONIC SURFACTANTS

    EPA Science Inventory

    Although surfactants have received considerable attention as a potential means for enhancing the recovery of organic compounds from the subsurface, only limited information is available regarding the micellar solubilization of common groundwater contaminants by nonionic surfactan...

  5. Concentration fluorescence quenching of cyanine dyes in micellar solutions and microemulsions

    SciTech Connect

    Razumov, V.F.; Ivanchenko, A.G.

    1995-10-01

    The concentration fluorescence quenching of cyanine dyes in micellar solutions and microemulsions is studied. The concentration quenching by dimers and statistical traps is analyzed. 14 refs., 4 figs., 1 tab.

  6. Application of micellar liquid chromatography for the determination of antitumoral and antiretroviral drugs in plasma.

    PubMed

    Peris-Vicente, Juan; Casas-Breva, Inmaculada; Roca-Genovés, Pasqual; Esteve-Romero, Josep

    2014-01-01

    In micellar liquid chromatography, the mobile phase is made of a surfactant and, eventually, an alcohol. This article describes several methods to measure the concentration of antitumoral and antiretroviral drugs in plasma, utilizing micellar liquid chromatography. Samples can be injected after dilution with a micellar solution and filtration, because proteins and other endogenous compounds are solubilized in micellar medium. We will discuss the following optimized parameters: dilution ratio, type of column, detection conditions and mobile phase composition. This article will also cover the validation performed following the International Conference on Harmonization guidelines and the results reported in the literature, indicating that the methods are useful for the routine analysis of plasma samples for clinical purposes.

  7. Role of non-covalent and covalent interactions in cargo loading capacity and stability of polymeric micelles.

    PubMed

    Ke, Xiyu; Ng, Victor Wee Lin; Ono, Robert J; Chan, Julian M W; Krishnamurthy, Sangeetha; Wang, Ying; Hedrick, James L; Yang, Yi Yan

    2014-11-10

    Polymeric micelles self-assembled from biodegradable amphiphilic block copolymers have been proven to be effective drug delivery carriers that reduce the toxicity and enhance the therapeutic efficacy of free drugs. Several reviews have been reported in the literature to discuss the importance of size/size distribution, stability and drug loading capacity of polymeric micelles for successful in vivo drug delivery. This review is focused on non-covalent and covalent interactions that are employed to enhance cargo loading capacity and in vivo stability, and to achieve nanosize with narrow size distribution. In particular, this review analyzes various non-covalent and covalent interactions and chemistry applied to introduce these interactions to the micellar drug delivery systems, as well as the effects of these interactions on micelle stability, drug loading capacity and release kinetics. Moreover, the factors that influence these interactions and the future research directions of polymeric micelles are discussed.

  8. Concise polymeric materials encyclopedia

    SciTech Connect

    Salamone, J.C.

    1999-01-01

    This comprehensive, accessible resource abridges the ``Polymeric Materials Encyclopedia'', presenting more than 1,100 articles and featuring contributions from more than 1,800 scientists from all over the world. The text discusses a vast array of subjects related to the: (1) synthesis, properties, and applications of polymeric materials; (2) development of modern catalysts in preparing new or modified polymers; (3) modification of existing polymers by chemical and physical processes; and (4) biologically oriented polymers.

  9. Redox reactions in micellar systems. communication 4. Eosin-photosensitized reduction of methylviologen

    SciTech Connect

    Nadtochenko, V.; Dzhabiev, T.S.; Rubtsov, I.V.

    1985-12-10

    The authors present data on photosensitized reduction of methylviologen (MV/sup 2 +/) by disodium ethylenediaminetetraacetate (EDTA) in micellar systems modeling, in a first approximation, the structural organization of components of the chain of energy and electron transfer in natural photosynthesis. Photosensitized reduction of methylviologen by EDTA in micellar solutions can model photosystem I of plants with structure formation of reagents and transfer of excitation energy before the step of occurrence of a redox reaction in the active center.

  10. Radical-Mediated Enzymatic Polymerizations

    PubMed Central

    Zavada, Scott R.; Battsengel, Tsatsral; Scott, Timothy F.

    2016-01-01

    Polymerization reactions are commonly effected by exposing monomer formulations to some initiation stimulus such as elevated temperature, light, or a chemical reactant. Increasingly, these polymerization reactions are mediated by enzymes―catalytic proteins―owing to their reaction efficiency under mild conditions as well as their environmental friendliness. The utilization of enzymes, particularly oxidases and peroxidases, for generating radicals via reduction-oxidation mechanisms is especially common for initiating radical-mediated polymerization reactions, including vinyl chain-growth polymerization, atom transfer radical polymerization, thiol–ene step-growth polymerization, and polymerization via oxidative coupling. While enzyme-mediated polymerization is useful for the production of materials intended for subsequent use, it is especially well-suited for in situ polymerizations, where the polymer is formed in the place where it will be utilized. Such polymerizations are especially useful for biomedical adhesives and for sensing applications. PMID:26848652

  11. Modelling bioconcentration of pesticides in fish using biopartitioning micellar chromatography.

    PubMed

    Bermúdez-Saldaña, José María; Escuder-Gilabert, Laura; Medina-Hernández, María José; Villanueva-Camañas, Rosa María; Sagrado, Salvador

    2005-01-21

    Ecotoxicity assessment is essential before placing new chemical substances on the market. An investigation of the use of the chromatographic retention (log k) in biopartitioning micellar chromatography (BMC) as an in vitro approach to evaluate the bioconcentration factor (BCF) of pesticides in fish is proposed. A heterogeneous set of 85 pesticides from six chemical families was used. For pesticides exhibiting bioconcentration in fish (experimental log BCF > 2), a quantitative retention-activity relationships (QRAR) model is able to perform precise log BCF estimations of new pesticides. Considering the present data, the results based on log k seem to be more reliable than those from available software (BCFWIN and KOWWIN) and from log P (quantitative structure-activity relationships (QSAR)). It is also possible to perform risk assessment tasks fixing a threshold value for log k, which substitute two common threshold values, log P and experimental log BCF, avoiding the experimental problems related with these two parameters.

  12. Micellar electrokinetic chromatography (MEKC) separation of furanonaphthoquinones from Tabebuia impetiginosa.

    PubMed

    Koyama, J; Morita, I; Kino, A; Tagahara, K

    2000-06-01

    The separation of nine furanonaphthoquinones by micellar electrokinetic chromatography (MEKC) is described. The running electrolytes used in this method were 0.03 M sodium dodecyl sulphate (SDS) in 0.09 M borate buffer (pH 9) containing 10% methanol, with an applied voltage of 20 kV. Application of this technique in the determination of the main furanonaphthoquinones, 5-hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione, 8-hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione, and 2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione, of Tabebuia impetiginosa is demonstrated in this paper.

  13. Separation of bisbenzylisoquinoline alkaloids by micellar electrokinetic chromatography.

    PubMed

    Kuo, Ching-Hua; Sun, Shao-Wen

    2002-01-01

    The micellar electrokinetic chromatographic (MEKC) separation of seven bisbenzylisoquinoline alkaloids has been developed. The effects of various separating factors were studied. Optimum separation was achieved using a buffer (pH 9.2) of 20 mM sodium borate and 20 mM sodium dihydrogen phosphate buffer containing 55 mM sodium cholate; the optimum voltage and injection time were 21 kV and 0.05 min, respectively. Highest peak efficiency was obtained when the analytes were dissolved in 10 mM sodium dodecyl sulphate as sample matrix for injection. The elution order of the bisbenzylisoquinoline alkaloids was related to their lipophilicity. The resolution, run time and detection limits of the MEKC method were compared with those of an HPLC method developed previously.

  14. Dynamics of concentration fluctuations for a micellar solution

    NASA Astrophysics Data System (ADS)

    Hamano, K.; Sato, T.; Koyama, T.; Kuwahara, N.

    1985-09-01

    The decay rate Γ for a micellar solution pentaethyleneglycol mono n-dodecyl ether +water has been examined near the critical mixing point by light scattering. We find that the dynamic scaling behavior of Γ*=[6πη(T)/kBT](Γ/k3 ) as a function of kξ over the range of 0.14<=kξ<=6.2 has an obvious kinship with that for a fluid mixture near the critical mixing point, where η(T) is the shear viscosity and ξ the correlation length. It is also found that the shear viscosity exhibits a critical-like power-law singularity and depends explicitly on shear gradients.

  15. Jet A fuel recovery using micellar flooding: Design and implementation.

    PubMed

    Kostarelos, Konstantinos; Lenschow, Søren R; Stylianou, Marinos A; de Blanc, Phillip C; Mygind, Mette Marie; Christensen, Anders G

    2016-09-01

    Surfactants offer two mechanisms for recovering NAPLs: 1) to mobilize NAPL by reducing NAPL/water interfacial tension, and; 2) to increase the NAPL's aqueous solubility-called solubilization-as an enhancement to pump & treat. The second approach has been well-studied and applied successfully in several pilot-scale and a few full-scale tests within the last 15years, known as Surfactant Enhanced Aquifer Remediation (SEAR). A useful source of information for this second approach is the "Surfactant-enhanced aquifer remediation (SEAR) design manual" from the U.S. Navy Facilities Engineering Command. Few attempts, however, have been made at recovering NAPLs using the mobilization approach presented in this paper. Now, a full-scale field implementation of the mobilization approach is planned to recover an LNAPL (Jet A fuel) from a surficial sand aquifer located in Denmark using a smaller amount of surfactant solution and fewer PVs of throughput compared with the SEAR approach. The approach will rely on mobilizing the LNAPL so that it is recovered ahead of the surfactant microemulsion, also known as a micellar flood. This paper will review the laboratory work performed as part of the design for a full-scale implementation of a micellar flood. Completed lab work includes screening of surfactants, phase behavior and detailed salinity scans of the most promising formulations, and generating a ternary diagram to be used for the numerical simulations of the field application. The site owners and regulators were able to make crucial decisions such as the anticipated field results based on this work.

  16. The effect of commercial sterilization regimens on micellar casein concentrates.

    PubMed

    Beliciu, C M; Sauer, A; Moraru, C I

    2012-10-01

    This work focused on evaluating the effects of UHT sterilization and in-container retorting on the stability and physical properties of micellar casein concentrates (MCC). The study was performed on MCC obtained by membrane separation, with casein concentrations between 5 and 10%. The UHT and retorting regimens were designed to achieve the same microbial inactivation effect. Ultra-high temperature treatment was performed in a pilot-scale MicroThermics heating system (MicroThermics Inc., Raleigh, NC), and retorting in an FMC multipurpose laboratory retort (Steritort; FMC Corp., San Jose, CA). The heat-treated and the non-heat-treated MCC controls were evaluated for pH, mineral profile, ζ-potential, particle size, and rheological properties for up to 24h after heat treatment. The treatments were performed in triplicate, and differences among samples were evaluated using statistical analyses. Retorting resulted in slight aggregation in the MCC, whereas UHT caused the formation of visible aggregates and coagulation. The UHT-treated MCC had higher viscosity than retorted MCC, and displayed predominantly solid-like rheological behavior, indicative of structure formation. These effects were, at least in part, attributed to a change in mineral equilibrium, which affected the stability of the casein micelles, but additional mechanisms such as κ-casein dissociation may also play a significant role in these heat-induced changes. Drying of MCC accentuated the observed instabilities, as dried and reconstituted micellar casein concentrates (R-MCC) were more unstable to UHT sterilization than the MCC that had not undergone drying. The results of this study provide valuable information about the sterilization behavior and physical properties of MCC, which can be useful to processors in the development and manufacture of shelf-stable casein-based products and beverages.

  17. Theoretical study of catalytic effects in micellar solutions.

    PubMed

    Rescic, J; Vlachy, V; Bhuiyan, L B; Outhwaite, C W

    2005-01-04

    The catalytic effect of charged micelles as manifested through the increased collision frequency between the counterions of an electrolyte in the presence of such micelles is explored by the Monte Carlo simulation technique and various theoretical approaches. The micelles and ions are pictured as charged hard spheres embedded in a dielectric continuum with the properties of water at 298 K with the charge on micelles varying from zero to z(m) = 50 negative elementary charges. Analytical theories such as (i) the symmetric Poisson-Boltzmann theory, (ii) the modified Poisson-Boltzmann theory, and (iii) the hypernetted-chain integral equation are applied and tested against the Monte Carlo data for micellar ions (m) with up to 50 negative charges in aqueous solution with monovalent counterions (c; z(c) = +1) and co-ions (co; z(co) = -1). The results for the counterion-counterion pair correlation function at contact, g(cc)(sigma(cc)), are calculated in a micellar concentration range from c(m) = 5 x 10(-)(6) to 0.1 mol/dm(3) with an added +1:-1 electrolyte concentration of 0.005 mol/dm(3) (for most cases), and for various model parameters. Our computations indicate that even a small concentration of a highly charged polyelectrolyte added to a +1:-1 electrolyte solution strongly increases the probability of finding two counterions in contact. This result is in agreement with experimental data. For low charge on the micelles (z(m) below -8), all the theories are in qualitative agreement with the new computer simulations. For highly charged micelles, the theories either fail to converge (the hypernetted-chain theory) or, alternatively, yield poor agreement with computer data (the symmetric Poisson-Boltzmann and modified Poisson-Boltzmann theories). The nonlinear Poisson-Boltzmann cell model results yield reasonably good agreement with computer simulations for this system.

  18. Studying the concentration dependence of the aggregation number of a micellar model system by SANS.

    PubMed

    Amann, Matthias; Willner, Lutz; Stellbrink, Jörg; Radulescu, Aurel; Richter, Dieter

    2015-06-07

    We present a small-angle neutron scattering (SANS) structural characterization of n-alkyl-PEO polymer micelles in aqueous solution with special focus on the dependence of the micellar aggregation number on increasing concentration. The single micellar properties in the dilute region up to the overlap concentration ϕ* are determined by exploiting the well characterized unimer exchange kinetics of the model system in a freezing and diluting experiment. The micellar solutions are brought to thermodynamic equilibrium at high temperatures, where unimer exchange is fast, and are then cooled to low temperatures and diluted to concentrations in the limit of infinite dilution. At low temperatures the kinetics, and therefore the key mechanism for micellar rearrangement, is frozen on the experimental time scale, thus preserving the micellar structure in the dilution process. Information about the single micellar structure in the semidilute and concentrated region are extracted from structure factor analysis at high concentrations where the micelles order into fcc and bcc close packed lattices and the aggregation number can be calculated by geometrical arguments. This approach enables us to investigate the aggregation behavior in a wide concentration regime from dilute to 6·ϕ*, showing a constant aggregation number with concentration over a large concentration regime up to a critical concentration about three times ϕ*. When exceeding this critical concentration, the aggregation number was found to increase with increasing concentration. This behavior is compared to scaling theories for star-like polymer micelles.

  19. Probing the binding sites of antibiotic drugs doxorubicin and N-(trifluoroacetyl) doxorubicin with human and bovine serum albumins.

    PubMed

    Agudelo, Daniel; Bourassa, Philippe; Bruneau, Julie; Bérubé, Gervais; Asselin, Eric; Tajmir-Riahi, Heidar-Ali

    2012-01-01

    We located the binding sites of doxorubicin (DOX) and N-(trifluoroacetyl) doxorubicin (FDOX) with bovine serum albumin (BSA) and human serum albumins (HSA) at physiological conditions, using constant protein concentration and various drug contents. FTIR, CD and fluorescence spectroscopic methods as well as molecular modeling were used to analyse drug binding sites, the binding constant and the effect of drug complexation on BSA and HSA stability and conformations. Structural analysis showed that doxorubicin and N-(trifluoroacetyl) doxorubicin bind strongly to BSA and HSA via hydrophilic and hydrophobic contacts with overall binding constants of K(DOX-BSA) = 7.8 (± 0.7) × 10(3) M(-1), K(FDOX-BSA) = 4.8 (± 0.5)× 10(3) M(-1) and K(DOX-HSA) = 1.1 (± 0.3)× 10(4) M(-1), K(FDOX-HSA) = 8.3 (± 0.6)× 10(3) M(-1). The number of bound drug molecules per protein is 1.5 (DOX-BSA), 1.3 (FDOX-BSA) 1.5 (DOX-HSA), 0.9 (FDOX-HSA) in these drug-protein complexes. Docking studies showed the participation of several amino acids in drug-protein complexation, which stabilized by H-bonding systems. The order of drug-protein binding is DOX-HSA > FDOX-HSA > DOX-BSA > FDOX>BSA. Drug complexation alters protein conformation by a major reduction of α-helix from 63% (free BSA) to 47-44% (drug-complex) and 57% (free HSA) to 51-40% (drug-complex) inducing a partial protein destabilization. Doxorubicin and its derivative can be transported by BSA and HSA in vitro.

  20. C-phycocyanin ameliorates doxorubicin-induced oxidative stress and apoptosis in adult rat cardiomyocytes.

    PubMed

    Khan, Mahmood; Varadharaj, Saradhadevi; Shobha, Jagdish C; Naidu, Madireddi U; Parinandi, Narasimham L; Kutala, Vijay Kumar; Kuppusamy, Periannan

    2006-01-01

    Doxorubicin (DOX), a potent antineoplastic agent, poses limitations for its therapeutic use due to the associated risk of developing cardiomyopathy and congestive heart failure. The cardiotoxicity of doxorubicin is associated with oxidative stress and apoptosis. We have recently shown that Spirulina, a blue-green alga with potent antioxidant properties, offered significant protection against doxorubicin-induced cardiotoxicity in mice. The aim of the present study was to establish the possible protective role of C-phycocyanin, one of the active ingredients of Spirulina, against doxorubicin-induced oxidative stress and apoptosis. The study was carried out using cardiomyocytes isolated from adult rat hearts. Doxorubicin significantly enhanced the formation of reactive oxygen species (ROS) in cells as measured by the 2',7'-dichlorodihydrofluorescein diacetate and dihydroethidium fluorescence. The doxorubicin-induced reactive oxygen species formation was significantly attenuated in cells pretreated with C-phycocyanin. It was further observed that the doxorubicin-induced DNA fragmentation and apoptosis, as assayed by TUNEL assay and flow cytometry coupled with BrdU-FITC/propidium iodide staining, were markedly attenuated by C-phycocyanin. C-phycocyanin also significantly attenuated the doxorubicin-induced increase in the expression of Bax protein, release of cytochrome c, and increase in the activity of caspase-3 in cells. In summary, C-phycocyanin ameliorated doxorubicin-induced oxidative stress and apoptosis in cardiomyocytes. This study further supports the crucial role of the antioxidant nature of C-phycocyanin in its cardioprotection against doxorubicin-induced oxidative stress and apoptosis.

  1. Human placental cell and tissue uptake of doxorubicin and its liposomal formulations.

    PubMed

    Soininen, Suvi K; Repo, Jenni K; Karttunen, Vesa; Auriola, Seppo; Vähäkangas, Kirsi H; Ruponen, Marika

    2015-12-03

    The anticancer drug doxorubicin and its liposomal formulations are in clinical use, doxorubicin also during pregnancy. However, little is known about how doxorubicin and its liposomal formulations are taken up by placental cells and whether they can cross human placenta. We therefore investigated quantitative cellular uptake and toxicity of doxorubicin and its two liposomal formulations, pH-sensitive liposomal doxorubicin (L-DOX) and commercially available pegylated liposomal doxorubicin (PL-DOX), in human placental choriocarcinoma (BeWo) cells. PL-DOX showed significantly lower cellular uptake and toxicity compared with doxorubicin and L-DOX. In preliminary studies with human placental perfusion, PL-DOX did not cross the placenta at all in 4h, whereas doxorubicin and L-DOX crossed the placenta at low levels (max 12% of the dose). Furthermore, PL-DOX did not accumulate in placental tissue while doxorubicin did (up to 70% of the dose). Surface pegylation probably explains the low placental cell and tissue uptake of PL-DOX. Formulation of doxorubicin thus seems to enable a decrease of fetal exposure.

  2. Reduced in vivo toxicity of doxorubicin by encapsulation in cholesterol-containing self-assembled nanoparticles.

    PubMed

    Gonzalez-Fajardo, Laura; Mahajan, Lalit H; Ndaya, Dennis; Hargrove, Derek; Manautou, José E; Liang, Bruce T; Chen, Ming-Hui; Kasi, Rajeswari M; Lu, Xiuling

    2016-05-01

    We previously reported the development of an amphiphilic brush-like block copolymer composed of polynorbornene-cholesterol/polyethylene glycol (P(NBCh9-b-NBPEG)) that self-assembles in aqueous media to form long circulating nanostructures capable of encapsulating doxorubicin (DOX-NPs). Biodistribution studies showed that this formulation preferentially accumulates in tumor tissue with markedly reduced accumulation in the heart and other major organs. The aim of the current study was to evaluate the in vivo efficacy and toxicity of DOX containing self-assembled polymer nanoparticles in a mouse xenograft tumor model and compare its effects with the hydrochloride non-encapsulated form (free DOX). DOX-NPs significantly reduced the growth of tumors without inducing any apparent toxicity. Conversely, mice treated with free DOX exhibited significant weight loss, early toxic cardiomyopathy, acute toxic hepatopathy, reduced hematopoiesis and fatal toxicity. The improved safety profile of the polymeric DOX-NPs can be explained by the low circulating concentration of non-nanoparticle-associated drug as well as the reduced accumulation of DOX in non-target organs. These findings support the use of P(NBCh9-b-NBPEG) nanoparticles as delivery platforms for hydrophobic anticancer drugs intended to reduce the toxicity of conventional treatments.

  3. Enhanced antitumoral activity of doxorubicin against lung cancer cells using biodegradable poly(butylcyanoacrylate) nanoparticles

    PubMed Central

    Melguizo, Consolación; Cabeza, Laura; Prados, Jose; Ortiz, Raúl; Caba, Octavio; Rama, Ana R; Delgado, Ángel V; Arias, José L

    2015-01-01

    Doxorubicin (Dox) is widely used for the combined chemotherapy of solid tumors. However, the use of these drug associations in lung cancer has low antitumor efficacy. To improve its efficacious delivery and activity in lung adenocarcinoma cells, we developed a biodegradable and noncytotoxic nanoplatform based on biodegradable poly(butylcyanoacrylate) (PBCA). The reproducible formulation method was based on an anionic polymerization process of the PBCA monomer, with the antitumor drug being entrapped within the nanoparticle (NP) matrix during its formation. Improved drug-entrapment efficiencies and sustained (biphasic) drug-release properties were made possible by taking advantage of the synthesis conditions (drug, monomer, and surfactant-agent concentrations). Dox-loaded NPs significantly enhanced cellular uptake of the drug in the A549 and LL/2 lung cancer cell lines, leading to a significant improvement of the drug’s antitumoral activity. In vivo studies demonstrated that Dox-loaded NPs clearly reduced tumor volumes and increased mouse-survival rates compared to the free drug. These results demonstrated that PBCA NPs may be used to optimize the antitumor activity of Dox, thus exhibiting a potential application in chemotherapy against lung adenocarcinoma. PMID:26715840

  4. Degradation of phenol accumulated in a micellar molybdovanadophosphate nanoreactor by air at ambient temperature and atmospheric pressure.

    PubMed

    Zhao, Shun; Sun, Congliang; Wang, Lei; Xu, Xiaobin; Wang, Xiaohong

    2010-06-07

    A novel route to facilitate the degradation of phenol is reported. This new approach is based on a micellar polyoxometalate (POM) catalytic system. The micellar POM catalyst could promote phenol molecules' degradation into a simple inorganic compound such as CO2 using only air as an oxidant under room conditions. The results of the recycling experiment suggests that the micellar POMs may be used as a potential catalyst for the degradation of phenol in wastewater.

  5. Solute-solvent interactions in micellar electrokinetic chromatography. III. Characterization of the selectivity of micellar electrokinetic chromatography systems.

    PubMed

    Fuguet, Elisabet; Ràfols, Clara; Bosch, Elisabeth; Abraham, Michael H; Rosés, Martí

    2002-01-04

    Several micellar electrokinetic chromatography (MEKC) systems (sodium dodecyl sulfate, lithium dodecyl sulfate, lithium perfluorooctanesulfonate, sodium cholate, sodium deoxycholate, tetradecyltrimethylammonium bromide and hexadecyltrimethylammonium bromide) have been characterized by means of the solvation parameter model. It has been observed that the coefficients of the correlation equations depend strongly on the particular set of compounds analyzed. Principal component analysis has been used to characterize the 2975 compounds with available solute descriptors and to select an appropriate subset of compounds to be analyzed by MEKC. With this set of compounds, the MEKC systems have been characterized. Principal component analysis has also been used to show the similarities and differences between the properties of the surfactants characterized by MEKC.

  6. A Novel Submicron Emulsion System Loaded with Doxorubicin Overcome Multi-Drug Resistance in MCF-7/ADR Cells

    PubMed Central

    Zhou, W. P.; Hua, H. Y.; Sun, P. C.; Zhao, Y. X.

    2015-01-01

    The purpose of the present study was to develop the Solutol HS15-based doxorubicin submicron emulsion with good stability and overcoming multi-drug resistance. In this study, we prepared doxorubicin submicron emulsion, and examined the stability after autoclaving, the in vitro cytotoxic activity, the intracellular accumulation and apoptpsis of doxorubicin submicron emulsion in MCF-7/ADR cells. The physicochemical properties of doxorubicin submicron emulsion were not significantly affected after autoclaving. The doxorubicin submicron emulsion significantly increased the intracellular accumulation of doxorubicin submicron emulsion and enhanced cytotoxic activity and apoptotic effects of doxorubicin. These results may be correlated to doxorubicin submicron emulsion inhibitory effects on efflux pumps through the progressive release of intracellular free Solutol HS15 from doxorubicin submicron emulsion. Furthermore, these in vitro results suggest that the Solutol HS15-based submicron emulsion may be a potentially useful drug delivery system to circumvent multi-drug resistance of tumor cells. PMID:26664069

  7. Doxorubicin and resveratrol co-delivery nanoparticle to overcome doxorubicin resistance

    PubMed Central

    Zhao, Yuan; Huan, Meng-lei; Liu, Miao; Cheng, Ying; Sun, Yang; Cui, Han; Liu, Dao-zhou; Mei, Qi-bing; Zhou, Si-yuan

    2016-01-01

    With the extensive application of doxorubicin (DOX), DOX resistance has become one of the main obstacles to the effective treatment of breast cancer. In this paper, DOX and resveratrol (RES) were co-encapsulated in a modified PLGA nanoparticle (NPS) to overcome the DOX resistance. CLSM results indicated that DOX and RES were simultaneously delivered into the nucleus of DOX-resistant human breast cancer cells by DOX/RES-loaded NPS. Consequently, DOX/RES-loaded NPS showed significant cytotoxicity on MDA-MB-231/ADR cells and MCF-7/ADR cells. Furthermore, DOX/RES-loaded NPS could overcome DOX resistance by inhibiting the expression of drug resistance-related protein such as P-gp, MRP-1 and BCRP, and induce apoptosis through down-regulating the expression of NF-κB and BCL-2. In tumor-bearing mice, DOX/RES-loaded NPS mainly delivered DOX and RES to tumor tissue. Compared with free DOX, DOX/RES-loaded NPS significantly inhibited the DOX-resistant tumor growth in tumor-bearing mice without causing significant systemic toxicity. In a word, DOX/RES-loaded NPS could overcome the DOX resistance and had the potential in the treatment of DOX-resistant breast cancer. PMID:27731405

  8. Effect of Doxorubicin/Pluronic SP1049C on Tumorigenicity, Aggressiveness, DNA Methylation and Stem Cell Markers in Murine Leukemia

    PubMed Central

    Li, Shu; Kabanov, Alexander V.

    2013-01-01

    Purpose Pluronic block copolymers are potent sensitizers of multidrug resistant cancers. SP1049C, a Pluronic-based micellar formulation of doxorubicin (Dox) has completed Phase II clinical trial and demonstrated safety and efficacy in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction. This study elucidates the ability of SP1049C to deplete cancer stem cells (CSC) and decrease tumorigenicity of cancer cells in vivo. Experimental Design P388 murine leukemia ascitic tumor was grown in BDF1 mice. The animals were treated with: (a) saline, (b) Pluronics alone, (c) Dox or (d) SP1049C. The ascitic cancer cells were isolated at different passages and examined for 1) in vitro colony formation potential, 2) in vivo tumorigenicity and aggressiveness, 3) development of drug resistance and Wnt signaling activation 4) global DNA methylation profiles, and 5) expression of CSC markers. Results SP1049C treatment reduced tumor aggressiveness, in vivo tumor formation frequency and in vitro clonogenic potential of the ascitic cells compared to drug, saline and polymer controls. SP1049C also prevented overexpression of BCRP and activation of Wnt-β-catenin signaling observed with Dox alone. Moreover, SP1049C significantly altered the DNA methylation profiles of the cells. Finally, SP1049C decreased CD133+ P388 cells populations, which displayed CSC-like properties and were more tumorigenic compared to CD133− cells. Conclusions SP1049C therapy effectively suppresses the tumorigenicity and aggressiveness of P388 cells in a mouse model. This may be due to enhanced activity of SP1049C against CSC and/or altered epigenetic regulation restricting appearance of malignant cancer cell phenotype. PMID:23977261

  9. Paclitaxel isomerisation in polymeric micelles based on hydrophobized hyaluronic acid.

    PubMed

    Smejkalová, Daniela; Nešporová, Kristina; Hermannová, Martina; Huerta-Angeles, Gloria; Cožíková, Dagmar; Vištejnová, Lucie; Safránková, Barbora; Novotný, Jaroslav; Kučerík, Jiří; Velebný, Vladimír

    2014-05-15

    Physical and chemical structure of paclitaxel (PTX) was studied after its incorporation into polymeric micelles made of hyaluronic acid (HA) (Mw=15 kDa) grafted with C6 or C18:1 acyl chains. PTX was physically incorporated into the micellar core by solvent evaporation technique. Maximum loading capacity for HAC6 and HAC18:1 was determined to be 2 and 14 wt.%, respectively. The loading efficiency was higher for HAC18:1 and reached 70%. Independently of the derivative, loaded HA micelles had spherical size of approximately 60-80 nm and demonstrated slow and sustained release of PTX in vitro. PTX largely changed its form from crystalline to amorphous after its incorporation into the micelle's interior. This transformation increased PTX sensitivity towards stressing conditions, mainly to UV light exposure, during which the structure of amorphous PTX isomerized and formed C3C11 bond within its structure. In vitro cytotoxicity assay revealed that polymeric micelles loaded with PTX isomer had higher cytotoxic effect to normal human dermal fibroblasts (NHDF) and human colon carcinoma cells (HCT-116) than the same micelles loaded with non-isomerized PTX. Further observation indicated that PTX isomer influenced in different ways cell morphology and markers of cell cycle. Taken together, PTX isomer loaded in nanocarrier systems may have improved anticancer activity in vivo than pure PTX.

  10. Photo-responsive polymeric micelles.

    PubMed

    Huang, Yu; Dong, Ruijiao; Zhu, Xinyuan; Yan, Deyue

    2014-09-07

    Photo-responsive polymeric micelles have received increasing attention in both academic and industrial fields due to their efficient photo-sensitive nature and unique nanostructure. In view of the photo-reaction mechanism, photo-responsive polymeric micelles can be divided into five major types: (1) photoisomerization polymeric micelles, (2) photo-induced rearrangement polymeric micelles, (3) photocleavage polymeric micelles, (4) photo-induced crosslinkable polymeric micelles, and (5) photo-induced energy conversion polymeric micelles. This review highlights the recent advances of photo-responsive polymeric micelles, including the design, synthesis and applications in various biomedical fields. Especially, the influence of different photo-reaction mechanisms on the morphology, structure and properties of the polymeric micelles is emphasized. Finally, the possible future directions and perspectives in this emerging area are briefly discussed.

  11. Antioxidant activities of celery and parsley juices in rats treated with doxorubicin.

    PubMed

    Kolarovic, Jovanka; Popovic, Mira; Zlinská, Janka; Trivic, Svetlana; Vojnovic, Matilda

    2010-09-03

    We have examined the influence of diluted pure celery and parsley leaf and root juices and their combinations with doxorubicin on the antioxidant status [as measured by the content of reduced glutathione (GSH) and ferric reducing antioxidant power (FRAP)] in liver homogenate and hemolysate and on the contents of cytochrome P450 in liver homogenate. It was found that doxorubicin significantly decreased the content of reduced glutathione and the total antioxidative status (FRAP) in liver homogenate and hemolysate, while celery and parsley juices alone and in combination with doxorubicin had different actions. Doxorubicin and celery juice had no effect on content of cytochrome P450. However, in combination with doxorubicin, parsley root juice significant increased, and parsley leaves juice decreased the cytochrome P450 content (compared to doxorubicin treated animals). Only parsley root juice significantly increased the content of cytochrome P450.

  12. Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes

    PubMed Central

    Zhao, Liqun; Zhang, Baolin

    2017-01-01

    Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. The mechanisms of doxorubicin-induced cardiotoxicity remain incompletely understood. Here we investigated doxorubicin-induced cytotoxicity in human induced pluripotent stem cells-derived cardiomyocytes (iPS-CMs). We found that doxorubicin and related anthracycline agents (e.g., daunorubicin, idarubicin, and epirubicin) significantly upregulated the expression of death receptors (DRs) (TNFR1, Fas, DR4 and DR5) in iPS-derived cardiomyocytes at both protein and mRNA levels. The resulting iPS-CMs cells underwent spontaneous apoptosis which was further enhanced by physiologically relevant death ligands including TNF-related apoptosis inducing ligand (TRAIL). Furthermore, TRAIL potentiated doxorubicin-induced decrease in beating rate and amplitude of iPS-derived cardiomyocytes. These data demonstrate that the induction of death receptors in cardiomyocytes is likely a critical mechanism by which doxorubicin causes cardiotoxicity. PMID:28300219

  13. Apoferritin Modified Magnetic Particles as Doxorubicin Carriers for Anticancer Drug Delivery

    PubMed Central

    Blazkova, Iva; Nguyen, Hoai Viet; Dostalova, Simona; Kopel, Pavel; Stanisavljevic, Maja; Vaculovicova, Marketa; Stiborova, Marie; Eckschlager, Tomas; Kizek, Rene; Adam, Vojtech

    2013-01-01

    Magnetic particle mediated transport in combination with nanomaterial based drug carrier has a great potential for targeted cancer therapy. In this study, doxorubicin encapsulation into the apoferritin and its conjugation with magnetic particles was investigated by capillary electrophoresis with laser-induced fluorescence detection (CE-LIF). The quantification of encapsulated doxorubicin was performed by fluorescence spectroscopy and compared to CE-LIF. Moreover, the significant enhancement of the doxorubicin signal was observed by addition of methanol into the sample solution. PMID:23807501

  14. Calcium flux and metabolism in the pigeon heart following doxorubicin treatment: an acute study

    SciTech Connect

    Revis, N.

    1981-01-01

    The present studies were performed to determine in vivo the initial and secondary acute effects of doxorubicin on the influx of calcium into myocardial cells. Studies are also described showing the effect of doxorubicin on a calcium-activated neutral protease from cardiac tissue. These latter studies were performed in an attempt to explain the loss of myofibrilular structures in myocardial cells following doxorubicin treatment.

  15. Acetal-linked polymeric prodrug micelles for enhanced curcumin delivery.

    PubMed

    Li, Man; Gao, Min; Fu, Yunlan; Chen, Chao; Meng, Xuan; Fan, Aiping; Kong, Deling; Wang, Zheng; Zhao, Yanjun

    2016-04-01

    On-demand curcumin delivery via stimuli-responsive micellar nanocarriers holds promise for addressing its solubility and stability problem. Polymer-curcumin prodrug conjugate micelle is one of such nanosystems. The diversity of linker and conjugation chemistry enabled the generation and optimization of different curcumin micelles with tunable stimuli-responsiveness and delivery efficiency. The aim of the current work was to generate and assess acetal-linked polymeric micelles to enrich the pH-responsive curcumin delivery platforms. Curcumin was slightly modified prior to conjugating to amphiphilic methoxy poly(ethylene glycol)-poly(lactic acid) (mPEG-PLA) copolymer via an acetal bond, whereas an ester bond-linked conjugate was used as the control. The acetal-containing micelles showed a hydrodynamic diameter of 91.1 ± 2.9(nm) and the accompanying core size of 63.5 ± 7.1 (nm) with a zeta potential of -10.9 ± 0.7(mV). Both control and pH-labile micelles displayed similar critical micelle concentration at 1.6 μM. The acetal-containing nanocarriers exhibited a pH-dependent drug release behavior, which was faster at lower pH values. The cytotoxicity study in HepG2 cells revealed a significantly lower IC50 at 51.7 ± 9.0(μM) for acetal-linked micelles in contrast to the control at 103.0 ± 17.8(μM), but the polymer residue showed no cytotoxicity upon drug release. The acetal-linked micellar nanocarrier could be a useful addition to the spectrum of currently available stimuli-responsive curcumin nano-formulations.

  16. Serial exercise gated radionuclide ventriculograms (RVG) in monitoring doxorubicin cardiotoxicity

    SciTech Connect

    Goldstein, H.A.; Lahoda, J.; Fox, L.

    1985-05-01

    The resting RVG (Radionuclide Ventriculograms) are demonstrated to be an effective monitor of the cardiotoxicity of doxorubicin. The exercise RVG has not been as well studied to see if it yields additional information or detects toxicity effects earlier. Sixteen patients receiving doxorubicin for chemotherapy had 2-6 serial exercise studies with intervals between studies of 1 month to 15 months. The patients exercised varying amounts with cardiac work indicated by their double products (HR x Sys. BP). Although all patients started with a normal resting LVEF (>50%), 5 of the 16 did not have a normal response (greater than or equal to5% increase in LVEF) with initial exercise study. Of the 11 patients with an initially normal response to exercise, on at least one subsequent study, 3 had an abnormal response to exercise. On a later follow up study 1 of these 3 patients again had a normal response to exercise. Six of these 11 patients had had RVG evidence of cardiotoxicity. Four of these 6 patients had continually normal exercise responses, while 2 of these 5 patients had had an abnormal exercise response. An initial exercise RVG may be reasonable to detect unsuspected CAD in cancer victims. These patients are reported to be more sensitive to the toxic effects of doxorubicin. Follow up exercise RVGs do not contribute useful information, do not predict cardiotoxicity, and may be misleading.

  17. Protective effect of Co-enzyme Q10 On doxorubicin-induced cardiomyopathy of rat hearts.

    PubMed

    Chen, Pei-Yu; Hou, Chien-Wen; Shibu, Marthandam Asokan; Day, Cecilia Hsuan; Pai, Peiying; Liu, Zhao-Rong; Lin, Tze-Yi; Viswanadha, Vijaya Padma; Kuo, Chia-Hua; Huang, Chih-Yang

    2017-02-01

    Q10 is a powerful antioxidant often used in medical nutritional supplements for cancer treatment. This study determined whether Q10 could effectively prevent cardio-toxicity caused by doxorubicin treatment. Four week old SD rats were segregated into groups namely control, doxorubicin group (challenged with doxorubicin), Dox + Q10 group (with doxorubicin challenge and oral Q10 treatment), and Q10 group (with oral Q10 treatment). Doxorubicin groups received IP doxorubicin (2.5 mg/kg) every 3 days and Q10 groups received Q10 (10 mg/kg) every day. Three weeks of doxorubicin challenge caused significant reduction in heart weight, disarray in cardiomyocyte arrangement, elevation of collagen accumulation, enhancement of fibrosis and cell death associated proteins, and inhibition of survival proteins. However, Q10 effectively protected cardiomyocytes and ameliorated fibrosis and cell death induced by doxorubicin. Q10 is, therefore, evidently a potential drug to prevent heart damage caused by doxorubicin. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 679-689, 2017.

  18. The antitumor agent doxorubicin binds to Fanconi anemia group F protein.

    PubMed

    Kusayanagi, Tomoe; Tsukuda, Senko; Shimura, Satomi; Manita, Daisuke; Iwakiri, Kanako; Kamisuki, Shinji; Takakusagi, Yoichi; Takeuchi, Toshifumi; Kuramochi, Kouji; Nakazaki, Atsuo; Sakaguchi, Kengo; Kobayashi, Susumu; Sugawara, Fumio

    2012-11-01

    Doxorubicin, a commonly used cancer chemotherapy agent, elicits several potent biological effects, including synergistic-antitumor activity in combination with cisplatin. However, the mechanism of this synergism remains obscure. Here, we employed an improved T7 phage display screening method to identify Fanconi anemia group F protein (FANCF) as a doxorubicin-binding protein. The FANCF-doxorubicin interaction was confirmed by pull-down assay and SPR analysis. FANCF is a component of the Fanconi anemia complex, which monoubiquitinates D2 protein of Fanconi anemia group as a cellular response against DNA cross-linkers such as cisplatin. We observed that the monoubiquitination was inhibited by doxorubicin treatment.

  19. Human colon cancer HT-29 cell death responses to doxorubicin and Morus Alba leaves flavonoid extract.

    PubMed

    Fallah, S; Karimi, A; Panahi, G; Gerayesh Nejad, S; Fadaei, R; Seifi, M

    2016-03-31

    The mechanistic basis for the biological properties of Morus alba flavonoid extract (MFE) and chemotherapy drug of doxorubicin on human colon cancer HT-29 cell line death are unknown. The effect of doxorubicin and flavonoid extract on colon cancer HT-29 cell line death and identification of APC gene expression and PARP concentration of HT-29 cell line were investigated. The results showed that flavonoid extract and doxorubicin induce a dose dependent cell death in HT-29 cell line. MFE and doxorubicin exert a cytotoxic effect on human colon cancer HT-29 cell line by probably promoting or induction of apoptosis.

  20. Astragalus polysaccharide restores autophagic flux and improves cardiomyocyte function in doxorubicin-induced cardiotoxicity

    PubMed Central

    Cao, Yuan; Shen, Tao; Huang, Xiuqing; Lin, Yajun; Chen, Beidong; Pang, Jing; Li, Guoping; Wang, Que; Zohrabian, Sylvia; Duan, Chao; Ruan, Yang; Man, Yong; Wang, Shu; Li, Jian

    2017-01-01

    Doxorubicin (adriamycin), an anthracycline antibiotic, is commonly used to treat many types of solid and hematological malignancies. Unfortunately, clinical usage of doxorubicin is limited due to the associated acute and chronic cardiotoxicity. Previous studies demonstrated that Astragalus polysaccharide (APS), the extracts of Astragalus membranaceus, had strong anti-tumor activities and anti-inflammatory effects. However, whether APS could mitigate chemotherapy-induced cardiotoxicity is unclear thus far. We used a doxorubicin-induced neonatal rat cardiomyocyte injury model and a mouse heart failure model to explore the function of APS. GFP-LC3 adenovirus-mediated autophagic vesicle assays, GFP and RFP tandemly tagged LC3 (tfLC3) assays and Western blot analyses were performed to analyze the cell function and cell signaling changes following APS treatment in cardiomyocytes. First, doxorubicin treatment led to C57BL/6J mouse heart failure and increased cardiomyocyte apoptosis, with a disturbed cell autophagic flux. Second, APS restored autophagy in doxorubicin-treated primary neonatal rat ventricular myocytes and in the doxorubicin-induced heart failure mouse model. Third, APS attenuated doxorubicin-induced heart injury by regulating the AMPK/mTOR pathway. The mTOR inhibitor rapamycin significantly abrogated the protective effect of APS. These results suggest that doxorubicin could induce heart failure by disturbing cardiomyocyte autophagic flux, which may cause excessive cell apoptosis. APS could restore normal autophagic flux, ameliorating doxorubicin-induced cardiotoxicity by regulating the AMPK/mTOR pathway. PMID:27902477

  1. Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase

    PubMed Central

    Liu, Yan; Asnani, Aarti; Zou, Lin; Bentley, Victoria L.; Yu, Min; Wang, You; Dellaire, Graham; Sarkar, Kumar S.; Dai, Matthew; Chen, Howard H.; Sosnovik, David E.; Shin, Jordan T.; Haber, Daniel A.; Berman, Jason N.; Chao, Wei; Peterson, Randall T.

    2015-01-01

    Doxorubicin is a highly effective anti-cancer chemotherapy agent, but its usage is limited by its cardiotoxicity. To develop a drug that prevents the cardiac toxicity of doxorubicin while preserving its anti-tumor potency, we established a doxorubicin-induced cardiomyopathy model in zebrafish that recapitulated the cardiomyocyte apoptosis and contractility decline observed in patients. Using this model, we screened 3000 compounds and discovered that visnagin (VIS) and diphenylurea (DPU) rescue cardiac performance and circulatory defects caused by doxorubicin treatment in zebrafish. VIS and DPU reduced doxorubicin-induced apoptosis in cultured cardiomyocytes and in vivo in zebrafish and mouse hearts. Furthermore, VIS treatment improved cardiac contractility in doxorubicin-treated mice. Importantly, VIS and DPU caused no reduction in the chemotherapeutic efficacy of doxorubicin in several cultured tumor lines or in zebrafish and mouse xenograft models. Using affinity chromatography, we discovered that VIS binds to mitochondrial malate dehydrogenase (MDH2), one of the key enzymes in the tricarboxylic acid cycle. As with VIS, treatment with the MDH2 inhibitors mebendazole, thyroxine, and iodine prevented doxorubicin cardiotoxicity, as did treatment with malate itself, suggesting that modulation of MDH2 activity is responsible for VIS’s cardioprotective effects. Taken together, this study identified VIS and DPU as potent cardioprotective compounds and implicates MDH2 as a previously undescribed, druggable target for doxorubicin-induced cardiomyopathy. PMID:25504881

  2. TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin

    PubMed Central

    Moruno Manchon, Jose Felix; Uzor, Ndidi-Ese; Kesler, Shelli R.; Wefel, Jeffrey S.; Townley, Debra M.; Nagaraja, Archana Sidalaghatta; Pradeep, Sunila; Mangala, Lingegowda S.; Sood, Anil K.; Tsvetkov, Andrey S.

    2016-01-01

    Doxorubicin, a commonly used chemotherapy agent, induces severe cardio- and neurotoxicity. Molecular mechanisms of cardiotoxicity have been extensively studied, but mechanisms by which doxorubicin exhibits its neurotoxic properties remain unclear. Here, we show that doxorubicin impairs neuronal autophagy, leading to the accumulation of an autophagy substrate p62. Neurons treated with doxorubicin contained autophagosomes, damaged mitochondria, and lipid droplets. The brains from mice treated with pegylated liposomal doxorubicin exhibited autophagosomes, often with mitochondria, lipofuscin, and lipid droplets. Interestingly, lysosomes were less acidic in doxorubicin-treated neurons. Overexpression of the transcription factor EB (TFEB), which controls the autophagy-lysosome axis, increased survival of doxorubicin-treated neurons. 2-Hydroxypropyl-β-cyclodextrin (HPβCD), an activator of TFEB, also promoted neuronal survival, decreased the levels of p62, and lowered the pH in lysosomes. Taken together, substantial changes induced by doxorubicin contribute to neurotoxicity, cognitive disturbances in cancer patients and survivors, and accelerated brain aging. The TFEB pathway might be a new approach for mitigating damage of neuronal autophagy caused by doxorubicin. PMID:27992857

  3. Doxorubicin-loaded nanosized micelles of a star-shaped poly(ε-caprolactone)-polyphosphoester block co-polymer for treatment of human breast cancer.

    PubMed

    Cuong, Nguyen-Van; Hsieh, Ming-Fa; Chen, Yung-Tsung; Liau, Ian

    2011-01-01

    Star-shaped co-polymers based on the backbone of poly(ε-caprolactone) were synthesized by a ring-opening reaction using pentaerythritol as initiator and Sn(Oct)(2) as catalyst. The star-shaped poly(ε-caprolactone) polymer was then chain extended with a terminal block of poly(ethyl ethylene phosphate) to form a copolymer, poly(ε-caprolactone)-poly(ethyl ethylene phosphate), when using the cyclic ethyl ethylene phosphate monomer. The amphiphilic block co-polymers can self-assemble into nanoscopic micelles with a mean diameter of 150 nm and a spherical shape. Additionally, the prepared micelles did not induce hemolysis and nitric oxide production in vitro based on nitric oxide, hemolytic tests and MTT assays. The hydrophobic micellar cores encapsulated doxorubicin (DOX) in an aqueous solution with a loading efficiency of 55.2%. The in vitro release of DOX from DOX-loaded micelles was pH dependent. DOX-loaded micelles present significantly enhanced cytotoxicity to both MCF-7/drug-sensitive and MCF-7/drug-resistant cells after second incubation. Moreover, results of confocal microscopy and flow cytometry of DOX-loaded micelles demonstrate the feasibility of this delivery system for effective therapy of drug-resistant tumours.

  4. Salinomycin enhances doxorubicin-induced cytotoxicity in multidrug resistant MCF-7/MDR human breast cancer cells via decreased efflux of doxorubicin.

    PubMed

    Kim, Kwang-Youn; Kim, Sang-Hun; Yu, Sun-Nyoung; Park, Suel-Ki; Choi, Hyeun-Deok; Yu, Hak-Sun; Ji, Jae-Hoon; Seo, Young-Kyo; Ahn, Soon-Cheol

    2015-08-01

    Salinomycin is a monocarboxylic polyether antibiotic, which is widely used as an anticoccidial agent. The anticancer property of salinomycin has been recognized and is based on its ability to induce apoptosis in human multidrug resistance (MDR). The present study investigated whether salinomycin reverses MDR towards chemotherapeutic agents in doxorubicin-resistant MCF-7/MDR human breast cancer cells. The results demonstrated that doxorubicin-mediated cytotoxicity was significantly enhanced by salinomycin in the MCF-7/MDR cells, and this occurred in a dose-dependent manner. This finding was consistent with subsequent observations made under a confocal microscope, in which the doxorubicin fluorescence signals of the salinomycin-treated cells were higher compared with the cells treated with doxorubicin alone. In addition, flow cytometric analysis revealed that salinomycin significantly increased the net cellular uptake and decreased the efflux of doxorubicin. The expression levels of MDR-1 and MRP-1 were not altered at either the mRNA or protein levels in the cells treated with salinomycin. These results indicated that salinomycin was mediated by its ability to increase the uptake and decrease the efflux of doxorubicin in MCF-7/MDR cells. Salinomycin reversed the resistance of doxorubicin, suggesting that chemotherapy in combination with salinomycin may benefit MDR cancer therapy.

  5. Influence of pH on retention and selectivity in micellar liquid chromatography: consequences of micellar-induced shifts of ionization constants.

    PubMed

    Rodgers, A H; Khaledi, M G

    1994-02-01

    The retention and selectivity of ionizable solutes in the two-surfactant-mediated reversed-phase LC techniques (micellar and ion pair) are compared through the use of a general retention equation for mono- and zwitterionic solutes. In RPLC with different mobile-phase modifiers (organic solvents, surfactants), the influence of pH can be quantitatively described by one general equation. The existing theory for the secondary chemical equilibria has been applied to compare selectivity effects in micellar and ion-pair chromatography. In order to predict the influence of different mobile-phase compositions on the selectivity of ionizable compounds, one should determine how a mobile-phase parameter influences the ionization equilibria (i.e., selective shifts of pKa) and self-selectivity (defined as the ratio of retention factors of the acid/conjugate base). For example, the first ionization constants of amino acids and peptides in aqueous mobile phase are between pH 2.3 and 3.4. Consequently, the pH required to maximize the retention of these solutes by ion suppression is less than the operational pH range of silica-based columns. In addition, since the pKa1 values of these solutes are similar, adjustment of pH has little effect on separation selectivity. In contrast, ion-pairing and micellar mobile phases with SDS surfactant increase the magnitude and range of the ionization constants. These trends are more pronounced with micellar mobile phase. The displacement of solute ionization constants to higher PH with micellar mobile phase allows the maximal, limiting, retention of zwitterionic solutes to be observed within the pH limits of silica-based columns.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Chemometric Deconvolution of Continuous Electrokinetic Injection Micellar Electrokinetic Chromatography Data for the Quantitation of Trinitrotoluene in Mixtures of Other Nitroaromatic Compounds

    DTIC Science & Technology

    2014-02-24

    ABSTRACT Chemometric Deconvolution of Continuous Electrokinetic Injection Micellar Electrokinetic Chromatography Data for the Quantitation of...Unclassified Unlimited Unclassified Unlimited 13 Braden C. Giordano (202) 404-6320 Micellar electrokinetic chromatography Nitroaromatic explosives...Capillary electrophoresis DNT – Dinitrotoluene EOF – Electroosmotic flow MEKC – Micellar electrokinetic chromatography PLS – Partial least squares regression TNT – Trinitrotoluene 11

  7. Lenghty reverse poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) polymeric micelles and gels for sustained release of antifungal drugs.

    PubMed

    Figueroa-Ochoa, Edgar B; Villar-Alvarez, Eva M; Cambón, Adriana; Mistry, Dharmista; Llovo, José; Attwood, David; Barbosa, Silvia; Soltero, J F Armando; Taboada, Pablo

    2016-08-20

    In this work, we present a detailed study of the potential application of polymeric micelles and gels of four different reverse triblock poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) copolymers (BOnEOmBOn, where n denotes the respective block lengths), specifically BO8EO90BO8, BO14EO378BO14, BO20EO411BO20 and BO21EO385BO21, as effective drug transport nanocarriers. In particular, we tested the use of this kind of polymeric nanostructures as reservoirs for the sustained delivery of the antifungals griseofulvin and fluconazole for oral and topical administration. Polymeric micelles and gels formed by these copolymers were shown to solubilize important amounts of these two drugs and to have a good stability in physiologically relevant conditions for oral or topical administration. These polymeric micellar nanocarriers were able to release drugs in a sustained manner, being the release rate slower as the copolymer chain hydrophobicity increased. Different sustained drug release profiles were observed depending on the medium conditions. Gel nanocarriers were shown to display longer sustained release rates than micellar formulations, with the existence of a pulsatile-like release mode under certain solution conditions as a result of their inner network structure. Certain bioadhesive properties were observed for the polymeric physical gels, being moderately tuned by the length and hydrophobicity of the polymeric chains. Furthermore, polymeric gels and micelles showed activity against the yeast Candida albicans and the mould demartophytes (Trichophyton rubrum and Microsporum canis) and, thus, may be useful for the treatment of different cutaneous fungal infections.

  8. Polymerized and functionalized triglycerides

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plant oils are useful sustainable raw materials for the development of new chemical products. As part of our research emphasis in sustainability and green polymer chemistry, we have explored a new method for polymerizing epoxidized triglycerides with the use of fluorosulfonic acid. Depending on the ...

  9. Flame retardant polymeric materials

    SciTech Connect

    Lewin, M.; Atlas, S.M.; Pearce, E.M.

    1982-01-01

    The flame retardation of polyolefins is the focus of this volume. Methods for reduction of smoke and experimental evaluation of flammability parameters for polymeric materials are discussed. The flammability evaluation methods for textiles and the use of mass spectrometry for analysis of polymers and their degradation products are also presented.

  10. Variable Effect during Polymerization

    ERIC Educational Resources Information Center

    Lunsford, S. K.

    2005-01-01

    An experiment performing the polymerization of 3-methylthiophene(P-3MT) onto the conditions for the selective electrode to determine the catechol by using cyclic voltammetry was performed. The P-3MT formed under optimized conditions improved electrochemical reversibility, selectivity and reproducibility for the detection of the catechol.

  11. Protein specific polymeric immunomicrospheres

    NASA Technical Reports Server (NTRS)

    Rembaum, Alan (Inventor); Yen, Shiao-Ping S. (Inventor); Dreyer, William J. (Inventor)

    1980-01-01

    Small, round, bio-compatible microspheres capable of covalently bonding proteins and having a uniform diameter below about 3500 A are prepared by substantially instantaneously initiating polymerization of an aqueous emulsion containing no more than 35% total monomer including an acrylic monomer substituted with a covalently bondable group such as hydroxyl, amino or carboxyl and a minor amount of a cross-linking agent.

  12. A thermodynamic micellization model for asphaltene precipitation: Part 1: Micellar size and growth

    SciTech Connect

    Pan, H.; Firoozabadi, A.

    1996-12-31

    Asphaltene precipitation is a serious problem in the production of some petroleum reservoirs. A thermodynamic predictive model is a challenge and currently does not exist. Published models do not yet represent a realistic picture of asphaltenes in the crude. A large number of recent experimental studies have shown that asphaltenes aggregate in the crude to form micelles. The size of the micelle changes due to changes in composition and temperature. In this study, we present a simple thermodynamic micellization model to describe asphaltene aggregation in crude mixtures. The asphaltene molecules are assumed to form the micellar core and the resin molecules adsorb onto the core surface to stabilize the micelle. The asphaltene and resin molecules in a micelle are in equilibrium with the asphaltene and resin monomers in the bulk crude. The principle of the minimization of Gibbs free energy is used to determine the micellar structure and concentration. The predicted micellar size and growth when the crude is diluted with normal alkanes are in line with experimental observations. The predicted effects of temperature and pressure on the micellar size are also in agreement with data. The expression for the micellar concentration in our simple approach is the same as the published expression based on the multiple chemical equilibrium principle.

  13. Effect of mixed micellar lipid on the absorption of cholesterol and vitamin D3 into lymph

    PubMed Central

    Thompson, Gilbert R.; Ockner, Robert K.; Isselbacher, Kurt J.

    1969-01-01

    The absorption of endogenous cholesterol, labeled with tracer doses of cholesterol 14C or cholesterol-3H and of near physiological doses of vitamin D3-3H was studied in rats with cannulated intestinal lymphatics. The effects of administering mixed micellar solutions of fatty acid, monoglyceride, and bile salt on the absorption of these labeled sterols was determined. It was observed that the specific activity of free cholesterol and the amounts of vitamin D3 appearing in lymph were significantly increased during the intraduodenal administration of mixed micellar solutions of either linoleic or palmitic acid, in contrast to control rats receiving a micellar solution of taurocholate. These increases were related linearly to the lymph triglyceride level. In addition it was observed that when the linoleic acid solution was administered there was a more marked increase in the ratio of the specific activities of free and esterified cholesterol in lymph than with either the palmitic acid or taurocholate solutions. Additional studies in rats with intact lymphatics showed that the uptake of labeled cholesterol and vitamin D3 from the intestinal lumen into the wall was similar whether the sterols were administered in taurocholate or in mixed micellar solution. These findings suggest that mixed micellar lipid increased the rate of appearance of labeled free cholesterol and vitamin D3 in lymph by enhancing their transport out of the intestinal mucosa, rather than by an effect on uptake. PMID:4303790

  14. Selection of reservoirs amenable to micellar flooding. First annual report, October 1978-December 1979

    SciTech Connect

    Goldburg, A.; Price, H.

    1980-12-01

    The overall project objective is to build a solid engineering base upon which the Department of Energy (DOE) can improve and accelerate the application of micellar-polymer recovery technology to Mid-Continent and California sandstone reservoirs. The purpose of the work carried out under these two contracts is to significantly aid, both DOE and the private sector, in gaining the following Project Objectives: to select the better micellar-polymer prospects in the Mid-Continent and California regions; to assess all of the available field and laboratory data which has a bearing on recovering oil by micellar-polymer projects in order to help identify and resolve both the technical and economic constraints relating thereto; and to design and analyze improved field pilots and tests and to develop a micellar-polymer applications matrix for use by the potential technology users; i.e., owner/operators. The report includes the following: executive summary and project objectives; development of a predictive model for economic evaluation of reservoirs; reservoir data bank for micellar-polymer recovery evaluation; PECON program for preliminary economic evaluation; ordering of candidate reservoirs for additional data acquisition; validation of predictive model by numerical simulation; and work forecast. Tables, figures and references are included.

  15. Quantification of Lipophilicity of 1,2,4-Triazoles Using Micellar Chromatography.

    PubMed

    Janicka, Małgorzata; Stępnik, Katarzyna; Pachuta-Stec, Anna

    2012-05-01

    High-performance liquid chromatography (HPLC), over-pressured-layer chromatography (OPLC) and thin-layer chromatography (TLC) techniques with micellar mobile phases were proposed to evaluate the lipophilicity of 21 newly synthesized 1,2,4-triazoles, compounds of potential importance in medicine or agriculture as fungicides. Micellar parameters log k(m) were compared with extrapolated R(M0) values determined from reversed-phase (RP) TLC experimental data obtained on RP-8 stationary phases as well as with log P values (Alog Ps, AClog P, Alog P, Mlog P, KowWin, xlog P2 and xlog P3) calculated from molecular structures of solutes tested. The results obtained by applying principal component analysis (PCA) and linear regression showed considerable similarity between partition and retention parameters as alternative lipophilicity descriptors, and indicated micellar chromatography as a suitable technique to study lipophilic properties of organic substances. In micellar HPLC, RP-8e column (Purospher) was applied, whereas in OPLC and TLC, RP-CN plates were applied, which was the novelty of this study and allowed the use of micellar effluents in planar chromatography measurements.

  16. Microchip separations of neutral species via micellar electrokinetic capillary chromatography

    SciTech Connect

    Moore, A.W. Jr.; Jacobson, S.C.; Ramsey, J.M.

    1995-11-15

    Micellar electrokinetic capillary chromatography (MECC) of three neutral coumarin dyes was performed on glass microchips. Manifolds of channels for analyte injection and separation were machined into one surface of the glass substrates using standard photolithographic, etching, and deposition techniques. Cover plates were then directly bonded over these channels to form capillary networks, with fluid flow in these networks controlled by varying the applied high-voltage potentials at the outlets. The separation capillary was 16.5 cm long for a serpentine channel chip and 1.3 cm long for a straight channel chip. Detection of analyte zones was accomplished by laser-induced fluorescence using the UV lines (nearly 350 nm) of an argon ion laser. At low applied electric field strengths, MECC analyses with on-chip injections gave high reproducibilities in peak areas and migration times (<1% for two of the three coumarins) and near constant separation efficiencies throughout the analysis. At high fields (>400 V/cm), analysis times were shorter, but separation efficiency decreased at later migration times. These peaks showed significant broadening, consistent with mass transfer effects. 14 refs., 6 figs., 2 tabs.

  17. Model for phase equilibria in micellar solutions of nonionic surfactants

    NASA Astrophysics Data System (ADS)

    Goldstein, Raymond E.

    1986-03-01

    The formation of spherical micelles in aqueous solutions of nonionic surfactants and the equilibria between two such micellar phases are studied with a phenomenological model incorporating hydrophobic interactions and the configurational entropy of the amphiphiles. The distribution of micelle sizes is determined over the entire temperature-composition phase diagram, and moments of that distribution function determine the consolute point parameters. In a generalization of an analysis given by Stillinger and Ben-Naim, the mathematical properties of various thermodynamic functions in the neighborhood of the critical micelle concentration are related to the location of branch points of the osmotic pressure in the complex concentration plane. The model attributes the experimentally observed lower critical solution points in these systems to surfactant-water hydrogen bonding, whose temperature dependence is described with a mean field approximation. Calculated phase diagrams are in qualitative agreement with those from experiments, in particular, exhibiting closed solubility loops with quite distinct upper and lower critical compositions, and values for the lower critical composition on the order of several percent volume fraction. The relevance of certain aspects of the model to the understanding of microemulsions is discussed.

  18. Micellar electrokinetic chromatographic determination of triazine herbicides in water samples.

    PubMed

    Li, Zhi; Zhang, Shuaihua; Yin, Xiaofang; Wang, Chun; Wang, Zhi

    2014-09-01

    Dispersive liquid-liquid microextraction combined with online sweeping preconcentration in micellar electrokinetic chromatography was developed for the simultaneous determination of five triazine herbicides (atrazine, simazine, propazine, prometon and simetryn) in water samples. Several experimental parameters affecting the extraction efficiencies such as the type and volume of both the extraction and dispersive solvents, the addition of salt to sample solution, the extraction time and the pH of the sample solution were investigated. Under optimum conditions, the linearity of the method was good in the range from 0.33 to 20 ng mL(-1) for simazine, propazine, atrazine and simetryn, and from 0.17 to 20 ng mL(-1) for prometon, respectively. The sensitivity enrichment factors were in the range from 1750 to 2100, depending on the compound. The limit of detection (S/N = 3) ranged from 0.05 to 0.10 ng mL(-1). The developed method was successfully applied to the analysis of the five triazines in river, ground and well waters.

  19. Molecular thermodynamics for micellar branching in solutions of ionic surfactants.

    PubMed

    Andreev, Vasily A; Victorov, Alexey I

    2006-09-26

    We develop an analytical molecular-thermodynamic model for the aggregation free energy of branching portions of wormlike ionic micelles in 1:1 salt solution. The junction of three cylindrical aggregates is represented by a combination of pieces of the torus and bilayer. A geometry-dependent analytical solution is obtained for the linearized Poisson-Boltzmann equation. This analytical solution is applicable to saddle-like structures and reduces to the solutions known previously for planar, cylindrical, and spherical aggregates. For micellar junctions, our new analytical solution is in excellent agreement with numerical results over the range of parameters typical of ionic surfactant systems with branching micelles. Our model correctly predicts the sequence of stable aggregate morphologies, including a narrow bicontinuous zone, in dependence of hydrocarbon tail length, head size, and solution salinity. For predicting properties of a spatial network of wormlike micelles, our aggregation free energy is used in the Zilman-Safran theory. Our predictions are compared with experimental data for branching micelles of ionic surfactants.

  20. Qualitative analysis of mycotoxins using micellar electrokinetic capillary chromatography

    SciTech Connect

    Holland, R.D.; Sepaniak, M.J. )

    1993-05-01

    Naturally occurring mycotoxins are separated using micellar electrokinetic capillary chromatography. Trends in the retention of these toxins, resulting from changes in mobile-phase composition and pH, are reported and presented as a means of alleviating coelution problems. Two sets of mobile-phase conditions are determined that provide unique separation selectivity. The facile manner by which mobile-phase conditions can be altered, without changes in instrumental configuration, allowed the acquisition of two distinctive, fully resolved chromatograms of 10 mycotoxins in a period of approximately 45 min. By adjusting retention times, using indigenous or added components in mycotoxin samples as normalization standards, it is possible to obtain coefficients of variation in retention time that average less than 1%. The qualitative capabilities of this methodology are evaluated by separating randomly generated mycotoxin-interferent mixtures. In this study, the utilization of normalized retention times applied to separations obtained with two sets of mobile-phase conditions permitted the identification of all the mycotoxins in five unknown samples without any misidentifications. 24 refs., 3 figs., 2 tabs.

  1. Micellar electrokinetic chromatography of organic and peroxide-based explosives.

    PubMed

    Johns, Cameron; Hutchinson, Joseph P; Guijt, Rosanne M; Hilder, Emily F; Haddad, Paul R; Macka, Mirek; Nesterenko, Pavel N; Gaudry, Adam J; Dicinoski, Greg W; Breadmore, Michael C

    2015-05-30

    CE methods have been developed for the analysis of organic and peroxide-based explosives. These methods have been developed for deployment on portable, in-field instrumentation for rapid screening. Both classes of compounds are neutral and were separated using micellar electrokinetic chromatography (MEKC). The effects of sample composition, separation temperature, and background electrolyte composition were investigated. The optimised separation conditions (25 mM sodium tetraborate, 75 mM sodium dodecyl sulfate at 25°C, detection at 200 nm) were applied to the separation of 25 organic explosives in 17 min, with very high efficiency (typically greater than 300,000 plates m(-1)) and high sensitivity (LOD typically less than 0.5 mg L(-1); around 1-1.5 μM). A MEKC method was also developed for peroxide-based explosives (10 mM sodium tetraborate, 100 mM sodium dodecyl sulfate at 25°C, detection at 200 nm). UV detection provided LODs between 5.5 and 45.0 mg L(-1) (or 31.2-304 μM), which is comparable to results achieved using liquid chromatography. Importantly, no sample pre-treatment or post-column reaction was necessary and the peroxide-based explosives were not decomposed to hydrogen peroxide. Both MEKC methods have been applied to pre-blast analysis and for the detection of post-blast residues recovered from controlled, small scale detonations of organic and peroxide-based explosive devices.

  2. Glass and percolation transitions in dense attractive micellar system

    NASA Astrophysics Data System (ADS)

    Mallamace, F.; Beneduci, R.; Gambadauro, P.; Lombardo, D.; Chen, S. H.

    2001-12-01

    In this work, we study a copolymer-micellar system characterized by clustering processes due to a short-range attractive interaction. This originates a percolation process and a new type of kinetic glass transition. We have studied these intriguing dynamical situations by means of an extensive set of light scattering and viscoelasticity experiments. Obtained data, in both the phenomena, are accounted for by considering in a proper way fractal clustering processes and the related scaling concepts. Near the percolation line the main role in the system structure and dynamics is played by the cluster's partial screening of hydrodynamic interaction, that behaves, on approaching the percolation threshold, dramatic effects on the rheological properties and on the density decay relaxations. The ergodic-nonergodic transition line (glass transition) is studied in terms of the intermediate scattering functions (ISF) in the frame of the mode coupling theory. The measured ISF gives evidence of a logarithmic decay on the density fluctuation followed by a power law behavior. This latter phenomenon is the signature of a high-order glass transition of the A3 type (cusp-like singularity).

  3. Simultaneous micellar LC determination of lidocaine and tolperisone.

    PubMed

    Youngvises, Napaporn; Liawruangrath, Boonsom; Liawruangrath, Saisunee

    2003-03-26

    A micellar liquid chromatography (MLC) procedure was developed for the simultaneous separation and determination of lidocaine hydrochloride (LD HCl) and tolperisone hydrochloride (TP HCl) using a short-column C18 (12.5 mm x 4.6 mm, 5 microm), sodium dodecyl sulfate (SDS) with a small amount of isopropanol, and diode array detector. The optimum conditions for the simultaneous determination of both drugs were 0.075 mol l(-1) SDS-7.5% (v/v) isopropanol with a flow rate of 0.7 ml min(-1) and detection at 210 nm. The LOD (2S/N) of LD HCl was 0.73 ng 20 microl(-1), whereas that of TP HCl was 1.43 ng 20 microl(-1). The calibration curves for LD HCl and TP HCl were linear over the ranges 0.125-500 microg ml(-1) (r(2)=0.9999) and 1.00-500 microg ml(-1) (r(2)=0.9997), respectively. The %recoveries of both drugs were in the range 98-103% and the %RSD values were less than 2. The proposed method has been successfully applied to the simultaneous determination of TP HCl and LD HCl in various pharmaceutical preparations.

  4. Propofol ameliorates doxorubicin-induced oxidative stress and cellular apoptosis in rat cardiomyocytes

    SciTech Connect

    Lai, H.C.; Yeh, Y.C.; Wang, L.C.; Ting, C.T.; Lee, W.L.; Lee, H.W.; Wang, K.Y.; Wu, A.; Su, C.S.; Liu, T.J.

    2011-12-15

    Background: Propofol is an anesthetic with pluripotent cytoprotective properties against various extrinsic insults. This study was designed to examine whether this agent could also ameliorate the infamous toxicity of doxorubicin, a widely-used chemotherapeutic agent against a variety of cancer diseases, on myocardial cells. Methods: Cultured neonatal rat cardiomyocytes were administrated with vehicle, doxorubicin (1 {mu}M), propofol (1 {mu}M), or propofol plus doxorubicin (given 1 h post propofol). After 24 h, cells were harvested and specific analyses regarding oxidative/nitrative stress and cellular apoptosis were conducted. Results: Trypan blue exclusion and MTT assays disclosed that viability of cardiomyocytes was significantly reduced by doxorubicin. Contents of reactive oxygen and nitrogen species were increased and antioxidant enzymes SOD1, SOD2, and GPx were decreased in these doxorubicin-treated cells. Mitochondrial dehydrogenase activity and membrane potential were also depressed, along with activation of key effectors downstream of mitochondrion-dependent apoptotic signaling. Besides, abundance of p53 was elevated and cleavage of PKC-{delta} was induced in these myocardial cells. In contrast, all of the above oxidative, nitrative and pro-apoptotic events could be suppressed by propofol pretreatment. Conclusions: Propofol could extensively counteract oxidative/nitrative and multiple apoptotic effects of doxorubicin in the heart; hence, this anesthetic may serve as an adjuvant agent to assuage the untoward cardiac effects of doxorubicin in clinical application. -- Highlights: Black-Right-Pointing-Pointer We evaluate how propofol prevents doxorubicin-induced toxicity in cardiomyocytes. Black-Right-Pointing-Pointer Propofol reduces doxorubicin-imposed nitrative and oxidative stress. Black-Right-Pointing-Pointer Propofol suppresses mitochondrion-, p53- and PKC-related apoptotic signaling. Black-Right-Pointing-Pointer Propofol ameliorates apoptosis and

  5. The influence of bile acids on the oral bioavailability of vitamin K encapsulated in polymeric micelles.

    PubMed

    van Hasselt, P M; Janssens, G E P J; Slot, T K; van der Ham, M; Minderhoud, T C; Talelli, M; Akkermans, L M; Rijcken, C J F; van Nostrum, C F

    2009-01-19

    The purpose of this study was to assess the ability of polymeric micelles to enable gastrointestinal absorption of the extremely hydrophobic compound vitamin K, by comparison of its absorption in bile duct ligated and sham operated rats. Hereto, vitamin K was encapsulated in micelles composed of mPEG(5000)-b-p(HPMAm-lac(2)), a thermosensitive block copolymer. Vitamin K plasma levels rose significantly upon gastric administration of 1 mg vitamin K encapsulated in polymeric micelles in sham operated rats, but not after bile duct ligation (AUC 4543 and 1.64 ng/mL/h respectively, p<0.01). Duodenal administration of polymeric micelles together with bile acids in bile duct ligated rats fully restored absorption. Dynamic light scattering time series showed a significant and dose dependent rise in micellar size in the presence of bile acids in vitro, indicating the gradual formation of mixed micelles during the first 3 h of incubation. The highest bile acid amounts (11 mM deoxycholic acid and 41 mM taurocholic acid) eventually caused aggregation of the loaded micelles after the formation of mixed micelles. These data suggest that the gastrointestinal absorption of encapsulated vitamin K from polymeric micelles is mediated by free bile and that uptake of intact micelles through pinocytosis is insignificant.

  6. Polymeric micelles for the solubilization and delivery of STAT3 inhibitor cucurbitacins in solid tumors

    PubMed Central

    Molavi, Ommoleila; Ma, Zengshuan; Mahmud, Abdullah; Alshamsan, Aws; Samuel, John; Lai, Raymond; Kwon, Glen S.; Lavasanifar, Afsaneh

    2009-01-01

    Poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) and newly developed poly(ethylene oxide)-block-poly(α-benzyl carboxylate ε-caprolactone) (PEO-b-PBCL) micelles were evaluated for the solubilization and delivery of cucurbitacin I and B, poorly water soluble inhibitors of signal transducer and activator of transcription 3 (STAT3). Encapsulation of cucurbitacins in PEO-b-PCL and PEO-b-PBCL by co-solvent evaporation technique resulted in polymeric micelles <90 nm in diameter. The aqueous solubility of both derivatives increased from less than 0.05 mg/mL in the absence of the copolymer to around 0.30–0.44 and 0.65–0.68 mg/mL in the presence of 5000–5000 and 5000–24,000 PEO-b-PCL micelles, respectively. Maximum cucurbitacin solubilization was achieved with PEO-b-PBCL micelles for both derivatives. PEO-b-PCL micelles having longer PCL block were found to be more efficient in sustaining the rate of release for cucurbitacins. The anti-cancer and STAT3 inhibitory activity of polymeric micellar cucurbitacins were comparable with free drugs in B16.F10 melanoma cell line in vitro. Intratumoral injection of 1 mg/kg/day cucurbitacin I resulted in the regression of established B16.F10 mouse melanoma tumors in vivo. In comparison to free cucurbitacin I, PEO-b-PBCL micellar cucurbitacin I was found to provide comparable anti-cancer effects against B16.F10 tumors and limit drug levels in animal serum while maintaining high drug levels in tumor following intratumoral administration. The results indicate the potential of polymeric micelles as suitable vehicles for the delivery of cucurbitacin- I and B. PMID:17681440

  7. Oseltamivir-conjugated polymeric micelles prepared by RAFT living radical polymerization as a new active tumor targeting drug delivery platform.

    PubMed

    Kapishon, Vitaliy; Allison, Stephanie; Whitney, Ralph A; Cunningham, Michael F; Szewczuk, Myron R; Neufeld, Ronald J

    2016-03-01

    Targeted drug delivery using polymeric nanostructures has been at the forefront of cancer research, engineered for safer, more efficient and effective use of chemotherapy. Here, we designed a new polymeric micelle delivery system for active tumor targeting followed by micelle-drug internalization via receptor-induced endocytosis. We recently reported that oseltamivir phosphate targets and inhibits Neu1 sialidase activity associated with receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) which are overexpressed in cancer cells. By decorating micelles with oseltamivir, we investigated whether they actively targeted human pancreatic PANC1 cancer cells. Amphiphilic block copolymers with oseltamivir conjugated at the hydrophilic end, oseltamivir-pPEGMEMA-b-pMMA (oseltamivir-poly(polyethylene glycol methyl ether methacrylate)-block-poly(methyl methacrylate), were synthesized using reversible addition-fragmentation chain transfer (RAFT) living radical polymerization. Oseltamivir-conjugated micelles have self-assembling properties to give worm-like micellar structures with molecular weight of 80 000 g mol(-1). Oseltamivir-conjugated water soluble pPEGMEMA, dose dependently, both inhibited sialidase activity associated with Neu1, and reduced viability of PANC1 cells. In addition, oseltamivir-conjugated micelles, labelled with a hydrophobic fluorescent dye within the micelle core, were subsequently internalized by PANC1 cells. Blocking cell surface Neu1 with anti-Neu1 antibody, reduced internalization of oseltamivir-conjugated micelles, demonstrating that Neu1 binding linked to sialidase inhibition were prerequisite steps for subsequent internalization of the micelles. The mechanism of internalization is likely that of receptor-induced endocytosis demonstrating potential as a new nanocarrier system for not only targeting a tumor cell, but also for directly reducing viability through Neu1 inhibition, followed by intracellular delivery of hydrophobic

  8. Effect of ripening, heat processing, and fat type on the micellarization of pigments from jalapeño peppers.

    PubMed

    Victoria-Campos, Claudia I; Ornelas-Paz, José de Jesús; Yahia, Elhadi M; Jiménez-Castro, Jorge A; Cervantes-Paz, Braulio; Ibarra-Junquera, Vrani; Pérez-Martínez, Jaime David; Zamudio-Flores, Paul B; Escalante-Minakata, Pilar

    2013-10-16

    Raw and heat-processed (boiled and grilled) jalapeño peppers at three intermediate ripening stages (brown, 50% red, and 75% red) were digested in vitro without fat and in the presence of soybean oil (SO) or beef tallow (BT), and the micellarization of their lipid soluble pigments (LSP) was measured. The micelles from digestions with brown, 50% red, and 75% red peppers contained up to 27, 35, and 29 different LSP, respectively. Boiling and grilling decreased the micellarization of LSP from brown peppers, whereas the opposite was observed with 75% red peppers. Heat processing did not clearly affect the micellarization of LSP from 50% red fruits. The impact of fat on LSP micellarization was ripening-dependent, but the micellarization of the less polar carotenoids was always increased by SO or BT. This positive effect of fat was higher with SO than with BT.

  9. Interaction between Tea Polyphenols and Bile Acid Inhibits Micellar Cholesterol Solubility.

    PubMed

    Ogawa, Kazuki; Hirose, Sayumi; Nagaoka, Satoshi; Yanase, Emiko

    2016-01-13

    The molecular mechanism by which tea polyphenols decrease the micellar solubility of cholesterol is not completely clear. To clarify this mechanism, this study investigated the interaction between tea polyphenols (catechins and oolongtheanins) and cholesterol micelles. A nuclear magnetic resonance (NMR) study was performed on a micellar solution containing taurocholic acid and epigallocatechin gallate (EGCg), and high-performance liquid chromatography (HPLC) analysis was carried out on the precipitate and the supernatant that formed when EGCg was added to a cholesterol-micelle solution. The data indicated a regiospecific interaction of EGCg with taurocholic acid. Therefore, the ability of EGCg to lower the solubility of phosphatidylcholine (PC) and cholesterol in micellar solutions can be attributed to their elimination from the micelles due to interaction between taurocholic acids and EGCg.

  10. Molecular motion of micellar solutes: a /sup 13/C NMR relaxation study

    SciTech Connect

    Stark, R.E.; Kasakevich, M.L.; Granger, J.W.

    1982-02-04

    A series of simple NMR relaxation experiments have been performed on nitrobenzene and aniline dissolved in the ionic detergents sodium dodecyl sulfate (SDS) and hexadecyltrimethylammonium bromide (CTAB). Using /sup 13/C relaxation rates at various molecular sites, and comparing data obtained in organic media with those for micellar solutions, the viscosity at the solubilization site was estimated and a detailed picture of motional restrictions imposed by the micellar enviroment was derived. Viscosities of 8 to 17 cp indicate a rather fluid environment for solubilized nitrobenzene; both additives exhibit altered motional preferences in CTAB solutions only. As an aid in interpretation of the NMR data, quasi-elastic light scattering and other physical techniques have been used to evaluate the influence of organic solutes on micellar size and shape. The NMR methods are examined critically in terms of their general usefulness for studies of solubilization in detergent mice

  11. Demonstrating Chemical and Analytical Concepts in the Undergraduate Laboratory Using Capillary Electrophoresis and Micellar Electrokinetic Chromatography

    NASA Astrophysics Data System (ADS)

    Palmer, Christopher P.

    1999-11-01

    This paper describes instrumental analysis laboratory exercises that utilize capillary electrophoresis and micellar electrokinetic chromatography to demonstrate several analytical and chemical principles. Alkyl parabens (4-hydroxy alkyl benzoates), which are common ingredients in cosmetic formulations, are separated by capillary electrophoresis. The electrophoretic mobilities of the parabens can be explained on the basis of their relative size. 3-Hydroxy ethylbenzoate is also separated to demonstrate the effect of substituent position on the acid dissociation constant and the effect this has on electrophoretic mobility. Homologous series of alkyl benzoates and alkyl phthalates (common plasticizers) are separated by micellar electrokinetic chromatography at four surfactant concentrations. This exercise demonstrates the separation mechanism of micellar electrokinetic chromatography, the concept of chromatographic phase ratio, and the concepts of micelle formation. A photodiode array detector is used in both exercises to demonstrate the advantages and limitations of the detector and to demonstrate the effect of pH and substituent position on the spectra of the analytes.

  12. Partitioning of quencher ions in the micellar microenvironment of polyoxyethylene nonyl phenol

    NASA Astrophysics Data System (ADS)

    Ghosh, Sujit Kumar; Khatua, Pijus Kanti; Ghosh, Jayanta Kumar; Bhattacharya, Subhash Chandra

    2005-01-01

    This paper has explored the quenching of fluorescence of the dye safranine T (ST) by the inorganic cations viz Cu 2+, Co 2+, Ni 2+ and Mn 2+ in micellar solutions of the surfactant dioxyethylene nonyl phenol (Igepal CO-210), pentaoxyethylene nonyl phenol (Igepal CO-520) and dodecaoxyethylene nonyl phenol (Igepal CO-720). The quenching results have been calculated in light of stern volmer equation (SV) to evaluate the extent of interaction between the fluorophore (ST) and quencher. The average concentration of the quencher ions in the micelle have been determined. The quenching efficiency of ST by inorganic ions in micellar medium is lower than that in aqueous medium. The results show that the ions get partitioned in the micellar medium. The values of the partition coefficient of the ions decrease with increase in HLB value and number of oxyethylene groups in Igepal.

  13. Partitioning of quencher ions in the micellar microenvironment of polyoxyethylene nonyl phenol.

    PubMed

    Ghosh, Sujit Kumar; Khatua, Pijus Kanti; Ghosh, Jayanta Kumar; Bhattacharya, Subhash Chandra

    2005-01-14

    This paper has explored the quenching of fluorescence of the dye safranine T (ST) by the inorganic cations viz Cu2+, Co2+, Ni2+ and Mn2+ in micellar solutions of the surfactant dioxyethylene nonyl phenol (Igepal CO-210), pentaoxyethylene nonyl phenol (Igepal CO-520) and dodecaoxyethylene nonyl phenol (Igepal CO-720). The quenching results have been calculated in light of stern volmer equation (SV) to evaluate the extent of interaction between the fluorophore (ST) and quencher. The average concentration of the quencher ions in the micelle have been determined. The quenching efficiency of ST by inorganic ions in micellar medium is lower than that in aqueous medium. The results show that the ions get partitioned in the micellar medium. The values of the partition coefficient of the ions decrease with increase in HLB value and number of oxyethylene groups in Igepal.

  14. Doxorubicin-loaded aromatic imine-contained amphiphilic branched star polymer micelles: synthesis, self-assembly, and drug delivery

    PubMed Central

    Qiu, Liang; Hong, Chun-Yan; Pan, Cai-Yuan

    2015-01-01

    Redox-and pH-sensitive branched star polymers (BSPs), BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAIGP)ns, have been successively prepared by two steps of reversible addition–fragmentation chain transfer (RAFT) polymerization. The first step is RAFT polymerization of 2-(N,N-dimethylaminoethyl)methacrylate (DMAEMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) in the presence of divinyl monomer, 2,2′-dithiodiethoxyl dimethacrylate (DTDMA). The resultant branched polymers were used as a macro-RAFT agent in the subsequent RAFT polymerization. After hydrolysis of the BSPs to form BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAGP)ns (BSP-H), the anticancer drug doxorubicin (DOX) was covalently linked to branched polymer chains by reaction of primary amine of DOX and aldehyde groups in the polymer chains. Their compositions, structures, molecular weights, and molecular weight distributions were respectively characterized by nuclear magnetic resonance spectra and gel permeation chromatography measurements. The DOX-loaded micelles were fabricated by self-assembly of DOX-containing BSPs in water, which were characterized by transmission electron microscopy and dynamic light scattering. Aromatic imine linkage is stable in neutral water, but is acid-labile; controlled release of DOX from the BSP-H-DOX micelles was realized at pH values of 5 and 6, and at higher acidic solution, fast release of DOX was observed. In vitro cytotoxicity experiment results revealed low cytotoxicity of the BSPs and release of DOX from micelles in HepG2 and HeLa cells. Confocal laser fluorescence microscopy observations showed that DOX-loaded micelles have specific interaction with HepG2 cells. Thus, this type of BSP micelle is an efficient drug delivery system. PMID:26056444

  15. Doxorubicin-loaded aromatic imine-contained amphiphilic branched star polymer micelles: synthesis, self-assembly, and drug delivery.

    PubMed

    Qiu, Liang; Hong, Chun-Yan; Pan, Cai-Yuan

    2015-01-01

    Redox-and pH-sensitive branched star polymers (BSPs), BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAIGP)(n)s, have been successively prepared by two steps of reversible addition-fragmentation chain transfer (RAFT) polymerization. The first step is RAFT polymerization of 2-(N,N-dimethylaminoethyl)methacrylate (DMAEMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) in the presence of divinyl monomer, 2,2'-dithiodiethoxyl dimethacrylate (DTDMA). The resultant branched polymers were used as a macro-RAFT agent in the subsequent RAFT polymerization. After hydrolysis of the BSPs to form BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAGP)(n)s (BSP-H), the anticancer drug doxorubicin (DOX) was covalently linked to branched polymer chains by reaction of primary amine of DOX and aldehyde groups in the polymer chains. Their compositions, structures, molecular weights, and molecular weight distributions were respectively characterized by nuclear magnetic resonance spectra and gel permeation chromatography measurements. The DOX-loaded micelles were fabricated by self-assembly of DOX-containing BSPs in water, which were characterized by transmission electron microscopy and dynamic light scattering. Aromatic imine linkage is stable in neutral water, but is acid-labile; controlled release of DOX from the BSP-H-DOX micelles was realized at pH values of 5 and 6, and at higher acidic solution, fast release of DOX was observed. In vitro cytotoxicity experiment results revealed low cytotoxicity of the BSPs and release of DOX from micelles in HepG2 and HeLa cells. Confocal laser fluorescence microscopy observations showed that DOX-loaded micelles have specific interaction with HepG2 cells. Thus, this type of BSP micelle is an efficient drug delivery system.

  16. Solute-solvent interactions in micellar electrokinetic chromatography: VII. Characterization of sodium cholate-sodium deoxycholate mixed-micellar systems.

    PubMed

    Hidalgo-Rodríguez, Marta; Fuguet, Elisabet; Ràfols, Clara; Rosés, Martí

    2010-03-05

    Micellar electrokinetic chromatography (MEKC) systems with mixed pseudostationary phases of the bile surfactants sodium cholate (SC) and sodium deoxycholate (SDC) have been characterized by means of the solvation parameter model. The importance of characterizing systems with an appropriate set of solutes that embrace a wide range of descriptor values has been proven as they can significantly influence the value of the system constants. The fit of the solvation parameter model to the experimental log k data has been compared for each SC-SDC system when the Abraham descriptors and the Poole optimized descriptors, recently proposed, are used. In both cases, the variation in MEKC surfactant composition results in similar changes in the coefficients of the correlation equations, which in turn leads to similar information on solute-solvent and solute-micelle interactions. It is demonstrated that SDC is more hydrogen-bond acidic and hydrophobic but slightly less polarizable than SC. Systems with intermediate selectivity are obtained through mixtures of both surfactants.

  17. Multifunctional polymeric nanoconstructs for biomedical applications (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Decuzzi, Paolo

    2016-09-01

    Multifunctional nanoconstructs are particle-based nano-scale systems designed for the `smart' delivery of therapeutic and imaging agents. The Laboratory of Nanotechnology for Precision Medicine at the Italian Institute of Technology synthesizes polymeric nanoconstructs with different sizes, ranging from a few tens of nanometers to a few microns; shapes, including spherical, cubical and discoidal; surface properties, with positive, negative, neutral coatings; and mechanical stiffness, varying from that of cells to rigid, inorganic materials, such as iron oxide. These are the 4S parameters - size, shape, surface, stiffness - which can be precisely tuned in the synthesis process enabling disease- and patient-specific designs of multifunctional nanoconstructs. In this lecture, the application of these nanoconstructs to the detection and treatment of cancer lesions and cardiovascular diseases, such as thrombosis and atherosclerosis, is discussed. The contribution of the 4S parameters in modulating nanoconstruct sequestration by the mononuclear phagocyte system, organ specific accumulation, and blood longevity is also critically presented. These polymeric nanoconstructs can be loaded with a variety of therapeutic payloads - anti-cancer molecules (docetaxel, paclitaxel, doxorubicin), anti-inflammatory molecules (curcumin, diclofenac, celecoxib) and small biologicals (peptides, siRNAs, miRNAs); and imaging agents - optical probes; Gd and iron oxide nanoparticles for MR imaging; and radio-isotopes for Nuclear Imaging.

  18. The sulphydryl containing ACE inhibitor Zofenoprilat protects coronary endothelium from Doxorubicin-induced apoptosis.

    PubMed

    Monti, Martina; Terzuoli, Erika; Ziche, Marina; Morbidelli, Lucia

    2013-10-01

    Pediatric and adult cancer patients, following the use of the antitumor drug Doxorubicin develop cardiotoxicity. Pharmacological protection of microvascular endothelium might produce a double benefit: (i) reduction of myocardial toxicity (the primary target of Doxorubicin action) and (ii) maintenance of the vascular functionality for the adequate delivery of chemotherapeutics to tumor cells. This study was aimed to evaluate the mechanisms responsible of the protective effects of the angiotensin converting enzyme inhibitor (ACEI) Zofenoprilat against the toxic effects exerted by Doxorubicin on coronary microvascular endothelium. We found that exposure of endothelial cells to Doxorubicin (0.1-1μM range) impaired cell survival by promoting their apoptosis. ERK1/2 related p53 activation, but not reactive oxygen species, was responsible for Doxorubicin induced caspase-3 cleavage. P53 mediated-apoptosis and impairment of survival were reverted by treatment with Zofenoprilat. The previously described PI-3K/eNOS/endogenous fibroblast growth factor signaling was not involved in the protective effect, which, instead, could be ascribed to cystathionine gamma lyase dependent availability of H2S from Zofenoprilat. Furthermore, considering the tumor environment, the treatment of endothelial/tumor co-cultures with Zofenoprilat did not affect the antitumor efficacy of Doxorubicin. In conclusion the ACEI Zofenoprilat exerts a protective effect on Doxorubicin induced endothelial damage, without affecting its antitumor efficacy. Thus, sulfhydryl containing ACEI may be a useful therapy for Doxorubicin-induced cardiotoxicity.

  19. Impact of body composition on pharmacokinetics of doxorubicin in children: A Glaser Pediatric Research Network study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We studied the relationship between doxorubicin pharmacokinetics and body composition in children with cancer. Children between 1 and 21 years of age, receiving doxorubicin as an infusion of any duration <24 h on either a 1-day or 2-day schedule, were eligible if they had no significant abnormality ...

  20. The regulatory mechanisms of myogenin expression in doxorubicin-treated rat cardiomyocytes.

    PubMed

    Liu, Shu-Ting; Huang, Shih-Ming; Ho, Ching-Liang; Yen, Li-Chen; Huang, Chi-Jung; Lin, Wei-Shiang; Chan, James Yi-Hsin

    2015-11-10

    Doxorubicin, an anthracycline antibiotic, has been used as an anti-neoplastic drug for almost 60 years. However, the mechanism(s) by which anthracyclines cause irreversible myocardial injury remains unclear. In order to delineate possible molecular signals involved in the myocardial toxicity, we assessed candidate genes using mRNA expression profiling in the doxorubicin-treated rat cardiomyocyte H9c2 cell line. In the study, it was confirmed that myogenin, an important transcriptional factor for muscle terminal differentiation, was significantly reduced by doxorubicin in a dose-dependent manner using both RT-PCR and western blot analyses. Also, it was identified that the doxorubicin-reduced myogenin gene level could not be rescued by most cardio-protectants. Furthermore, it was demonstrated how the signaling of the decreased myogenin expression by doxorubicin was altered at the transcriptional, post-transcriptional and translational levels. Based on these findings, a working model was proposed for relieving doxorubicin-associated myocardial toxicity by down-regulating miR-328 expression and increasing voltage-gated calcium channel β1 expression, which is a repressor of myogenin gene regulation. In summary, this study provides several lines of evidence indicating that myogenin is the target for doxorubicin-induced cardio-toxicity and a novel therapeutic strategy for doxorubicin clinical applications based on the regulatory mechanisms of myogenin expression.

  1. Human cytosolic sulfotransferase SULT1C4 mediates the sulfation of doxorubicin and epirubicin.

    PubMed

    Luo, Lijun; Zhou, Chunyang; Hui, Ying; Kurogi, Katsuhisa; Sakakibara, Yoichi; Suiko, Masahito; Liu, Ming-Cheh

    2016-04-01

    Doxorubicin, an anthracycline, has been reported to be excreted in sulfate conjugated form. The current study aimed to identify the human cytosolic sulfotransferase(s) (SULT(s)) that is(are) capable of sulfating doxorubicin and its analog epirubicin, and to verify whether sulfation of doxorubicin and epirubicin may occur under metabolic conditions. A systematic analysis of thirteen known human SULTs, previously cloned, expressed, and purified, revealed SULT1C4 as the only human SULT capable of sulfating doxorubicin and epirubicin. Cultured HepG2 human hepatoma cells and Caco-2 human colon carcinoma cells were labeled with [(35)S]sulfate in the presence of different concentrations of doxorubicin or epirubicin. Analysis of spent labeling media showed the generation and release of [(35)S]sulfated doxorubicin and epirubicin by HepG2 cells and Caco-2 cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed the expression of SULT1C4 in both HepG2 cells and Caco-2 cells. These results provided a molecular basis underlying the previous finding that sulfate-conjugated doxorubicin was excreted in the urine of patients treated with doxorubicin.

  2. Polyelectrolyte-Mediated Transport of Doxorubicin Through the Bilayer Lipid Membrane

    NASA Astrophysics Data System (ADS)

    Yaroslavov, Alexander A.; Kitaeva, Marina V.; Melik-Nubarov, Nikolay S.; Menger, Frederic M.

    A model is developed for the effect of ionic polymers on the transport of doxorubicin, an antitumor drug, through a bilayer membrane. Accordingly, a protonated (cationic) form of doxorubicin binds to an anionic polymer, poly(acrylic acid), the resulting complex being several hundred nanometers in size. Nevertheless, large complex species associate with neutral egg lecithin liposomes by means of hydrophobic attraction between the doxorubicin and the liposome bilayer. Then, the doxorubicin enters the liposome interior which has been imparted with an acidic buffer to protonate the doxorubicin. The rate of transmembrane Dox permeation decreases when elevating the polyacid-to-doxorubicin ratio. A cationic polymer, polylysine, being coupled with liposomes containing the negative lipid cardiolipin, accelerates membrane transport of doxorubicin with the maximum rate at a complete neutralization of the membrane charge by an interacting polycation. The effect of a polycation on doxorubicin transport becomes more pronounced as small negative liposomes (60-80 nm in diameter) are changed to larger ones (approx. 600 nm in diameter). An opportunity thus opens up for the manipulation of the kinetics of drug uptake by cells and, ultimately, the control of the pharmaceutical action of drugs.

  3. Liposomal delivery of doxorubicin to hepatocytes in vivo by targeting heparan sulfate

    PubMed Central

    Longmuir, Kenneth J.; Haynes, Sherry M.; Baratta, Janie L.; Kasabwalla, Natasha; Robertson, Richard T.

    2009-01-01

    Previous work demonstrated that liposomes, containing an amino acid sequence that binds to hepatic heparan sulfate glycosaminoglycan, show effective targeting to liver hepatocytes. These liposomes were tested to determine whether they can deliver doxorubicin selectively to liver and hepatocytes in vivo. Fluid-phase liposomes contained a lipid-anchored 19-amino acid glycosaminoglycan targeting peptide. Liposomes were loaded with doxorubicin and were non-leaky in the presence of serum. After intravenous administration to mice, organs were harvested and the doxorubicin content extracted and measured by fluorescence intensity and by fluorescence microscopy. The liposomal doxorubicin was recovered almost entirely from liver, with only trace amounts detectable in heart, lung, and kidney. Fluorescence microscopy demonstrated doxorubicin preferentially in hepatocytes, also in non-parenchymal cells of the liver, but not in cells of heart, lung or kidney. The doxorubicin was localized within liver cell nuclei within five minutes after intravenous injection. These studies demonstrated that liposomal doxorubicin can be effectively delivered to hepatocytes by targeting the heparan sulfate glycosaminoglycan of liver tissue. With the composition described here, the doxorubicin was rapidly released from the liposomes without the need for an externally supplied stimulus. PMID:19664697

  4. Micellar lipid composition affects micelle interaction with class B scavenger receptor extracellular loops.

    PubMed

    Goncalves, Aurélie; Gontero, Brigitte; Nowicki, Marion; Margier, Marielle; Masset, Gabriel; Amiot, Marie-Josèphe; Reboul, Emmanuelle

    2015-06-01

    Scavenger receptors (SRs) like cluster determinant 36 (CD36) and SR class B type I (SR-BI) play a debated role in lipid transport across the intestinal brush border membrane. We used surface plasmon resonance to analyze real-time interactions between the extracellular protein loops and various ligands ranging from single lipid molecules to mixed micelles. Micelles mimicking physiological structures were necessary for optimal binding to both the extracellular loop of CD36 (lCD36) and the extracellular loop of SR-BI (lSR-BI). Cholesterol, phospholipid, and fatty acid micellar content significantly modulated micelle binding to and dissociation from the transporters. In particular, high phospholipid micellar concentrations inhibited micelle binding to both receptors (-53.8 and -74.4% binding at 0.32 mM compared with 0.04 mM for lCD36 and lSR-BI, respectively, P < 0.05). The presence of fatty acids was crucial for micelle interactions with both proteins (94.4 and 81.3% binding with oleic acid for lCD36 and lSR-BI, respectively, P < 0.05) and fatty acid type substitution within the micelles was the component that most impacted micelle binding to the transporters. These effects were partly due to subsequent modifications in micellar size and surface electric charge, and could be correlated to micellar vitamin D uptake by Caco-2 cells. Our findings show for the first time that micellar lipid composition and micellar properties are key factors governing micelle interactions with SRs.

  5. Micellar lipid composition affects micelle interaction with class B scavenger receptor extracellular loops

    PubMed Central

    Goncalves, Aurélie; Gontero, Brigitte; Nowicki, Marion; Margier, Marielle; Masset, Gabriel; Amiot, Marie-Josèphe; Reboul, Emmanuelle

    2015-01-01

    Scavenger receptors (SRs) like cluster determinant 36 (CD36) and SR class B type I (SR-BI) play a debated role in lipid transport across the intestinal brush border membrane. We used surface plasmon resonance to analyze real-time interactions between the extracellular protein loops and various ligands ranging from single lipid molecules to mixed micelles. Micelles mimicking physiological structures were necessary for optimal binding to both the extracellular loop of CD36 (lCD36) and the extracellular loop of SR-BI (lSR-BI). Cholesterol, phospholipid, and fatty acid micellar content significantly modulated micelle binding to and dissociation from the transporters. In particular, high phospholipid micellar concentrations inhibited micelle binding to both receptors (−53.8 and −74.4% binding at 0.32 mM compared with 0.04 mM for lCD36 and lSR-BI, respectively, P < 0.05). The presence of fatty acids was crucial for micelle interactions with both proteins (94.4 and 81.3% binding with oleic acid for lCD36 and lSR-BI, respectively, P < 0.05) and fatty acid type substitution within the micelles was the component that most impacted micelle binding to the transporters. These effects were partly due to subsequent modifications in micellar size and surface electric charge, and could be correlated to micellar vitamin D uptake by Caco-2 cells. Our findings show for the first time that micellar lipid composition and micellar properties are key factors governing micelle interactions with SRs. PMID:25833688

  6. The magnetoviscous effect of micellar solutions doped with water based ferrofluids

    NASA Astrophysics Data System (ADS)

    Arantes, Fabiana R.; Odenbach, Stefan

    2015-09-01

    This work presents a magnetorheological study of micellar solutions of potassium laurate and water doped with magnetite nanoparticles, accompanied by auxiliary dynamic light scattering measurements. An increase in the viscosity of the samples under applied field was observed and, furthermore, a considerable magnetoviscous effect was revealed even at magnetic particles' concentrations as low as 0.005-0.01 vol%. This indicates that the rheological behavior of the micelles is changed by the interaction of the magnetic particles with the applied field, leading to different microscopic arrangements in the micellar solutions.

  7. Micropolarity and water penetration in micellar aggregates of linear and branched hydrocarbon surfactants

    SciTech Connect

    Varadaraj, R.; Bock, J.; Valint, P. Jr.; Brons, N. )

    1990-08-01

    The micropolarity of aqueous micellar solutions of ethoxylates, sodium ethoxy sulfates, and sulfates derived from linear and branched hydrocarbon alcohols was investigated by using a solvatochromic pyridinio-N-phenoxide betaine, ET-30, polarity probe. Branching of the hydrophobe resulted in a more porous micellar aggregate. Thermosolvatochromism of ET-30 allowed an investigation of the effect of temperature on micropolarity. Increase in temperature was observed to expel water from the hydrophobic regions of the aggregate and decrease the effective micropolarity in linear and branched surfactants.

  8. Direct measurement of depletion and structural forces in a micellar system

    NASA Astrophysics Data System (ADS)

    Richetti, P.; Kékicheff, P.

    1992-03-01

    The force as a function of separation is measured between two mica surfaces coated with adsorbed bilayers of cetyltrimethylammonium bromide (CTAB) and immersed in aqueous ionic micellar solutions of CTAB. At low separations double-layer forces are observed and arise soley from the dissociated counterions and free CTA+. At large separations, the repulsion is reduced and a secondary minimum in the interaction potential deepens when the micellar concentration is increased. Finally, at higher concentrations, structural effects superimpose an oscillatory force profile at further separations.

  9. Polymeric ion conductors

    SciTech Connect

    Nagai, J.; Mizuhashi, M.; Kamimori, T.

    1990-12-31

    There are several requirements for (polymeric) ion conductors in electrochromic window applications: (1) they have high ionic conductivity (desirably, > 1 {times} 10{sup {minus}4} Scm{sup {minus}1}); (2) they have high chemical and electrochemical stabilities with respect to the wide usable potential window and thermal and UV stabilities; (3) they are transparent in a specific wavelength region, which is, however, dependent of applications; and (4) they have enough adhesiveness to the substrates and have acceptable mechanical properties. Many kinds of polymeric ionic conductors have since been reported and some of them were applied to electrochromic uses. In this chapter, electrochemical and physicochemical properties of these materials are reviewed. However, certain aspects such as crystallographic studies and conduction models in detail have been omitted, which are still controversial.

  10. Organometallic polymerization catalysts

    SciTech Connect

    Waymouth, R.M.

    1993-12-31

    Well-defined transition metal catalysts have resulted in exciting new opportunities in polymer synthesis. The stereochemistry of vinyl polymers can be rationally controlled with choice of the appropriate catalysts. Studies with optically active catalyst precursors have revealed considerable information on the absolute stereochemistry of olefin polymerization and have led to the synthesis of novel chiral polyolefins. The development of homogeneous olefin metathesis catalysts has also led to a variety of well-defined new polymer structures with controlled molecular weight and molecular weight distribution. Recent advances in understanding the mechanisms and stereochemistry of homogeneous transition metal catalyzed polymerization will be discussed. The ability to control polymer structure through catalyst design presents exciting opportunities in the synthesis of {open_quotes}tailor-made{close_quotes} macromolecules.

  11. Effect of the paclitaxel vehicle, Cremophor EL, on the pharmacokinetics of doxorubicin and doxorubicinol in mice.

    PubMed Central

    Webster, L. K.; Cosson, E. J.; Stokes, K. H.; Millward, M. J.

    1996-01-01

    The effect of the paclitaxel vehicle Cremophor on the pharmacokinetics of doxorubicin and doxorubicinol was studied in two groups of mice given intravenously either 2.5 ml kg-1 Cremophor or saline followed 5 min later by 10 mg kg-1 doxorubicin. In each group three mice were sacrificed at ten time points and doxorubicin and doxorubicinol were measured in plasma by high-performance liquid chromatography (HPLC). With Cremophor present, doxorubicin AUC increased from 1420+/-440 to 2770+/-660 ng h ml(-1) (P<0.05) and doxorubicinol AUC increased from 130+/-76 to 320+/-88 ng h ml(-1) (p<0.05). Neither the terminal elimination half-lives nor the doxorubicinol-doxorubicin AUC ratio changed in the presence of Cremophor, suggesting a lack of a direct effect on drug metabolism. The possibility exists the Cremophor may change the pharmacokinetics of both paclitaxel and other drugs given concurrently. PMID:8595168

  12. Polymeric Microcapsule Arrays.

    DTIC Science & Technology

    1995-03-24

    support, microencapsulation and entrapment within a membrane/film or gel. The ideal enzyme immobilization method would (1) Employ mild chemical...yields hollow polymeric microcapsules of uniform diameter and length. These microcapsules are arranged in a high density array in which the...individual capsules protrude from a surface like the bristles of a brush. We have developed procedures for filling these microcapsules with high

  13. Surface polymerization agents

    SciTech Connect

    Taylor, C.; Wilkerson, C.

    1996-12-01

    This is the final report of a 1-year, Laboratory-Directed R&D project at LANL. A joint technical demonstration was proposed between US Army Missile Command (Redstone Arsenal) and LANL. Objective was to demonstrate that an unmanned vehicle or missile could be used as a platform to deliver a surface polymerization agent in such a manner as to obstruct the filters of an air-breathing mechanism, resulting in operational failure.

  14. Frontal Polymerization in Microgravity

    NASA Technical Reports Server (NTRS)

    Pojman, John A.

    1999-01-01

    Frontal polymerization systems, with their inherent large thermal and compositional gradients, are greatly affected by buoyancy-driven convection. Sounding rocket experiments allowed the preparation of benchmark materials and demonstrated that methods to suppress the Rayleigh-Taylor instability in ground-based research did not significantly affect the molecular weight of the polymer. Experiments under weightlessness show clearly that bubbles produced during the reaction interact very differently than under 1 g.

  15. Developments in polymerization lamps.

    PubMed

    Jiménez-Planas, Amparo; Martín, Juan; Abalos, Camilo; Llamas, Rafael

    2008-02-01

    Polymerization shrinkage of composite resins and the consequent stress generated at the composite-tooth interface continue to pose a serious clinical challenge. The development of high-intensity halogen lamps and the advent of curing units providing higher energy performance, such as laser lamps, plasma arc units, and, most recently, light-emitting diode (LED) curing units, have revolutionized polymerization lamp use and brought major changes in light-application techniques. A comprehensive review of the literature yielded the following conclusions: (1) the most reliable curing unit for any type of composite resin is the high-density halogen lamp, fitted with a programming device to enable both pulse-delay and soft-start techniques; (2) if any other type of curing unit is used, information must be available on the compatibility of the unit with the composite materials to be used; (3) polymerization lamp manufacturers need to focus on the ongoing development of LED technology; (4) further research is required to identify the most reliable light-application techniques.

  16. Mobilization and micellar solubilization of NAPL contaminants in aquifer rocks

    NASA Astrophysics Data System (ADS)

    Javanbakht, Gina; Goual, Lamia

    2016-02-01

    Surfactant-enhanced aquifer remediation is often performed to overcome the capillary forces that keep residual NAPL phases trapped within contaminated aquifers. The surfactant selection and displacement mechanism usually depend on the nature of NAPL constituents. For example, micellar solubilization is often used to cleanup DNAPLs from aquifers whereas mobilization is desirable in aquifers contaminated by LNAPLs. Although the majority of crude oils are LNAPLs, they often contain heavy organic macromolecules such as asphaltenes that are classified as DNAPLs. Asphaltenes contain surface-active components that tend to adsorb on rocks, altering their wettability. Previous studies revealed that surfactants that formed Winsor type III microemulsions could promote both mobilization and solubilization. However the extent by which these two mechanisms occur is still unclear, particularly in oil-contaminated aquifers. In this study we investigated the remediation of oil-contaminated aquifers using an environmentally friendly surfactant such as n-Dodecyl β-D-maltoside. Focus was given on asphaltenes to better understand the mechanisms of surfactant cleanup. Through phase behavior, spontaneous imbibition, dynamic interfacial tension and contact angle measurements, we showed that microemulsions formed by this surfactant are able to mobilize bulk NAPL (containing 9 wt.% asphaltenes) in the porous rock and solubilize DNAPL (i.e., 4-6 wt.% adsorbed asphaltenes) from the rock surface. Spontaneous imbibition tests, in particular, indicated that the ratio of mobilized to solubilized NAPL is about 6:1. Furthermore, aging the cores in NAPL beyond 3 days allowed for more NAPL to be trapped in the large pores of the rock but did not alter the amount of asphaltenes adsorbed on the mineral surface.

  17. Flow of wormlike micellar solutions around confined microfluidic cylinders.

    PubMed

    Zhao, Ya; Shen, Amy Q; Haward, Simon J

    2016-10-26

    Wormlike micellar (WLM) solutions are frequently used in enhanced oil and gas recovery applications in porous rock beds where complex microscopic geometries result in mixed flow kinematics with strong shear and extensional components. Experiments with WLM solutions through model microfluidic porous media have revealed a variety of complex flow phenomena, including the formation of stable gel-like structures known as a Flow-Induced Structured Phase (FISP), which undoubtedly play an important role in applications of WLM fluids, but are still poorly understood. A first step in understanding flows of WLM fluids through porous media can be made by examining the flow around a single micro-scale cylinder aligned on the flow axis. Here we study flow behavior of an aqueous WLM solution consisting of cationic surfactant cetyltrimethylammonium bromide (CTAB) and a stable hydrotropic salt 3-hydroxy naphthalene-2-carboxylate (SHNC) in microfluidic devices with three different cylinder blockage ratios, β. We observe a rich sequence of flow instabilities depending on β as the Weissenberg number (Wi) is increased to large values while the Reynolds number (Re) remains low. Instabilities upstream of the cylinder are associated with high stresses in fluid that accelerates into the narrow gap between the cylinder and the channel wall; vortex growth upstream is reminiscent of that seen in microfluidic contraction geometries. Instability downstream of the cylinder is associated with stresses generated at the trailing stagnation point and the resulting flow modification in the wake, coupled with the onset of time-dependent flow upstream and the asymmetric division of flow around the cylinder.

  18. Mobilization and micellar solubilization of NAPL contaminants in aquifer rocks.

    PubMed

    Javanbakht, Gina; Goual, Lamia

    2016-01-01

    Surfactant-enhanced aquifer remediation is often performed to overcome the capillary forces that keep residual NAPL phases trapped within contaminated aquifers. The surfactant selection and displacement mechanism usually depend on the nature of NAPL constituents. For example, micellar solubilization is often used to cleanup DNAPLs from aquifers whereas mobilization is desirable in aquifers contaminated by LNAPLs. Although the majority of crude oils are LNAPLs, they often contain heavy organic macromolecules such as asphaltenes that are classified as DNAPLs. Asphaltenes contain surface-active components that tend to adsorb on rocks, altering their wettability. Previous studies revealed that surfactants that formed Winsor type III microemulsions could promote both mobilization and solubilization. However the extent by which these two mechanisms occur is still unclear, particularly in oil-contaminated aquifers. In this study we investigated the remediation of oil-contaminated aquifers using an environmentally friendly surfactant such as n-Dodecyl β-D-maltoside. Focus was given on asphaltenes to better understand the mechanisms of surfactant cleanup. Through phase behavior, spontaneous imbibition, dynamic interfacial tension and contact angle measurements, we showed that microemulsions formed by this surfactant are able to mobilize bulk NAPL (containing 9wt.% asphaltenes) in the porous rock and solubilize DNAPL (i.e., 4-6wt.% adsorbed asphaltenes) from the rock surface. Spontaneous imbibition tests, in particular, indicated that the ratio of mobilized to solubilized NAPL is about 6:1. Furthermore, aging the cores in NAPL beyond 3days allowed for more NAPL to be trapped in the large pores of the rock but did not alter the amount of asphaltenes adsorbed on the mineral surface.

  19. Stabilization of mitochondrial membrane potential prevents doxorubicin-induced cardiotoxicity in isolated rat heart

    SciTech Connect

    Montaigne, David; Marechal, Xavier; Baccouch, Riadh; Modine, Thomas; Preau, Sebastien; Zannis, Konstantinos; Marchetti, Philippe; Lancel, Steve; Neviere, Remi

    2010-05-01

    The present study was undertaken to examine the effects of doxorubicin on left ventricular function and cellular energy state in intact isolated hearts, and, to test whether inhibition of mitochondrial membrane potential dissipation would prevent doxorubicin-induced mitochondrial and myocardial dysfunction. Myocardial contractile performance and mitochondrial respiration were evaluated by left ventricular tension and its first derivatives and cardiac fiber respirometry, respectively. NADH levels, mitochondrial membrane potential and glucose uptake were monitored non-invasively via epicardial imaging of the left ventricular wall of Langendorff-perfused rat hearts. Heart performance was reduced in a time-dependent manner in isolated rat hearts perfused with Krebs-Henseleit solution containing 1 muM doxorubicin. Compared with controls, doxorubicin induced acute myocardial dysfunction (dF/dt{sub max} of 105 +- 8 mN/s in control hearts vs. 49 +- 7 mN/s in doxorubicin-treated hearts; *p < 0.05). In cardiac fibers prepared from perfused hearts, doxorubicin induced depression of mitochondrial respiration (respiratory control ratio of 4.0 +- 0.2 in control hearts vs. 2.2 +- 0.2 in doxorubicin-treated hearts; *p < 0.05) and cytochrome c oxidase kinetic activity (24 +- 1 muM cytochrome c/min/mg in control hearts vs. 14 +- 3 muM cytochrome c/min/mg in doxorubicin-treated hearts; *p < 0.05). Acute cardiotoxicity induced by doxorubicin was accompanied by NADH redox state, mitochondrial membrane potential, and glucose uptake reduction. Inhibition of mitochondrial permeability transition pore opening by cyclosporine A largely prevented mitochondrial membrane potential dissipation, cardiac energy state and dysfunction. These results suggest that in intact hearts an impairment of mitochondrial metabolism is involved in the development of doxorubicin cardiotoxicity.

  20. Modulation of Induced Cytotoxicity of Doxorubicin by Using Apoferritin and Liposomal Cages

    PubMed Central

    Gumulec, Jaromir; Fojtu, Michaela; Raudenska, Martina; Sztalmachova, Marketa; Skotakova, Anna; Vlachova, Jana; Skalickova, Sylvie; Nejdl, Lukas; Kopel, Pavel; Knopfova, Lucia; Adam, Vojtech; Kizek, Rene; Stiborova, Marie; Babula, Petr; Masarik, Michal

    2014-01-01

    Doxorubicin is an effective chemotherapeutic drug, however, its toxicity is a significant limitation in therapy. Encapsulation of doxorubicin inside liposomes or ferritin cages decreases cardiotoxicity while maintaining anticancer potency. We synthesized novel apoferritin- and liposome-encapsulated forms of doxorubicin (“Apodox” and “lip-8-dox”) and compared its toxicity with doxorubicin and Myocet on prostate cell lines. Three different prostatic cell lines PNT1A, 22Rv1, and LNCaP were chosen. The toxicity of the modified doxorubicin forms was compared to conventional doxorubicin using the MTT assay, real-time cell impedance-based cell growth method (RTCA), and flow cytometry. The efficiency of doxorubicin entrapment was 56% in apoferritin cages and 42% in the liposome carrier. The accuracy of the RTCA system was verified by flow-cytometric analysis of cell viability. The doxorubicin half maximal inhibition concentrations (IC50) were determined as 170.5, 234.0, and 169.0 nM for PNT1A, 22Rv1, and LNCaP, respectively by RTCA. Lip8-dox is less toxic on the non-tumor cell line PNT1A compared to doxorubicin, while still maintaining the toxicity to tumorous cell lines similar to doxorubicin or epirubicin (IC50 = 2076.7 nM for PNT1A vs. 935.3 and 729.0 nM for 22Rv1 and LNCaP). Apodox IC50 was determined as follows: 603.1, 1344.2, and 931.2 nM for PNT1A, 22Rv1, and LNCaP. PMID:25514405

  1. LC-MS/MS method development for quantification of doxorubicin and its metabolite 13-hydroxy doxorubicin in mice biological matrices: Application to a pharmaco-delivery study.

    PubMed

    Mazzucchelli, Serena; Ravelli, Alessandro; Gigli, Fausto; Minoli, Mauro; Corsi, Fabio; Ciuffreda, Pierangela; Ottria, Roberta

    2017-04-01

    This study describes the development of simple, rapid and sensitive liquid chromatography tandem mass spectrometry method for the simultaneous analysis of doxorubicin and its major metabolite, doxorubicinol, in mouse plasma, urine and tissues. The calibration curves were linear over the range 5-250 ng/mL for doxorubicin and 1.25-25 ng/mL for doxorubicinol in plasma and tumor, over the range 25-500 ng/mL for doxorubicin and 1.25-25 ng/mL for doxorubicinol in liver and kidney, and over the range 25-1000 ng/mL for doxorubicin and doxorubicinol in urine. The study was validated, using quality control samples prepared in all different matrices, for accuracy, precision, linearity, selectivity, lower limit of quantification and recovery in accordance with the US Food & Drug Administration guidelines. The method was successfully applied in determining the pharmaco-distribution of doxorubicin and doxorubicinol after intravenously administration in tumor-bearing mice of drug, free or nano-formulated in ferritin nanoparticles or in liposomes. Obtained results demonstrate an effective different distribution and doxorubicin protection against metabolism linked to nano-formulation. This method, thanks to its validation in plasma and urine, could be a powerful tool for pharmaceutical research and therapeutic drug monitoring, which is a clinical approach currently used in the optimization of oncologic treatments.

  2. Fabrication of doxorubicin nanoparticles by controlled antisolvent precipitation for enhanced intracellular delivery.

    PubMed

    Tam, Yu Tong; To, Kenneth Kin Wah; Chow, Albert Hee Lum

    2016-03-01

    Over-expression of ATP-binding cassette transporters is one of the most important mechanisms responsible for multidrug resistance. Here, we aimed to develop a stable polymeric nanoparticle system by flash nanoprecipitation (FNP) for enhanced anticancer drug delivery into drug resistant cancer cells. As an antisolvent precipitation process, FNP works best for highly lipophilic solutes (logP>6). Thus we also aimed to evaluate the applicability of FNP to drugs with relatively low lipophilicity (logP=1-2). To this end, doxorubicin (DOX), an anthracycline anticancer agent and a P-gp substrate with a logP of 1.3, was selected as a model drug for the assessment. DOX was successfully incorporated into the amphiphilic diblock copolymer, polyethylene glycol-b-polylactic acid (PEG-b-PLA), by FNP using a four-stream multi-inlet vortex mixer. Optimization of key processing parameters and co-formulation with the co-stabilizer, polyvinylpyrrolidone, yielded highly stable, roughly spherical DOX-loaded PEG-b-PLA nanoparticles (DOX.NP) with mean particle size below 100nm, drug loading up to 14%, and drug encapsulation efficiency up to 49%. DOX.NP exhibited a pH-dependent drug release profile with higher cumulative release rate at acidic pHs. Surface analysis of DOX.NP by XPS revealed an absence of DOX on the particle surface, indicative of complete drug encapsulation. While there were no significant differences in cytotoxic effect on P-gp over-expressing LCC6/MDR cell line between DOX.NP and free DOX in buffered aqueous media, DOX.NP exhibited a considerably higher cellular uptake and intracellular retention after efflux. The apparent lack of cytotoxicity enhancement with DOX.NP may be attributable to its slow DOX release inside the cells.

  3. Hierarchical self-assembly: Self-organized nanostructures in a nematically ordered matrix of self-assembled polymeric chains

    NASA Astrophysics Data System (ADS)

    Mubeena, Shaikh; Chatterji, Apratim

    2015-03-01

    We report many different nanostructures which are formed when model nanoparticles of different sizes (diameter σn) are allowed to aggregate in a background matrix of semiflexible self-assembled polymeric wormlike micellar chains. The different nanostructures are formed by the dynamical arrest of phase-separating mixtures of micellar monomers and nanoparticles. The different morphologies obtained are the result of an interplay of the available free volume, the elastic energy of deformation of polymers, the density (chemical potential) of the nanoparticles in the polymer matrix, and, of course, the ratio of the size of self-assembling nanoparticles and self-avoidance diameter of polymeric chains. We have used a hybrid semi-grand-canonical Monte Carlo simulation scheme to obtain the (nonequilibrium) phase diagram of the self-assembled nanostructures. We observe rodlike structures of nanoparticles which get self-assembled in the gaps between the nematically ordered chains, as well as percolating gel-like network of conjoined nanotubes. We also find a totally unexpected interlocked crystalline phase of nanoparticles and monomers, in which each crystal plane of nanoparticles is separated by planes of perfectly organized polymer chains. We identified the condition which leads to such interlocked crystal structure. We suggest experimental possibilities of how the results presented in this paper could be used to obtain different nanostructures in the laboratory.

  4. Hierarchical self-assembly: Self-organized nanostructures in a nematically ordered matrix of self-assembled polymeric chains.

    PubMed

    Mubeena, Shaikh; Chatterji, Apratim

    2015-03-01

    We report many different nanostructures which are formed when model nanoparticles of different sizes (diameter σn) are allowed to aggregate in a background matrix of semiflexible self-assembled polymeric wormlike micellar chains. The different nanostructures are formed by the dynamical arrest of phase-separating mixtures of micellar monomers and nanoparticles. The different morphologies obtained are the result of an interplay of the available free volume, the elastic energy of deformation of polymers, the density (chemical potential) of the nanoparticles in the polymer matrix, and, of course, the ratio of the size of self-assembling nanoparticles and self-avoidance diameter of polymeric chains. We have used a hybrid semi-grand-canonical Monte Carlo simulation scheme to obtain the (nonequilibrium) phase diagram of the self-assembled nanostructures. We observe rodlike structures of nanoparticles which get self-assembled in the gaps between the nematically ordered chains, as well as percolating gel-like network of conjoined nanotubes. We also find a totally unexpected interlocked crystalline phase of nanoparticles and monomers, in which each crystal plane of nanoparticles is separated by planes of perfectly organized polymer chains. We identified the condition which leads to such interlocked crystal structure. We suggest experimental possibilities of how the results presented in this paper could be used to obtain different nanostructures in the laboratory.

  5. Dietary fat composition, food matrix and relative polarity modulate the micellarization and intestinal uptake of carotenoids from vegetables and fruits.

    PubMed

    Mashurabad, Purna Chandra; Palika, Ravindranadh; Jyrwa, Yvette Wilda; Bhaskarachary, K; Pullakhandam, Raghu

    2017-02-01

    Dietary fat increases carotenoid bioavailability by facilitating their transfer to the aqueous micellar fraction during digestion. However, the specific effect of both quantity and type of dietary fat required for optimal carotenoid absorption remained unexplored. In the present study, the effect of amount and type of vegetable oils on carotenoid micellarization from carrot, spinach, drumstick leaves and papaya using in vitro digestion/Caco-2 cell model have been assessed. Although, dietary fat (0.5-10% w/w) significantly increased the micellarization of carotenoids from all the test foods, the extent of increase was determined by the food matrix (papaya > drumstick = spinach > carrot) and polarity of carotenoids (lutein > β-carotene = α-carotene > lycopene). Among the dietary fats tested the carotenoid micellarization was twofold to threefold higher with dietary fat rich in unsaturated fatty acids (olive oil = soybean oil = sunflower oil) compared to saturated fatty acids (peanut oil = palm oil > coconut oil). Intestinal cell uptake of lutein exceeded that of β-carotene from micellar fraction of spinach leaves digested with various oils. However, cellular uptake of β-carotene is depended on the carotenoid content in micellar fraction rather than the type of fat used. Together these results suggest that food matrix, polarity of carotenoids and type of dietary fat determines the extent of carotenoid micellarization from vegetables and fruits.

  6. Solute-solvent interactions in micellar electrokinetic chromatography. 6. Optimization of the selectivity of lithium dodecyl sulfate-lithium perfluorooctanesulfonate mixed micellar buffers.

    PubMed

    Fuguet, Elisabet; Ràfols, Clara; Torres-Lapasió, José Ramón; García-Alvarez-Coque, María Celia; Bosch, Elisabeth; Rosés, Martí

    2002-09-01

    The optimization of the composition of mixed surfactants used as micellar electrokinetic chromatography (MEKC) pseudostationary phases is proposed as an effective method for the separation of complex mixtures of analytes. The solvation parameter model is used to select two surfactants (lithium dodecyl sulfate, LDS, and lithium perfluorooctanesulfonate, LPFOS) with contrasting solvation properties. Combination of these two surfactants allows variations of the solvation properties of MEKC pseudostationary phase along a wide range. Thus, the convenient variation of the proportion of both surfactants allows an effective control of the selectivity in such systems. An algorithm that predicts the overall resolution of a given mixture of compounds is described and applied to optimize the composition of the mixed surfactant for the separation of the mixture. The algorithm is based on the calculation of peak purities on simulated chromatograms as a function of the composition of the mixed LDS/LPFOS micellar buffer from data at several micellar buffer compositions. Successful separations were achieved for mixtures containing up to 20 compounds, in less than 12 min.

  7. Determination of selected synthetic cannabinoids and their metabolites by micellar electrokinetic chromatography--mass spectrometry employing perfluoroheptanoic acid-based micellar phase.

    PubMed

    Švidrnoch, Martin; Přibylka, Adam; Maier, Vítězslav

    2016-04-01

    Perfluoroheptanoic acid was employed as a volatile micellar phase in background electrolyte for micellar electrokinetic chromatography-tandem mass spectrometry separation and determination of 15 selected naphthoyl- and phenylacetylindole- synthetic cannabinoids and main metabolites derived from JWH-018, JWH-019, JWH-073, JWH-200 and JWH-250. The influence of concentration of perfluoroheptanoic acid in background electrolytes on the separation was studied as well as the influence of perfluoroheptanoic acid on mass spectrometry detection. The background electrolyte consisted of 75 mM perfluoroheptanoic acid, 150 mM ammonium hydroxide pH 9.2 with 10% (v/v) propane-2-ol allowed micellar electrokinetic chromatography separation together with mass spectrometry identification of the studied parent synthetic cannabinoids and their metabolites. The limits of detection of studied synthetic cannabinoids and metabolites were in the range from 0.9 ng/mL for JWH-073 to 3.0 ng/mL for JWH-200 employing liquid-liquid extraction. The developed method was applied on the separation and identification of studied analytes after liquid-liquid extraction of spiked urine and serum samples to demonstrate the potential of the method applicability for forensic and toxicological purposes.

  8. Electron spin echo modulation study of sodium dodecyl sulfate and dodecyltrimethylammonium bromide micellar solutions in the presence of urea: Evidence for urea interaction at the micellar surface

    SciTech Connect

    Baglioni, P. ); Ferroni, E. ); Kevan, L. )

    1990-05-17

    Electron spin echo studies have been carried out for a series of x-doxylstearic acid (x-DSA, x = 5,7,10,12,16) and 4-octanoyl-2,2,6,6-tetramethylpiperidine-1-oxy (C{sub 8}-TEMPO) spin probes in micellar solutions of anionic sodium dodecyl sulfate (SDS) and cationic dodecyltrimethylammonium bromide (DTAB) in D{sub 2}O and in the presence of 2 or 6 M urea or urea-d{sub 4}. Modulation effects due to the interaction of the unpaired electron with urea and water deuteriums show that urea does not affect the bent conformation of the x-DSA probe in the micelle. The analysis of the deuterium modulation depth and the Fourier transformation of the two-pulse electron spin echo spectra show that urea interacts with the surfactant polar headgroups at the micelle surface. These results support recent molecular dynamics and Monte Carlo calculations of micellar systems and are in agreement with direct interaction of urea at micellar surfaces in which it replaces some water molecules in the surface region.

  9. Preparation and characterization of solid lipid nanoparticles loaded with doxorubicin.

    PubMed

    Subedi, Robhash Kusam; Kang, Keon Wook; Choi, Hoo-Kyun

    2009-06-28

    Solid lipid nanoparticles (SLN) loaded with doxorubicin were prepared by solvent emulsification-diffusion method. Glyceryl caprate (Capmul)MCM C10) was used as lipid core, and curdlan as the shell material. Dimethyl sulfoxide (DMSO) was used to dissolve both lipid and drug. Polyethylene glycol 660 hydroxystearate (Solutol)HS15) was employed as surfactant. Major formulation parameters were optimized to obtain high quality nanoparticles. The mean particle size measured by photon correlation spectroscopy (PCS) was 199nm. The entrapment efficiency (EE) and drug loading capacity (DL), determined with fluorescence spectroscopy, were 67.5+/-2.4% and 2.8+/-0.1%, respectively. The drug release behavior was studied by in vitro method. Cell viability assay showed that properties of SLN remain unchanged during the process of freeze-drying. Stability study revealed that lyophilized SLN were equally effective (p<0.05) after 1 year of storage at 4 degrees C. In conclusion, SLN with small particle size, high EE, and relatively high DL for doxorubicin can be obtained by this method.

  10. Glucocorticoid Induced Leucine Zipper inhibits apoptosis of cardiomyocytes by doxorubicin

    SciTech Connect

    Aguilar, David; Strom, Joshua; Chen, Qin M.

    2014-04-01

    Doxorubicin (Dox) is an indispensable chemotherapeutic agent for the treatment of various forms of neoplasia such as lung, breast, ovarian, and bladder cancers. Cardiotoxicity is a major concern for patients receiving Dox therapy. Previous work from our laboratory indicated that glucocorticoids (GCs) alleviate Dox-induced apoptosis in cardiomyocytes. Here we have found Glucocorticoid-Induced Leucine Zipper (GILZ) to be a mediator of GC-induced cytoprotection. GILZ was found to be induced in cardiomyocytes by GC treatment. Knocking down of GILZ using siRNA resulted in cancelation of GC-induced cytoprotection against apoptosis by Dox treatment. Overexpressing GILZ by transfection was able to protect cells from apoptosis induced by Dox as measured by caspase activation, Annexin V binding and morphologic changes. Western blot analyses indicate that GILZ overexpression prevented cytochrome c release from mitochondria and cleavage of caspase-3. When bcl-2 family proteins were examined, we found that GILZ overexpression causes induction of the pro-survival protein Bcl-xL. Since siRNA against Bcl-xL reverses GC induced cytoprotection, Bcl-xL induction represents an important event in GILZ-induced cytoprotection. Our data suggest that GILZ functions as a cytoprotective gene in cardiomyocytes. - Highlights: • Corticosteroids act as a cytoprotective agent in cardiomyocytes • Corticosteroids induce GILZ expression in cardiomyocytes • Elevated GILZ results in resistance against apoptosis induced by doxorubicin • GILZ induces Bcl-xL protein without inducing Bcl-xL mRNA.

  11. Fullerenol nanoparticles prevents doxorubicin-induced acute hepatotoxicity in rats.

    PubMed

    Jacevic, Vesna; Djordjevic, Aleksandar; Srdjenovic, Branislava; Milic-Tores, Vukosava; Segrt, Zoran; Dragojevic-Simic, Viktorija; Kuca, Kamil

    2017-03-16

    Doxorubicin (DOX), commonly used antineoplastic agent, affects bone marrow, intestinal tract and heart, but it also has some hepatotoxic effects. Main mechanism of its toxicity is the production of free reactive oxygen species. Polyhidroxilated C60 fullerene derivatives, fullerenol nanoparticles (FNP), act as free radical scavengers in in vitro systems. The aim of the study was to investigate potential FNP protective role against DOX-induced hepatotoxicity in rats. Experiments were performed on adult male Wistar rats. Animals were divided into five groups: (1) 0.9% NaCl (control), (2) 100mg/kg ip FNP, (3) 10mg/kg DOX iv, (4) 50mg/kg ip FNP 30min before 10mg/kg iv DOX, (5) 100mg/kg ip FNP 30min before 10mg/kg iv DOX. A general health condition, body and liver weight, TBARS level and antioxidative enzyme activity, as well as pathohistological examination of the liver tissue were conducted on days 2 and 14 of the study. FNP, applied alone, did not alter any examinated parameters. However, when used as a pretreatment it significantly increased survival rate, body and liver weight, and decreased TBARS level, antioxidative enzyme activity and hepatic damage score in DOX-treated rats. FNP administered at a dose of 100mg/kg significantly attenuated effects of doxorubicin administered in a single high dose in rats, concerning general condition, body and liver weight, lipid peroxidation level and antioxidative enzyme activity as well as structural alterations of the hepatic tissue.

  12. Magnesium Modulates Doxorubicin Activity through Drug Lysosomal Sequestration and Trafficking.

    PubMed

    Trapani, Valentina; Luongo, Francesca; Arduini, Daniela; Wolf, Federica I

    2016-03-21

    Magnesium is directly involved in the control of cell growth and survival, but its role in cancer biology and therapy is multifaceted; in particular, it is highly controversial whether magnesium levels can affect therapy outcomes. Here we investigated whether magnesium availability can modulate cellular responses to the widely used chemotherapeutic doxorubicin. We used an in vitro model consisting of mammary epithelial HC11 cells and found that high magnesium availability was correlated with diminished sensitivity both in cells chronically adapted to high magnesium concentrations and in acutely magnesium-supplemented cells. This decrease in sensitivity resulted from reduced intracellular doxorubicin accumulation in the face of a similar drug uptake rate. We observed that high-magnesium conditions caused a decrease in intracellular drug retention by altering drug lysosomal sequestration and trafficking. In our model, magnesium supplementation correspondingly modulated expression of the TRPM7 channel, which is known to control cytoskeletal organization and dynamics and may be involved in the proposed mechanism. Our findings suggest that magnesium supplementation in hypomagnesemic cancer patients may hinder response to therapy.

  13. Essential Oil from Myrica rubra Leaves Potentiated Antiproliferative and Prooxidative Effect of Doxorubicin and its Accumulation in Intestinal Cancer Cells.

    PubMed

    Ambrož, Martin; Hanušová, Veronika; Skarka, Adam; Boušová, Iva; Králová, Věra; Langhasová, Lenka; Skálová, Lenka

    2016-01-01

    Essential oil from the leaves of Myrica rubra, a subtropical Asian fruit tree traditionally used in folk medicines, has a significant antiproliferative effect in several intestinal cancer cell lines. Doxorubicin belongs to the most important cytostatics used in cancer therapy. The present study was designed to evaluate the effects of defined essential oil from M. rubra leaves on efficacy, prooxidative effect, and accumulation of doxorubicin in cancer cell lines and in non-cancerous cells. For this purpose, intestinal adenocarcinoma CaCo2 cells were used. Human fibroblasts (periodontal ligament) and a primary culture of rat hepatocytes served as models of non-cancerous cells. The results showed that the sole essential oil from M. rubra has a strong prooxidative effect in cancer cells while it acts as a mild antioxidant in hepatocytes. Combined with doxorubicin, the essential oil enhanced the antiproliferative and prooxidative effects of doxorubicin in cancer cells. At higher concentrations, synergism of doxorubicin and essential oil from M. rubra was proved. In non-cancerous cells, the essential oil did not affect the toxicity of doxorubicin and the doxorubicin-mediated reactive oxygen species formation. The essential oil increased the intracellular concentration of doxorubicin and enhanced selectively the doxorubicin accumulation in nuclei of cancer cells. Taken together, essential oil from M. rubra leaves could be able to improve the doxorubicin efficacy in cancer cells due to an increased reactive oxygen species production, and the doxorubicin accumulation in nuclei of cancer cells.

  14. Doxorubicin as a molecular nanotheranostic agent: effect of doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound-mediated intracellular delivery and nuclear trafficking

    PubMed Central

    Mohan, Praveena; Rapoport, Natalya

    2010-01-01

    Doxorubicin (DOX) is one of the most commonly used chemotherapeutic drugs and a popular research tool due to the inherent fluorescence of the DOX molecule. After DOX injection, fluorescence imaging of organs or cells can provide information on drug biodistribution. Therapeutic and imaging capabilities combined in a DOX molecule make it an excellent theranostic agent. However, DOX fluorescence depends on a number of factors that should be taken into consideration when interpreting results of DOX fluorescence measurements. Discussing these problems is the main thrust of the current paper. The sensitivity of DOX fluorescence intensity to DOX concentration, local microenvironment, and interaction with model cellular components is illustrated by fluorescence spectra of paired DOX/phosphilipid, DOX/histone, DOX/DNA, and triple DOX/histone/DNA and DOX/phospholipid/DNA systems. DOX fluorescence is dramatically quenched upon intercalation into the DNA; DOX fluorescence is also self-quenched at high concentrations of molecularly dissolved DOX; in contrast, DOX fluorescence is increased after binding to the histone or partitioning into the phospholipid phase of PEG-phospholipid micelles or hydrophobic cores of polymeric micelles. While flow cytometry is commonly used for characterization of DOX intracellular uptake, the above aspects of DOX fluorescence may significantly complicate interpretation of flow cytometry results. High cell fluorescence measured by flow cytometry may provide deceptive information on the actual intracellular DOX concentration and may not correlate with the therapeutic efficacy if DOX does not penetrate into the site of action in cell nuclei. These problems are illustrated in the experiments on the intracellular trafficking of DOX encapsulated in poly(ethylene oxide)-co-polycaprolactone (PEG-PCL) micelles or PEG-PCL stabilized perfluorocarbon nanodroplets, with and without the application of ultrasound used as an external trigger. For efficient

  15. SANS study of the micellar structure of PEO/PPO/PEO aqueous solution

    SciTech Connect

    Wu, G.; Chu, B.; Schneider, D.K.

    1995-04-06

    Small-angle neutron scattering (SANS) was used to investigate the micellar structure formed by a poly(oxyethylene-oxypropylene-oxyethylene) (PEO{sub 13}PPO{sub 30}PEO{sub 13}, Pluronic L64) copolymer in D{sub 2}O over a temperature range of 8.4-35.0{degree}C. The intermicellar interactions were corrected by using an equivalent hard sphere approximation with an equivalent hard sphere radius. The aggregation number of the micelles decreased with decreasing temperature. The micellar scattering behavior could be well described by a core-shell structure. Based on the core-shell model, the volume fraction of the polymer segments in the micellar shell was less than 0.2. The micellar molar mass became larger after having introduced an organic solvent (xylene) into the system and increased with increasing amount of solubilized xylene. The maximum amount of solubilized xylene in the micelle was of the order of 0.3-0.4 xylene molecule per PO unit. 35 refs., 7 figs., 3 tabs.

  16. Deracemization of bilirubin as the marker of the chirality of micellar aggregates.

    PubMed

    Sorrenti, Alessandro; Altieri, Barbara; Ceccacci, Francesca; Di Profio, Pietro; Germani, Raimondo; Giansanti, Luisa; Savelli, Gianfranco; Mancini, Giovanna

    2012-01-01

    The deracemization of bilirubin in micellar aggregates of structurally correlated chiral surfactants was studied by circular dichroism experiments and exploited as the marker of the expression of chirality of the aggregates. The obtained results suggest that the hydrophobic interactions control the transfer of chirality from the monomers to the aggregates, and that different regions of the same aggregate might feature opposite enantiorecognition capabilities.

  17. Observation of an unprecedented body centered cubic micellar mesophase from rod-coil molecules.

    PubMed

    Lee, Eunji; Ryu, Ja-Hyoung; Park, Myoung-Hwan; Lee, Myongsoo; Han, Kyung-Hee; Chung, Yeon-Wook; Cho, Byoung-Ki

    2007-07-28

    We have demonstrated that rod-coil molecules based on a tetra-p-phenylene rod and a poly(propylene oxide) coil self-assemble into an unprecedented body centered cubic micellar structure in the melt, through detailed morphological analysis by X-ray scattering and transmission electron microscopy experiments.

  18. Accelerating Strain-Promoted Azide-Alkyne Cycloaddition Using Micellar Catalysis.

    PubMed

    Anderton, Grant I; Bangerter, Alyssa S; Davis, Tyson C; Feng, Zhiyuan; Furtak, Aric J; Larsen, Jared O; Scroggin, Triniti L; Heemstra, Jennifer M

    2015-08-19

    Bioorthogonal conjugation reactions such as strain-promoted azide-alkyne cycloaddition (SPAAC) have become increasingly popular in recent years, as they enable site-specific labeling of complex biomolecules. However, despite a number of improvements to cyclooctyne design, reaction rates for SPAAC remain significantly lower than those of the related copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Here we explore micellar catalysis as a means to increase reaction rate between a cyclooctyne and hydrophobic azide. We find that anionic and cationic surfactants provide the most efficient catalysis, with rate enhancements of up to 179-fold for reaction of benzyl azide with DIBAC cyclooctyne. Additionally, we find that the presence of surfactant can provide up to 51-fold selectivity for reaction with a hydrophobic over hydrophilic azide. A more modest, but still substantial, 11-fold rate enhancement is observed for micellar catalysis of the reaction between benzyl azide and a DIBAC-functionalized DNA sequence, demonstrating that micellar catalysis can be successfully applied to hydrophilic biomolecules. Together, these results demonstrate that micellar catalysis can provide higher conjugation yields in reduced time when using hydrophobic SPAAC reagents.

  19. Bioavailability of mixtures of PAHs partitioned into the micellar phase of a nonionic surfactant

    SciTech Connect

    Guha, S.; Jaffe, P.R.; Peters, C.A.

    1998-08-01

    This study extends the understanding of the bioavailability of the micellar phase for a single compound to a multicomponent system of contaminants. Biodegradation experiments were conducted with binary and ternary mixtures of naphthalene, phenanthrene, and pyrene in the presence of a nonionic surfactant, Triton X-100. A mixed bacterial culture, isolated and enriched from a PAH-contaminated soil at the Wurstsmith Air Force Base, MI, was used for the biodegradation experiments. In the absence of the surfactant and at surfactant concentrations below cmc, the multisubstrate Monod kinetics adequately simulated the biodegradation kinetics of the binary and ternary mixtures. In the multicomponent systems, as in single solute systems, the solutes in the micelle were found to be directly bioavailable, and the bioavailability of each compound in the micellar phase decreased with increasing surfactant concentration. For a given surfactant concentration, the bioavailability was higher for the lower molecular weight PAHs. There was little difference in the bioavailability of the same compound as a dingle solute or in different binary and ternary mixtures. To predict the bioavailability of the micellar phase substrates, a mass transfer-based model was formulated that describes the transfer of substrate from the micellar phase to the microorganisms. The predictions matched the experimental observations well, indicating the validity of the model and its potential for applications in remediation designs.

  20. [Solubilization of nitrobenzene in micellar solutions of Tween 80 and inorganic salts].

    PubMed

    Li, Sui; Zhao, Yong-sheng; Xu, Wei; Dai, Ning

    2008-04-01

    The solubilization of nitrobenzene by a nonionic surfactant Tween 80 was investigated at 10 degrees C. Experimental results indicated that the solubility of nitrobenzene in water was greatly enhanced by Tween 80 at surfactant concentration above CMC(critical micelle concentration) and a linear relationship was obtained between surfactant concentration and nitrobenzene concentration from the solubility curve. The molar solubilization ratio (MSR) value was 5.093 and IgKm was 3.499. The solubilization was attributed to the ethoxylation group in Tween 80 micellar. Effect of four inorganic salts such as NaCl, KCl, CaCl2 , MgCl2 on water solubilities of nitrobenzene in Tween 80 micellar solutions was also investigated by a matrix of batch experiments. Mix the Tween 80-inorganic salts at the total mass ratios of 2:1, 5:1 and 10:1. The results show that the inorganic salts at a high concentration( > or = 500 mg x L(-1)) can enhance the solubilization capacities of Tween 80 micellar solution and increase the value of MSR and IgKm . Because of the salting-out effect between the micellar of Tween 80 and inorganic salts, the volume of micelle turns bigger, which may provide larger solubility volume for nitrobenzene. The mixture of nonionic surfactant and inorganic salts can be used in subsurface remediation as a flushing solution.

  1. Hafnocene-Based Olefin Polymerizations

    NASA Astrophysics Data System (ADS)

    Diesner, T.; Troll, C.; Rieger, B.

    Zirconocenes have been used for a long time in the field of olefin polymerization using MAO as cocatalyst. The equivalent hafnocenes were seldom used due to a lack of productivity while using MAO activation. In the last few years borane and borate activation has come into the focus of research for olefin polymerization. A variety of different hafnocenes were used to investigate the polymerization mechanism and the different cocatalysts.

  2. Self-assemblies of pH-activatable PEGylated multiarm poly(lactic acid-co-glycolic acid)-doxorubicin prodrugs with improved long-term antitumor efficacies.

    PubMed

    Ding, Jianxun; Li, Di; Zhuang, Xiuli; Chen, Xuesi

    2013-10-01

    Two pH-activatable star-shaped prodrugs are synthesized through the condensation reaction between Y- or dumbbell-shaped poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PEG-PLGA) copolymer and acid-sensitive cis-aconityl-doxorubicin. The prodrugs self-assemble into micelles with favorable hydrodynamic radii and relatively low critical micelle concentrations. In vitro DOX release from prodrug micelles is accelerated by the decrease of the PLGA content or at the late endosomal pH. The efficient cellular uptake and intracellular DOX release of the prodrug micelles are confirmed and the improved long-term anti-proliferative activities of prodrug micelles are revealed. These features suggest that the prodrugs provide a favorable approach to construct effective polymeric drug delivery systems for malignancy therapy.

  3. Bimorphic polymeric photomechanical actuator

    NASA Technical Reports Server (NTRS)

    Sarkisov, Sergey S. (Inventor); Curley, Michael J. (Inventor); Adamovsky, Grigory (Inventor); Sarkisov, Jr., Sergey S. (Inventor); Fields, Aisha B. (Inventor)

    2006-01-01

    A bimorphic polymeric photomechanical actuator, in one embodiment using polyvinylidene fluoride (PVDF) as a photosensitive body, transmitting light over fiber optic cables, and controlling the shape and pulse duration of the light pulse to control movement of the actuator. Multiple light beams are utilized to generate different ranges of motion for the actuator from a single photomechanical body and alternative designs use multiple light beams and multiple photomechanical bodies to provide controlled movement. Actuator movement using one or more ranges of motion is utilized to control motion to position an actuating element in three dimensional space.

  4. Living olefin polymerization processes

    DOEpatents

    Schrock, R.R.; Baumann, R.

    1999-03-30

    Processes for the living polymerization of olefin monomers with terminal carbon-carbon double bonds are disclosed. The processes employ initiators that include a metal atom and a ligand having two group 15 atoms and a group 16 atom or three group 15 atoms. The ligand is bonded to the metal atom through two anionic or covalent bonds and a dative bond. The initiators are particularly stable under reaction conditions in the absence of olefin monomer. The processes provide polymers having low polydispersities, especially block copolymers having low polydispersities. It is an additional advantage of these processes that, during block copolymer synthesis, a relatively small amount of homopolymer is formed.

  5. Living olefin polymerization processes

    DOEpatents

    Schrock, Richard R.; Baumann, Robert

    1999-01-01

    Processes for the living polymerization of olefin monomers with terminal carbon-carbon double bonds are disclosed. The processes employ initiators that include a metal atom and a ligand having two group 15 atoms and a group 16 atom or three group 15 atoms. The ligand is bonded to the metal atom through two anionic or covalent bonds and a dative bond. The initiators are particularly stable under reaction conditions in the absence of olefin monomer. The processes provide polymers having low polydispersities, especially block copolymers having low polydispersities. It is an additional advantage of these processes that, during block copolymer synthesis, a relatively small amount of homopolymer is formed.

  6. Living olefin polymerization processes

    DOEpatents

    Schrock, Richard R.; Baumann, Robert

    2003-08-26

    Processes for the living polymerization of olefin monomers with terminal carbon-carbon double bonds are disclosed. The processes employ initiators that include a metal atom and a ligand having two group 15 atoms and a group 16 atom or three group 15 atoms. The ligand is bonded to the metal atom through two anionic or covalent bonds and a dative bond. The initiators are particularly stable under reaction conditions in the absence of olefin monomer. The processes provide polymers having low polydispersities, especially block copolymers having low polydispersities. It is an additional advantage of these processes that, during block copolymer synthesis, a relatively small amount of homopolymer is formed.

  7. Living olefin polymerization processes

    DOEpatents

    Schrock, Richard R.; Bauman, Robert

    2006-11-14

    Processes for the living polymerization of olefin monomers with terminal carbon-carbon double bonds are disclosed. The processes employ initiators that include a metal atom and a ligand having two group 15 atoms and a group 16 atom or three group 15 atoms. The ligand is bonded to the metal atom through two anionic or covalent bonds and a dative bond. The initiators are particularly stable under reaction conditions in the absence of olefin monomer. The processes provide polymers having low polydispersities, especially block copolymers having low polydispersities. It is an additional advantage of these processes that, during block copolymer synthesis, a relatively small amount of homopolymer is formed.

  8. Polymerization Evaluation by Spectrophotometric Measurements.

    ERIC Educational Resources Information Center

    Dunach, Jaume

    1985-01-01

    Discusses polymerization evaluation by spectrophotometric measurements by considering: (1) association degrees and molar absorptivities; (2) association degrees and equilibrium constants; and (3) absorbance and equilibrium constants. (JN)

  9. Sustainable polymerizations in recoverable microemulsions.

    PubMed

    Chen, Zhenzhen; Yan, Feng; Qiu, Lihua; Lu, Jianmei; Zhou, Yinxia; Chen, Jiaxin; Tang, Yishan; Texter, John

    2010-03-16

    Free radical and atom-transfer radical polymerizations were conducted in monomer/ionic liquid microemulsions. After the polymerization and isolation of the resultant polymers, the mixture of the catalyst and ionic liquids (surfactant and continuous phase) can be recovered and reused, thereby dramatically improving the environmental sustainability of such chemical processing. The addition of monomer to recovered ionic liquid mixtures regenerates transparent, stable microemulsions that are ready for the next polymerization cycle upon addition of initiator. The method combines the advantages of IL recycling and microemulsion polymerization and minimizes environmental disposable effects from surfactants and heavy metal ions.

  10. Tween 20 increases intestinal transport of doxorubicin in vitro but not in vivo.

    PubMed

    Al-Saraf, Amal; Holm, René; Nielsen, Carsten Uhd

    2016-02-10

    The chemotherapeutic drug substance doxorubicin has been reported to be a substrate of P-gp, which induces a barrier for oral administration and leads to a bioavailability of 3% in male Sprague Dawley rats. Literature studies have reported increased transport of P-pg substrates, like digoxin, when co-administered with P-gp inhibitors (non-ionic surfactants) in vitro and in vivo . The aim of the present study was thus to investigate if different non-ionic surfactants would have a similar effect on the in vitro and in vivo absorption of doxorubicin. This was investigated in vitro in Caco-2 cells and by oral co-administration of doxorubicin together with tween 20 to male Sprague Dawley rats. 200 μM (0.025%) tween 20 increased the intestinal absorptive permeability of doxorubicin in vitro by 48 ± 4% from 8.8 × 10(-6)cm/s to 13.0 × 10(-6)cm/s. Further, the efflux ratio was reduced from 2.2 ± 0.06 to 1.2 ± 0.03 (n=3-7). In vivo, co-administration of doxorubicin and 0-25% tween 20 did not yield detectable doxorubicin plasma concentrations, probably due to extensive intestinal metabolism. In conclusion, the present study demonstrated that non-ionic surfactants increased the transport of doxorubicin in vitro, most likely by inhibition of the efflux activity. However, this effect was not transferable to the in vivo situation.

  11. DNA methyltransferase I is a mediator of doxorubicin-induced genotoxicity in human cancer cells

    SciTech Connect

    Tan, Hwee Hong; Porter, Alan George

    2009-05-01

    Doxorubicin can induce the formation of extra-nuclear bodies during mitosis termed micronuclei but the underlying causes remain unknown. Here, we show that sub-lethal exposure to doxorubicin-induced micronuclei formation in human cancer cells but not in non-tumorigenic cells. Occurrence of micronuclei coincided with stability of DNMT1 upon doxorubicin assault, and DNMT1 was localized to the micronuclei structures. Furthermore, 5-aza-2'-deoxycytidine-mediated DNMT1 depletion or siDNMT1 knock-down attenuated the frequency of doxorubicin-induced micronucleated cells. Human DNMT1{sup -/-} cells displayed significantly fewer micronuclei compared to DNMT1{sup +/+} cells when challenged with doxorubicin, providing additional evidence for the involvement of DNMT1 in mediating such chromosomal aberrations. Collectively, our results demonstrate a role for DNMT1 in promoting DNA damage-induced genotoxicity in human cancer cells. DNMT1, recently identified as a candidate for doxorubicin-mediated cytotoxicity, is over-expressed in various cancer cell types. We propose that DNMT1 levels in tumor cells may determine the effectiveness of doxorubicin in chemotherapy.

  12. Temozolomide reverses doxorubicin resistance by inhibiting P-glycoprotein in malignant glioma cells.

    PubMed

    Zhang, Rong; Saito, Ryuta; Shibahara, Ichiyo; Sugiyama, Shinichiro; Kanamori, Masayuki; Sonoda, Yukihiko; Tominaga, Teiji

    2016-01-01

    Temozolomide is a standard chemotherapy agent for malignant gliomas, but the efficacy is still not satisfactory. Therefore, combination chemotherapy using temozolomide with other anti-tumor compounds is now under investigation. Here we studied the mechanism of the synergistic anti-tumor effect achieved by temozolomide and doxorubicin, and elucidated the inhibitory effect of temozolomide on P-glycoprotein (P-gp). Temozolomide significantly enhanced sensitivity to P-gp substrate in glioma cells, particularly in P-gp-overexpressed cells. Synergetic effects, as determined by isobologram analysis, were observed by combining temozolomide and doxorubicin. Subsequently, flow cytometry was utilized to assess the intracellular retention of doxorubicin in cells treated with doxorubicin with or without temozolomide. Temozolomide significantly increased the accumulation of doxorubicin in these cells. The P-gp adenosine triphosphatase (ATPase) assay showed that temozolomide inhibited the ATPase activity of P-gp. In addition, temozolomide combined with doxorubicin significantly prolonged the survival of 9L intracranial allografted glioma-bearing rats compared to single agent treatment. Collectively, our findings suggest that temozolomide can reverse doxorubicin resistance by directly affecting P-gp transport activity. Combination chemotherapy using temozolomide with other agents may be effective against gliomas in clinical applications.

  13. Novel alginate-stabilized doxorubicin-loaded nanodroplets for ultrasounic theranosis of breast cancer.

    PubMed

    Baghbani, Fatemeh; Moztarzadeh, Fathollah; Mohandesi, Jamshid Aghazadeh; Yazdian, Fatemeh; Mokhtari-Dizaji, Manijhe

    2016-12-01

    Perfluorocarbon nanoemulsions are a new class of multifunctional stimuli-responsive nanocarriers which combine the properties of passive-targeted drug carriers, ultrasound imaging contrast agents, and ultrasound-responsive drug delivery systems. Doxorubicin-loaded alginate stabilized perflourohexane (PFH) nanodroplets were synthesized via nanoemulsion preparation method and their ultrasound responsivity, imaging, and therapeutic properties were studied. Doxorubicin was loaded into the nanodroplets (39.2nm) with encapsulation efficiency of 92.2%. In vitro release profile of doxorubicin from nanodroplets was an apparently biphasic release process and 12.6% of drug released from nanodroplets after 24h incubation in PBS, pH=7.4. Sonication with 28kHz therapeutic ultrasound for 10min triggered droplet-to-bubble transition in PFH nanodroplets which resulted in the release of 85.95% of doxorubicin from nanodroplets. Microbubbles formed by acoustic vaporization of the nanodroplets underwent inertial cavitation. In the breast cancer mice models, ultrasound-mediated therapy with doxorubicin-loaded PFH nanodroplets showed excellent anti-cancer effects characterized by tumor regression. Complete tumor regression was observed for the group in which doxorubicin-loaded nanodroplets were combined with ultrasound, whereas the tumor growth inhibition of doxorubicin -loaded nanodroplets was 89.6%. These multifunctional nanodroplets, with excellent therapeutic and ultrasound properties, could be promising drug delivery systems for chemotherapeutic application.

  14. p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis

    SciTech Connect

    Grethe, Simone; Coltella, Nadia; Di Renzo, Maria Flavia; Poern-Ares, M. Isabella . E-mail: isabella.ares@helsinki.fi

    2006-09-01

    Doxorubicin is the anthracycline with the widest spectrum of antitumor activity, and it has been shown that the antitumor activity is mediated in vivo by selective triggering of apoptosis in proliferating endothelial cells. We studied cultured human endothelial cells and observed that doxorubicin-induced apoptosis was mediated by p38 mitogen-activated protein kinase (MAPK). Doxorubicin-provoked apoptosis was significantly inhibited by expression of dominant negative p38 MAPK or pharmacological inhibition with SB203580. Furthermore, blocking phosphatidylinositol-3-kinase/Akt signaling significantly increased doxorubicin-induced caspase-3 activity and cell death, indicating that Akt is a survival factor in this system. Notably, we also found that doxorubicin-provoked apoptosis included p38 MAPK-mediated inhibition of Akt and Bad phosphorylation. Furthermore, doxorubicin-stimulated phosphorylation of Bad in cells expressing dominant negative p38 MAPK was impeded by the inhibition of PI3-K. In addition to the impact on Bad phosphorylation, doxorubicin-treatment caused p38 MAPK-dependent downregulation of Bcl-xL protein.

  15. Modeling Doxorubicin-Induced Cardiotoxicity in Human Pluripotent Stem Cell Derived-Cardiomyocytes

    PubMed Central

    Maillet, Agnes; Tan, Kim; Chai, Xiaoran; Sadananda, Singh N.; Mehta, Ashish; Ooi, Jolene; Hayden, Michael R.; Pouladi, Mahmoud A.; Ghosh, Sujoy; Shim, Winston; Brunham, Liam R.

    2016-01-01

    Doxorubicin is a highly efficacious anti-cancer drug but causes cardiotoxicity in many patients. The mechanisms of doxorubicin-induced cardiotoxicity (DIC) remain incompletely understood. We investigated the characteristics and molecular mechanisms of DIC in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). We found that doxorubicin causes dose-dependent increases in apoptotic and necrotic cell death, reactive oxygen species production, mitochondrial dysfunction and increased intracellular calcium concentration. We characterized genome-wide changes in gene expression caused by doxorubicin using RNA-seq, as well as electrophysiological abnormalities caused by doxorubicin with multi-electrode array technology. Finally, we show that CRISPR-Cas9-mediated disruption of TOP2B, a gene implicated in DIC in mouse studies, significantly reduces the sensitivity of hPSC-CMs to doxorubicin-induced double stranded DNA breaks and cell death. These data establish a human cellular model of DIC that recapitulates many of the cardinal features of this adverse drug reaction and could enable screening for protective agents against DIC as well as assessment of genetic variants involved in doxorubicin response. PMID:27142468

  16. Protective effects of berberine on doxorubicin-induced hepatotoxicity in mice.

    PubMed

    Zhao, Xiaoyan; Zhang, Jie; Tong, Nannan; Chen, Youran; Luo, Yonghuang

    2012-01-01

    Doxorubicin, a very potent and often used anti-cancer drug, is largely limited due to the dose-related toxic effects. The present study investigated whether berberine, a natural product alkaloid, can reduce the liver injury induced by doxorubicin. Mice of either gender were randomly divided into four groups: the control group, doxorubicin group, berberine group, and berberine+doxorubicin group. In the tests, body weight, general condition and mortality of the mice were observed, and serum alanine aminotransferase and aspartate transaminase levels were determined to evaluate liver function. Furthermore, the liver was excised for determination of the weight changes, as well as histopathological analysis in the tissues. Mortality rate and significant decline in body weight, and increased plasma alanine aminotransferase and aspartate transaminase activities were observed in doxorubicin-treated mice. These changes were significantly prevented by pretreatment with berberine. Histopathological studies showed that doxorubicin caused structural injuries, such as vascular congestion, inflammatory cell infiltration, hepatocellular degeneration and necrosis, fibrosis in the liver. These histopathological changes were largely attenuated by berberine pretreatment. These findings indicate that berberine has the hepatoprotective effect on doxorubicin-induced liver injury in mice.

  17. Dasatinib and Doxorubicin Treatment of Sarcoma Initiating Cells: A Possible New Treatment Strategy

    PubMed Central

    Aggerholm-Pedersen, Ninna; Demuth, Christina; Meldgaard, Peter; Kassem, Moustapha; Sandahl Sorensen, Boe

    2016-01-01

    Background. One of the major challenges affecting sarcoma treatment outcome, particularly that of metastatic disease, is resistance to chemotherapy. Cancer-initiating cells are considered a major contributor to this resistance. Methods. An immortalised nontransformed human stromal (mesenchymal) stem cell line hMSC-TERT4 and a transformed cell line hMSC-TERT20-CE8, known to form sarcoma-like tumours when implanted in immune-deficient mice, were used as models. Receptor tyrosine kinase (RTK) activation was analysed by RTK arrays and cellular viability after tyrosine kinases inhibitor (TKI) treatment with or without doxorubicin was assessed by MTS assay. Results. Initial results showed that the hMSC-TERT4 was more doxorubicin-sensitive while hMSC-TERT20-CE8 was less doxorubicin-sensitive evidenced by monitoring cell viability in the presence of doxorubicin at different doses. The epidermal growth factor receptor (EGFR) was activated in both cell lines. However hMSC-TERT20-CE8 exhibited significantly higher expression of the EGFR ligands. EGFR inhibitors such as erlotinib and afatinib alone or in combination with doxorubicin failed to further decrease cell viability of hMSC-TERT20-CE8. However, inhibition with the TKI dasatinib in combination with doxorubicin decreased cell viability of the hMSC-TERT20-CE8 cell line. Conclusion. Our results demonstrate that dasatinib, but not EGFR-directed treatment, can decrease cell viability of stromal cancer stem cells less sensitive to doxorubicin. PMID:26788073

  18. Postoperative adjuvant combination therapy with doxorubicin and noncytotoxic suramin in dogs with appendicular osteosarcoma.

    PubMed

    Alvarez, Francisco J; Kisseberth, William; Hosoya, Kenji; Lara-Garcia, Ana; Kosarek, Carrie; Murahari, Sridhar; Au, Jessie L-S; Wientjes, M Guillaume; Couto, Jason; Couto, Guillermo

    2014-01-01

    Although conventional treatment of dogs with osteosarcoma (OSA) by amputation and chemotherapy results in reported survival times (STs) of 262-413 days, no major improvements in STs have occurred in the past 2 decades. Suramin is a polysulfonated napthylurea, which at noncytotoxic concentrations in vitro, increases tumor sensitivity to chemotherapy, including doxorubicin. The study authors evaluated the combination of noncytotoxic suramin and doxorubicin after amputation in dogs with OSA. The hypothesis was that treatment of dogs with appendicular OSA with amputation, adjuvant doxorubicin, and noncytotoxic suramin would be well tolerated and result in STs at least comparable to those of doxorubicin alone. Forty-seven dogs received 6.75 mg/kg of suramin IV followed by 30 mg/m(2) of doxorubicin IV 4 hr later. Treatment was repeated q 2 wk for five doses. The median disease free time (DFI) was 203 days (range, 42-1,580+ days) and the median ST for all dogs was 369 days (range, 92-1,616+ days). There was no statistical difference in ST and DFI between greyhounds and nonngreyhounds. Adjuvant doxorubicin and noncytotoxic suramin was well tolerated in dogs with OSA following amputation. Additional studies are needed to determine if this combination treatment protocol provides additional clinical benefit compared with doxorubicin alone.

  19. The role of milk thistle extract in breast carcinoma cell line (MCF-7) apoptosis with doxorubicin.

    PubMed

    Rastegar, Hussein; Ahmadi Ashtiani, Hamidreza; Anjarani, Soghra; Bokaee, Saeed; Khaki, Arash; Javadi, Leila

    2013-01-01

    Breast cancer is the most commonly diagnosed invasive malignancy and first leading cause of cancer-related deaths in Iranian women. Based on silymarin's unique characteristics, its application in chemotherapy combined with doxorubicin can be effective to enhance the efficacy together with a reduced toxicity on normal tissues. The present study focus on evaluate the efficacy of silymarin in combination with doxorubicin, on viability and apoptosis of estrogen-dependent breast carcinoma cell line (MCF-7). After being cultured, MCF-7 cells were divided into 8 groups and treated as follows: 1st group received 75 μg silymarin, groups 2, 3, and 4 were treated with 10, 25, and 50 nM doxorubicin, respectively, and groups 5, 6, and 7 respectively received 10, 25, and 50 nM doxorubicin as well as 75 μg silymarin. Viability percentage and apoptosis of the cells were assessed with Trypan Blue staining after 16, 24, and 48 hours. Silymarin has a synergistic effect on the therapeutic potential of doxorubicin. Use of silymarin in combination with doxorubicin can be more effective on the therapeutic potential of doxorubicin and decreases its dose-limiting side effects.

  20. Impact of Doxorubicin Treatment on the Physiological Functions of White Adipose Tissue

    PubMed Central

    Cruz, Maysa Mariana; Cunha, Roberta D. C.; Alonso-Vale, Maria Isabel; Oyama, Lila Missae; Nascimento, Claudia M. Oller; Pimentel, Gustavo Duarte; dos Santos, Ronaldo V. T.; Lira, Fabio Santos

    2016-01-01

    White adipose tissue (WAT) plays a fundamental role in maintaining energy balance and important endocrine functions. The loss of WAT modifies adipokine secretion and disrupts homeostasis, potentially leading to severe metabolic effects and a reduced quality of life. Doxorubicin is a chemotherapeutic agent used clinically because of its good effectiveness against various types of cancer. However, doxorubicin has deleterious effects in many healthy tissues, including WAT, liver, and skeletal and cardiac muscles. Our objective was to investigate the effects of doxorubicin on white adipocytes through in vivo and in vitro experiments. Doxorubicin reduced the uptake of glucose by retroperitoneal adipocytes and 3T3-L1 cells via the inhibition of AMP-activated protein kinase Thr172 phosphorylation and glucose transporter 4 content. Doxorubicin also reduced the serum level of adiponectin and, to a greater extent, the expression of genes encoding lipogenic (Fas and Acc) and adipogenic factors (Pparg, C/ebpa, and Srebp1c) in retroperitoneal adipose tissue. In addition, doxorubicin inhibited both lipogenesis and lipolysis and reduced the hormone-sensitive lipase and adipose tissue triacylglycerol lipase protein levels. Therefore, our results demonstrate the impact of doxorubicin on WAT. These results are important to understand some side effects observed in patients receiving chemotherapy and should encourage new adjuvant treatments that aim to inhibit these side effects. PMID:27015538

  1. Impact of Doxorubicin Treatment on the Physiological Functions of White Adipose Tissue.

    PubMed

    Biondo, Luana Amorim; Lima Junior, Edson Alves; Souza, Camila Oliveira; Cruz, Maysa Mariana; Cunha, Roberta D C; Alonso-Vale, Maria Isabel; Oyama, Lila Missae; Nascimento, Claudia M Oller; Pimentel, Gustavo Duarte; Dos Santos, Ronaldo V T; Lira, Fabio Santos; Rosa Neto, José Cesar

    2016-01-01

    White adipose tissue (WAT) plays a fundamental role in maintaining energy balance and important endocrine functions. The loss of WAT modifies adipokine secretion and disrupts homeostasis, potentially leading to severe metabolic effects and a reduced quality of life. Doxorubicin is a chemotherapeutic agent used clinically because of its good effectiveness against various types of cancer. However, doxorubicin has deleterious effects in many healthy tissues, including WAT, liver, and skeletal and cardiac muscles. Our objective was to investigate the effects of doxorubicin on white adipocytes through in vivo and in vitro experiments. Doxorubicin reduced the uptake of glucose by retroperitoneal adipocytes and 3T3-L1 cells via the inhibition of AMP-activated protein kinase Thr172 phosphorylation and glucose transporter 4 content. Doxorubicin also reduced the serum level of adiponectin and, to a greater extent, the expression of genes encoding lipogenic (Fas and Acc) and adipogenic factors (Pparg, C/ebpa, and Srebp1c) in retroperitoneal adipose tissue. In addition, doxorubicin inhibited both lipogenesis and lipolysis and reduced the hormone-sensitive lipase and adipose tissue triacylglycerol lipase protein levels. Therefore, our results demonstrate the impact of doxorubicin on WAT. These results are important to understand some side effects observed in patients receiving chemotherapy and should encourage new adjuvant treatments that aim to inhibit these side effects.

  2. Use of 99mTc-doxorubicin scintigraphy in females with breast cancer: a pilot study

    PubMed Central

    Araujo, F I; Proença, F P P; Ferreira, C G; Ventilari, S C; Rosado de Castro, P H; Moreira, R D; Fonseca, L M B; Gutfilen, B

    2015-01-01

    Objective: Doxorubicin (Eurofarma, São Paulo, Brazil) is an antitumour agent widely used in the treatment of breast cancer and can be used for tumour tracking when labelled with a radionuclide. Here, we present the results obtained with technetium-99m (99mTc)-doxorubicin, using the direct method, to evaluate its uptake in breast cancer. Methods: Four females with confirmed breast carcinoma diagnosis and breast image reporting and data system Category 5 on mammography underwent whole-body and thorax single-photon emission CT/CT imaging 1 and 3 h after 99mTc-doxorubicin administration. Results: We observed increased uptake in breast carcinoma lesions and elimination via renal and hepatic pathways. Conclusion: These preliminary results suggest that 99mTc-doxorubicin may be a promising radiopharmaceutical for the evaluation of patients with breast cancer. Further studies are ongoing. Advances in knowledge: To our knowledge, this is the first study to evaluate the use of a directly labelled doxorubicin tracer in humans. 99mTc-doxorubicin could provide information on the response of tumours to doxorubicin. PMID:26111270

  3. Doxorubicin-induced oxidative stress: The protective effect of nicorandil on HL-1 cardiomyocytes.

    PubMed

    Asensio-López, Mari C; Soler, Fernando; Pascual-Figal, Domingo; Fernández-Belda, Francisco; Lax, Antonio

    2017-01-01

    The primary cardiotoxic action of doxorubicin when used as antitumor drug is attributed to the generation of reactive oxygen species (ROS) therefore effective cardioprotection therapies are needed. In this sense, the antianginal drug nicorandil has been shown to be effective in cardioprotection from ischemic conditions but the underlying molecular mechanism to cope with doxorubicin-induced ROS is unclear. Our in vitro study using the HL-1 cardiomyocyte cell line derived from mouse atria reveals that the endogenous nitric oxide (NO) production was stimulated by nicorandil and arrested by NO synthase inhibition. Moreover, while the NO synthase activity was inhibited by doxorubicin-induced ROS, the NO synthase inhibition did not affect doxorubicin-induced ROS. The inhibition of NO synthase activity by doxorubicin was totally prevented by preincubation with nicorandil. Nicorandil also concentration-dependently (10 to 100 μM) decreased doxorubicin-induced ROS and the effect was antagonized by 5-hydroxydecanoate. The inhibition profile of doxorubicin-induced ROS by nicorandil was unaltered when an L-arginine derivative or a protein kinase G inhibitor was present. Preincubation with pinacidil mimicked the effect of nicorandil and the protection was eliminated by glibenclamide. Quantitative colocalization of fluorescence indicated that the mitochondrion was the target organelle of nicorandil and the observed response was a decrease in the mitochondrial inner membrane potential. Interference with H+ movement across the mitochondrial inner membrane, leading to depolarization, also protected from doxorubicin-induced ROS. The data indicate that activation of the mitochondrial ATP-sensitive K+ channel by nicorandil causing mitochondrial depolarization, without participation of the NO donor activity, was responsible for inhibition of the mitochondrial NADPH oxidase that is the main contributor to ROS production in cardiomyocytes. Impairment of the cytosolic Ca2+ signal induced

  4. A long non-coding RNA contributes to doxorubicin resistance of osteosarcoma.

    PubMed

    Zhang, Chun-Lin; Zhu, Kun-Peng; Shen, Guo-Qi; Zhu, Zhong-Sheng

    2016-02-01

    Long non-coding RNAs (lncRNAs) are emerging in molecular biology as crucial regulators of cancer. Although the aberrant expression of lncRNAs has been observed in osteosarcoma (OS), the molecular mechanisms underlying lncRNAs in doxorubicin resistance of OS still unknown. In the current study, we investigated a novel lncRNA, termed ODRUL (osteosarcoma doxorubicin-resistance related up-regulated lncRNA), and evaluated its role in the occurrence of doxorubicin resistance in OS. LncRNA microarray revealed that lncRNA ODRUL was the most up-regulated expressed in the doxorubicin-resistant OS cell line. Quantitative real-time PCR (qRT-PCR) confirmed that lncRNA ODRUL was higher in different doxorubicin-resistant OS cell lines and lower in different doxorubicin-sensitive OS cell lines. Moreover, we showed that lncRNA ODRUL was increased in specimens of OS patients with a poor chemoresponse and lung metastasis. We further demonstrated that lncRNA ODRUL inhibition could inhibit OS cell proliferation, migration, and partly reversed doxorubicin resistance in vitro. In addition, we found that the expression of classical drug resistance-related ATP-binding cassette, subfamily B, member 1 (ABCB1) gene was decreased after the lncRNA ODRUL knockdown. Thus, we concluded that lncRNA ODRUL may act as a pro-doxorubicin-resistant molecule through inducing the expression of the classical multidrug resistance-related ABCB1 gene in osteosarcoma cells .These findings may provide a novel target for reversing doxorubicin resistance in OS.

  5. Doxorubicin has a synergistic cytotoxicity with cucurbitacin B in anaplastic thyroid carcinoma cells.

    PubMed

    Kim, Si Hyoung; Kang, Jun Goo; Kim, Chul Sik; Ihm, Sung-Hee; Choi, Moon Gi; Yoo, Hyung Joon; Lee, Seong Jin

    2017-02-01

    In this study, the combined effect of doxorubicin with cucurbitacin B on survival of anaplastic thyroid carcinoma cells was evaluated. For experiments, 8505C and CAL62 human anaplastic thyroid carcinoma cells were used. Cell viability, the percentage of viable cells, and cytotoxic activity were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, multiplexed cytotoxicity assay, and cytotoxicity assay, respectively. Reactive oxygen species production was measured. In experiments, doxorubicin and cucurbitacin B reduced cell viability in a dose- and time-dependent manner. Cotreatment of doxorubicin and cucurbitacin B, compared with treatment of doxorubicin alone, decreased the percentage of viable cells and increased cytotoxic activity. All of the combination index values were lower than 1.0, suggesting the synergism between doxorubicin and cucurbitacin B in induction of cytotoxicity. In cells treated with both doxorubicin and cucurbitacin B, compared with doxorubicin alone, the protein levels of cleaved poly(adenosine diphosphate-ribose) polymerase and cyclooxygenase 2 and reactive oxygen species production were enhanced. In contrast, the protein levels of B-cell chronic lymphocytic leukemia/lymphoma 2 and survivin and B-cell chronic lymphocytic leukemia/lymphoma 2/B-cell chronic lymphocytic leukemia/lymphoma 2-associated x protein ratio were diminished. The protein levels of Janus kinase 2 and signal transducer and activator of transcription 3 were reduced, while phospho-extracellular signal-regulated kinase 1/2 protein levels were elevated without change in total extracellular signal-regulated kinase 1/2 protein levels. These results suggest that doxorubicin synergizes with cucurbitacin B in induction of cytotoxicity in anaplastic thyroid carcinoma cells. Moreover, synergistic cytotoxicity of doxorubicin with cucurbitacin B is mediated by B-cell chronic lymphocytic leukemia/lymphoma 2 family proteins, survivin, and reactive oxygen

  6. Ameliorative effects of sildenafil and/or febuxostat on doxorubicin-induced nephrotoxicity in rats.

    PubMed

    Khames, Ali; Khalaf, Marwa M; Gad, Amany M; Abd El-Raouf, Ola M

    2017-02-28

    Sildenafil and febuxostat protect against doxorubicin-induced nephrotoxicity; however the exact mechanism remains to be elucidated. The effect of sildenafil and febuxostat on doxorubicin-induced nephrotoxicity in rats was studied. Male rats were subdivided into nine groups. The 1st group served as normal control, the 2nd group received dimethylsulfoxide 50% (DMSO), the 3rd group received doxorubicin (3.5mg/kg, i.p.), twice weekly for 3 weeks. The next 3 groups received sildenafil (5mg/kg; p.o.), febuxostat (10mg/kg; p.o.) and their combination, respectively daily for 21 days. The last 3 groups received doxorubicin in combination with sildenafil, febuxostat or their combination. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically through measuring the following parameters, Kidney function biomarkers [serum levels of urea, creatinine and uric acid], oxidative stress biomarkers [kidney contents of glutathione reduced (GSH) and malondialdehyde (MDA)], The apoptotic marker namely; caspase-3 in kidney tissue and the inflammatory mediator tumor necrosis factor alpha (TNF-α). doxorubicin-induced a significant elevation in nephrotoxicity markers, expression of caspase-3 and caused induction of inflammation and oxidative stress. Histological changes in the kidney was tubular necrosis. Sildenafil and/or febuxostat administration with doxorubicin caused a significant decrease in nephrotoxicity markers and inflammatory mediators, restoration of normal values of oxidative stress biomarkers and hampering the expression of renal caspase-3. They also ameliorate histological changes induced by doxorubicin. sildenafil and febuxostat are promising protective agents against doxorubicin-nephrotoxicity through improving biochemical, inflammatory, histopathological and immunohistochemical alterations induced by doxorubicin.

  7. Pharmacological modulation of blood-brain barrier increases permeability of doxorubicin into the rat brain.

    PubMed

    Sardi, Iacopo; la Marca, Giancarlo; Cardellicchio, Stefania; Giunti, Laura; Malvagia, Sabrina; Genitori, Lorenzo; Massimino, Maura; de Martino, Maurizio; Giovannini, Maria G

    2013-01-01

    Our group recently demonstrated in a rat model that pretreatment with morphine facilitates doxorubicin delivery to the brain in the absence of signs of increased acute systemic toxicity. Morphine and other drugs such as dexamethasone or ondansetron seem to inhibit MDR proteins localized on blood-brain barrier, neurons and glial cells increasing the access of doxorubicin to the brain by efflux transporters competition. We explored the feasibility of active modification of the blood-brain barrier protection, by using morphine dexamethasone or ondansetron pretreatment, to allow doxorubicin accumulation into the brain in a rodent model. Rats were pretreated with morphine (10 mg/kg, i.p.), dexamethasone (2 mg/kg, i.p.) or ondansetron (2 mg/kg, i.p.) before injection of doxorubicin (12 mg/kg, i.p.). Quantitative analysis of doxorubicin was performed by mass spectrometry. Acute hearth and kidney damage was analyzed by measuring doxorubicin accumulation, LDH activity and malondialdehyde plasma levels. The concentration of doxorubicin was significantly higher in all brain areas of rats pretreated with morphine (P < 0.001) or ondansetron (P < 0.05) than in control tissues. The concentration of doxorubicin was significantly higher in cerebral hemispheres and brainstem (P < 0.05) but not in cerebellum of rats pretreated with dexamethasone than in control tissues. Pretreatment with any of these drugs did not increase LDH activity or lipid peroxidation compared to controls. Our data suggest that morphine, dexamethasone or ondansetron pretreatment is able to allow doxorubicin penetration inside the brain by modulating the BBB. This effect is not associated with acute cardiac or renal toxicity. This finding might provide the rationale for clinical applications in the treatment of refractory brain tumors and pave the way to novel applications of active but currently inapplicable chemotherapeutic drugs.

  8. Doxorubicin-induced oxidative stress: The protective effect of nicorandil on HL-1 cardiomyocytes

    PubMed Central

    Pascual-Figal, Domingo; Fernández-Belda, Francisco; Lax, Antonio

    2017-01-01

    The primary cardiotoxic action of doxorubicin when used as antitumor drug is attributed to the generation of reactive oxygen species (ROS) therefore effective cardioprotection therapies are needed. In this sense, the antianginal drug nicorandil has been shown to be effective in cardioprotection from ischemic conditions but the underlying molecular mechanism to cope with doxorubicin-induced ROS is unclear. Our in vitro study using the HL-1 cardiomyocyte cell line derived from mouse atria reveals that the endogenous nitric oxide (NO) production was stimulated by nicorandil and arrested by NO synthase inhibition. Moreover, while the NO synthase activity was inhibited by doxorubicin-induced ROS, the NO synthase inhibition did not affect doxorubicin-induced ROS. The inhibition of NO synthase activity by doxorubicin was totally prevented by preincubation with nicorandil. Nicorandil also concentration-dependently (10 to 100 μM) decreased doxorubicin-induced ROS and the effect was antagonized by 5-hydroxydecanoate. The inhibition profile of doxorubicin-induced ROS by nicorandil was unaltered when an L-arginine derivative or a protein kinase G inhibitor was present. Preincubation with pinacidil mimicked the effect of nicorandil and the protection was eliminated by glibenclamide. Quantitative colocalization of fluorescence indicated that the mitochondrion was the target organelle of nicorandil and the observed response was a decrease in the mitochondrial inner membrane potential. Interference with H+ movement across the mitochondrial inner membrane, leading to depolarization, also protected from doxorubicin-induced ROS. The data indicate that activation of the mitochondrial ATP-sensitive K+ channel by nicorandil causing mitochondrial depolarization, without participation of the NO donor activity, was responsible for inhibition of the mitochondrial NADPH oxidase that is the main contributor to ROS production in cardiomyocytes. Impairment of the cytosolic Ca2+ signal induced

  9. Preserved learning and memory in mice following chemotherapy: 5-Fluorouracil and doxorubicin single agent treatment, doxorubicin-cyclophosphamide combination treatment.

    PubMed

    Fremouw, Thane; Fessler, Christy L; Ferguson, Robert J; Burguete, Yamil

    2012-01-01

    Clinical studies suggest that chemotherapy is associated with long-term cognitive impairment in some patients. A number of underlying mechanisms have been proposed, however, the etiology of chemotherapy-related cognitive dysfunction remains relatively unknown. As part of a multifaceted approach, animal models of chemotherapy induced cognitive impairment are being developed. Thus far, the majority of animal studies have utilized rats, however, mice may prove particularly beneficial in studying genetic risk factors for developing chemotherapy induced cognitive impairment. Thus, C57BL/6J mice were treated once a week for three weeks with saline, doxorubicin and cyclophosphamide (D&C), doxorubicin (Dox), or 5-fluorouracil (5-FU). Recent and remote contextual fear conditioning and novel object recognition (NOR) was assessed. Despite significant toxic effects as assessed by weight loss, the chemotherapy treated mice performed as well as control mice on all task. As are some humans, C57BL/6J mice may be resistant to at least some aspects of chemotherapy induced cognitive decline.

  10. In vitro and in vivo efficacy of doxorubicin loaded biodegradable semi-interpenetrating hydrogel implants of poly (acrylic acid)/gelatin for post surgical tumor treatment.

    PubMed

    Jaiswal, Maneesh; Naz, Farhat; Dinda, Amit K; Koul, Veena

    2013-08-01

    The paper describes the preparation and evaluation of doxorubicin loaded semi-interpenetrating polymeric hydrogel network of polyacrylic acid (PAc) and gelatin (G). Post surgical antitumor efficacy and biodistribution of doxorubicin from the implanted degradable hydrogels was investigated on Ehrlich's ascites tumor model using albino mice. Polycaprolactone diacrylate (PCL-DAr) was employed as a crosslinking agent for PAc chains whereas G was kept free. The effect of crosslinking concentration on various physico-chemical properties such as thermal behavior, swelling, degradation behavior, drug release and polymer-polymer interactions was investigated by various physico-chemical tools. Semi-interpenetrating polymeric networks (IPNs) with 0.2 mol% crosslinking concentration showed degradation within 20 days in phosphate buffer (pH 6.5). To determine the in vivo anticancer efficacy, placebo and drug laden cylindrical implants (65 ± 5 µg/implant of 10 mg) were implanted in tumor cavity post tumor excision. After predetermined time intervals (day 7, 11, 14, 20 and 25), drug biodistribution was assessed in tumor, tumor periphery, residual hydrogel and all vital organs i.e. liver, spleen, kidney, heart, lung and blood (spectrofluorimetrically). The drug distribution study showed the concentration of drug in the tumor, tumor periphery and residual hydrogel decreased with increasing time; on the 7th day, drug concentration was highest while, on the 25th day, it was negligible; however, insignificant quantities of the drug was found in vital organs. Histological examination revealed no sign of tumor recurrence until the 25th day with 100% necrosis and slight inflammation in treated the group. In vivo results established that these biodegradable implants can be utilized as post surgical therapy for solid tumors.

  11. Composition-insensitive highly viscous wormlike micellar solutions formed in anionic and cationic surfactant systems.

    PubMed

    Aramaki, Kenji; Iemoto, Suzuka; Ikeda, Naoaki; Saito, Keitaro

    2010-01-01

    We investigated phase behavior and rheological properties of aqueous micellar phase formed in water/cocoyl glutamate neutralized with triethanol amine (CGT-n)/hexadecyl trimethylammonium salt (CTAB or CTAC) systems, where n is a degree of neutralization. Micellar phase appears in wide composition range with respect to the surfactant mixing fraction in ternary phase diagrams at 25 degrees C. At high mixing fraction of cationic surfactant in the water/CGT-n/CTAB systems, one can observe a highly viscous micellar phase in which worm-like micelles are expected to form. Contrary to conventional systems in which worm-like micelles are formed, the zero-shear viscosity of the micellar solution in the water/CGT-n/CTAB system with n=1.2 increases with the addition of cationic cosurfactant and once decreases after a maximum, then increases again and decreases after the second maximum. At n=1.5 and 2, highly viscous solution is observed in the relatively wide range of surfactant mixing fraction instead of two maxima of the viscosity curve observed at n=1.2. In the case of CTAC instead of CTAB we can observe narrow composition range for the maximum viscosity. Frequency sweep measurements were performed on the highly viscous samples in the water/CGT-1.5/CTAB system. Typical viscoelastic behavior of worm-like micellar solutions is observed; i.e. the curves of storage (G') and loss (G") moduli make a crossover and the data points of G' and G" can be fitted to the Maxwell model. Relaxation time against the mixing fraction of two surfactants behaves similarly to the zero-shear viscosity change, whereas the plateau modulus continuously increases in the plateau region for the zero-shear viscosity curve.

  12. Micellar acid-base potentiometric titrations of weak acidic and/or insoluble drugs.

    PubMed

    Gerakis, A M; Koupparis, M A; Efstathiou, C E

    1993-01-01

    The effect of various surfactants [the cationics cetyl trimethyl ammonium bromide (CTAB) and cetyl pyridinium chloride (CPC), the anionic sodium dodecyl sulphate (SDS), and the nonionic polysorbate 80 (Tween 80)] on the solubility and ionization constant of some sparingly soluble weak acids of pharmaceutical interest was studied. Benzoic acid (and its 3-methyl-, 3-nitro-, and 4-tert-butyl-derivatives), acetylsalicylic acid, naproxen and iopanoic acid were chosen as model examples. Precise and accurate acid-base titrations in micellar systems were made feasible using a microcomputer-controlled titrator. The response curve, response time and potential drift of the glass electrode in the micellar systems were examined. The cationics CTAB and CPC were found to increase considerably the ionization constant of the weak acids (delta pKa ranged from -0.21 to -3.57), while the anionic SDS showed negligible effect and the nonionic Tween 80 generally decreased the ionization constants. The solubility of the acids in aqueous micellar and acidified micellar solutions was studied spectrophotometrically and it was found increased in all cases. Acetylsalicylic acid, naproxen, benzoic acid and iopanoic acid could be easily determined in raw material and some of them in pharmaceutical preparations by direct titration in CTAB-micellar system instead of using the traditional non-aqueous or back titrimetry. Precisions of 0.3-4.3% RSD and good correlation with the official tedious methods were obtained. The interference study of some excipients showed that a preliminary test should be carried out before the assay of formulations.

  13. Stepwise dynamics of an anionic micellar film - Formation of crown lenses.

    PubMed

    Lee, Jongju; Nikolov, Alex; Wasan, Darsh

    2017-06-15

    We studied the stepwise thinning of a microscopic circular foam film formed from an anionic micellar solution of sodium dodecyl sulfate (SDS). The foam film formed from the SDS micellar solution thins in a stepwise manner by the formation and expansion of a dark spot(s) of one layer less than the film thickness. During the last stages of film thinning (e.g., a film with one micellar layer), the dark spot expansion occurs via two steps. Initially, a small dark circular spot inside a film of several microns in size is formed, which expands at a constant rate. Then, a ridge along the expanding spot is formed. As the ridge grows, it becomes unstable and breaks into regular crown lenses, which are seen as white spots in the reflected light at the border of the dark spot with the surrounding thicker film. The Rayleigh type of instability contributes to the formation of the lenses, which results in the increase of the dark spot expansion rate with time. We applied the two-dimensional micellar-vacancy diffusion model and took into consideration the effects of the micellar layering and film volume on the rate of the dark spot expansion [Lee et al., 2016] to predict the rate of the dark spot expansion for a 0.06M SDS film in the presence of lenses. We briefly discuss the Rayleigh type of instability in the case of a 0.06M SDS foam film. The goals of this study are to reveal why the crown lenses are formed during the foam film stratification and to elucidate their effect on the rate of spot expansion.

  14. Thermoresponsive supramolecular micellar drug delivery system based on star-linear pseudo-block polymer consisting of β-cyclodextrin-poly(N-isopropylacrylamide) and adamantyl-poly(ethylene glycol).

    PubMed

    Song, Xia; Zhu, Jing-Ling; Wen, Yuting; Zhao, Feng; Zhang, Zhong-Xing; Li, Jun

    2017-03-15

    Chemotherapy is facing several limitations such as low water solubility of anticancer drugs and multidrug resistance (MDR) in cancer cells. To overcome these limitations, a thermoresponsive micellar drug delivery system formed by a non-covalently connected supramolecular block polymer was developed. The system is based on the host-guest interaction between a well-defined β-cyclodextrin (β-CD) based poly(N-isopropylacrylamide) star host polymer and an adamantyl-containing poly(ethylene glycol) (Ad-PEG) guest polymer. The structures of the host and guest polymers were characterized by (1)H and (13)C NMR, GPC and FTIR. Subsequently, they formed a pseudo-block copolymer via inclusion complexation between β-CD core and adamantyl-moiety, which was confirmed by 2D NMR. The thermoresponsive micellization of the copolymer was investigated by UV-vis spectroscopy, DLS and TEM. At 37°C, the copolymer at a concentration of 0.2mg/mL in PBS formed micelles with a hydrodynamic diameter of ca. 282nm. The anticancer drug, doxorubicin (DOX), was successfully loaded into the core of the micelles with a loading level of 6% and loading efficiency of 17%. The blank polymer micelles showed good biocompatibility in cell cytotoxicity studies. Moreover, the DOX-loaded micelles demonstrated superior therapeutic effects in AT3B-1-N (MDR-) and AT3B-1 (MDR+) cell lines as compared to free DOX control, overcoming MDR in cancer cells.

  15. An equilibrium model for ligand-modified micellar-enhanced ultrafiltration. Selective separation of metal ions using iminoacetic substituted polyamines and a theoretical model for the titration behavior of polyamines

    SciTech Connect

    Dharmawardana, Udeni Rajaratna

    1992-01-01

    This thesis consists of three chapters. Chapter 1, An equilibrium model for ligand-modified micellar-enhanced ultrafiltration, describes a theoretical model and experimental investigations which used the semi-equilibrium-dialysis method with N-n-dodecyl iminodiacetic acid as the ligand. In Chapter 2, Selective separation of metal ions using iminoacetic substituted polyamines, polyamines with a substituted ligand group are synthesized and used in investigating selective separation of copper ions from aqueous solution. In Chapter 3, A theoretical model for the titration behavior of polyamines, a novel approach to explain the titration behavior of polymeric amines based on the binding behavior of counterions is described. The application of this study is to the investigation of inexpensive and efficient methods of industrial waste water treatment.

  16. Serious stomatitis and esophagitis: a peculiar mucous reaction induced by pegylated liposomal doxorubicin.

    PubMed

    Ma, Han; Chen, Meilan; Liu, Junru; Li, Ying; Li, Juan

    2015-01-01

    Pegylated liposomal doxorubicin is an important antineoplastic agent with activity in a variety of solid tumors. It has a totally different profile of pharmacokinetics and toxicity compared with doxorubicin. It rarely causes side-effects like cardiotoxicity or hair loss, but frequently results in many kinds of mucocutaneous reactions, including palmar-plantar erythrodysesthesia, diffuse follicular rash, intertrigo-like eruption, new formation of melanotic macules, stomatitis and radiation recall dermatitis. We present a rare case of multiple myeloma who immediately developed serious stomatitis and esophatitis associated with minor palmar-plantar erythrodysesthesia after a single course of pegylated liposomal doxorubicin.

  17. Organometallic Polymeric Conductors

    NASA Technical Reports Server (NTRS)

    1997-01-01

    For aerospace applications, the use of polymers can result in tremendous weight savings over metals. Suitable polymeric materials for some applications like EMI shielding, spacecraft grounding, and charge dissipation must combine high electrical conductivity with long-term environmental stability, good processability, and good mechanical properties. Recently, other investigators have reported hybrid films made from an electrically conductive polymer combined with insulating polymers. In all of these instances, the films were prepared by infiltrating an insulating polymer with a precursor for a conductive polymer (either polypyrrole or polythiophene), and oxidatively polymerizing the precursor in situ. The resulting composite films have good electrical conductivity, while overcoming the brittleness inherent in most conductive polymers. The highest conductivities reported (approximately 4/Scm) were achieved with polythiophene in a polystyrene host polymer. The best films using a polyamide as base polymer were four orders of magnitude less conductive than the polystyrene films. The authors suggested that this was because polyimides were unable to swell sufficiently for infiltration of monomer as in the polystyrene. It was not clear, however, if the different conductivities obtained were merely the result of differing oxidation conditions. Oxidation time, temperature and oxidant concentration varied widely among the studies.

  18. Gratings in polymeric waveguides

    NASA Astrophysics Data System (ADS)

    Mishakov, G.; Sokolov, V.; Kocabas, A.; Aydinli, A.

    2007-04-01

    Laser-induced formation of polymer Bragg grating filters for Dense Wavelength Division Multiplexing (DWDM) applications is discussed. Acrylate monomers halogenated with both fluorine and chlorine, which possess absorption losses less than 0.25 dB/cm and wide choice of refractive indices (from 1.3 to 1.5) in the 1.5 μm telecom wavelength region were used. The monomers are highly intermixable thus permitting to adjust the refractive index of the composition within +/-0.0001. Moreover they are photocurable under UV exposure and exhibit high contrast in polymerization. These properties make halogenated acrylates very promising for fabricating polymeric waveguides and photonic circuits. Single-mode polymer waveguides were fabricated on silicon wafers using resistless contact lithography. Submicron index gratings have been written in polymer waveguides using holographic exposure with He-Cd laser beam (325 nm) through a phase mask. Both uniform and apodized gratings have been fabricated. The gratings are stable and are not erased by uniform UV exposure. The waveguide gratings possess narrowband reflection spectra in the 1.5 μm wavelength region of 0.4 nm width, nearly rectangular shape of the stopband and reflectivity R > 99%. The fabricated Bragg grating filters can be used for multiplexing/demultiplexing optical signals in high-speed DWDM optical fiber networks.

  19. Ultrasonic-Activated Micellar Drug Delivery for Cancer Treatment

    PubMed Central

    Husseini, Ghaleb A.; Pitt, William G.

    2008-01-01

    The use of nanoparticles and ultrasound in medicine continues to evolve. Great strides have been made in the areas of producing micelles, nanoemulsions and solid nanoparticles that can be used in drug delivery. An effective nanocarrier allows for the delivery of a high concentration of potent medications to targeted tissue while minimizing the side effect of the agent to the rest of the body. Polymeric micelles have been shown to encapsulate therapeutic agents and maintain their structural integrity at lower concentrations. Ultrasound is currently being used in drug delivery as well as diagnostics, and has many advantages that elevate its importance in drug delivery. The technique is non-invasive, thus no surgery is needed; the ultrasonic waves can be easily controlled by advanced electronic technology so that they can be focused on the desired target volume. Additionally, the physics of ultrasound are widely used and well understood; thus ultrasonic application can be tailored towards a particular drug delivery system. In this article, we review the recent progress made in research that utilizes both polymeric micelles and ultrasonic power in drug delivery. PMID:18506804

  20. Micellar and sub-micellar ultra-high performance liquid chromatography of hydroxybenzoic acid and phthalic acid positional isomers.

    PubMed

    Fasciano, Jennifer M; Danielson, Neil D

    2016-03-18

    Micellar liquid chromatography (MLC) has been used primarily for the separation of neutral analytes of varying polarities, most commonly phenols and polyaromatic hydrocarbons, but does not seem to have been used to study aromatic hydroxy acids in detail. We have studied the separation of hydroxybenzoic acid mixtures, including monohydroxybenzoic and dihydroxybenzoic acid positional isomers by MLC. Sodium dodecylsulfate (SDS) is investigated as the modifying surfactant on a C18 ultra-high performance liquid chromatography (UHPLC) column (100 × 2.1mm, 1.8 μm). The addition of only SDS (no organic solvent) to the mobile phase reduced the influence of hydrophobic interactions while improving the retention times, resolution, and peak shapes, even at concentrations below the critical micellization concentration (CMC). The UHPLC separation of 7 hydroxybenzoic acids, including 6 dihydroxybenzoic acid positional isomers and one trihydroxybenzoic acid, is achieved with high efficiency using 0.1% SDS in 1.84 mM sulfuric acid (pH 2.43) mobile phase, in less than 6 min with a flow rate of 0.3 mL min(-1), and in less than four min with a flow rate of 0.7 mL min(-1). Six monohydroxybenzoic acid isomers are also effectively separated by MLC, using a 0.5% SDS mobile phase modifier, in less than 20 min with a flow rate of 0.3 mL min(-1), and in less than 14 min with a flow rate of 0.7 mL min(-1). The 3 phthalic acid isomers could be separated using a similar mobile phase and flow rates in less than 6 and 4 min. Solute-micelle equilibrium constants and partition coefficients are calculated for 6 monohydroxybenzoic acids based on a plot of MLC retention factor vs. mobile phase micelle concentration. All aromatic acid isomers studied can be classified as binding solutes in the MLC retention mechanism. Less effective separations are observed with shorter chain surfactants, leading to higher retention times and poor peak shapes. It is concluded that increasing chain length led to more

  1. Coating of plasma polymerized film

    NASA Technical Reports Server (NTRS)

    Morita, S.; Ishibashi, S.

    1980-01-01

    Plasma polymerized thin film coating and the use of other coatings is suggested for passivation film, thin film used for conducting light, and solid body lubrication film of dielectrics of ultra insulators for electrical conduction, electron accessories, etc. The special features of flow discharge development and the polymerized film growth mechanism are discussed.

  2. Platelet interaction with polymerizing fibrin.

    PubMed

    Niewiarowski, S; Regoeczi, E; Stewart, G J; Senyl, A F; Mustard, J F

    1972-03-01

    Interaction of washed pig, rabbit, or human platelets with fibrinogen was studied during its transition to fibrin using photometric, isotopic, and electron microscopic techniques. Untreated fibrinogen and fully polymerized fibrin had no detectable effect on platelets. Fibrinogen, incubated with low concentrations of reptilase or thrombin, formed intermediate products which readily became associated with platelets and caused their aggregation. Neutralization of the thrombin did not prevent this interaction. In the absence of fibrinogen, reptilase did not affect platelets. The interaction of polymerizing fibrin with platelets was accompanied by small losses of platelet constituents (serotonin, adenine nucleotides, platelet factor 4, and lactic dehydrogenase). This loss did not appear to be the result of the platelet release reaction. Inhibitors of the release reaction or of adenosine diphosphate (ADP)-induced aggregation did not prevent the interaction of platelets with polymerizing fibrin. Apyrase or prostaglandin E(1) (PGE(1)) reduced the extent of platelet aggregation by polymerizing fibrin, but the amount of protein associated with platelets was slightly increased. The interaction of polymerizing fibrin with platelets was completely inhibited by ethylenediaminetetraacetate (EDTA) or ethylene glycol bis (beta-aminoethyl ether) N, N,N',N'-tetraacetic acid (EGTA).Fibers formed in solutions of polymerizing fibrin were larger in the presence than in the absence of washed platelets, suggesting that platelets affect fibrin polymerization. The adherence of platelets to polymerizing fibrin may be responsible for the establishment of links between platelets and fibrin in hemostatic plugs and thrombi.

  3. Amplification of actin polymerization forces

    PubMed Central

    Dmitrieff, Serge; Nédélec, François

    2016-01-01

    The actin cytoskeleton drives many essential processes in vivo, using molecular motors and actin assembly as force generators. We discuss here the propagation of forces caused by actin polymerization, highlighting simple configurations where the force developed by the network can exceed the sum of the polymerization forces from all filaments. PMID:27002174

  4. Amplification of actin polymerization forces.

    PubMed

    Dmitrieff, Serge; Nédélec, François

    2016-03-28

    The actin cytoskeleton drives many essential processes in vivo, using molecular motors and actin assembly as force generators. We discuss here the propagation of forces caused by actin polymerization, highlighting simple configurations where the force developed by the network can exceed the sum of the polymerization forces from all filaments.

  5. TRACE ANALYSIS OF FLUORESCEIN-DERIVATIZED PHENOXY ACID HERBICIDES BY MICELLAR ELECTROKINETIC CHROMATOGRAPHY WITH LASER-INDUCTED FLUORESCENCE DETECTION

    EPA Science Inventory

    Micellar electrokinetic chromatography (MEKC) with laser-induced fluorescence (LIF) detection was used for the trace analysis of phenoxy acid herbicides. Capillary electrophoresis (CE) with LIF detection, which has not previously been used for pesticide analysis, overcomes the po...

  6. Effect of alteration of caveolin-1 expression on doxorubicin-induced apoptosis in H9c2 cardiac cells.

    PubMed

    Takaguri, Akira; Kamato, Maiko; Satoh, Yoshiaki; Ohtsuki, Kazuaki; Satoh, Kumi

    2015-09-01

    Doxorubicin is an anthracycline antibiotic widely used in cancer treatment. Although its antitumor efficacy appears to be dose dependent, its clinical use is greatly restricted by the development of cardiotoxicity associated with apoptosis. Although caveolin-1, the major structural protein in caveolae, can positively or negatively regulate apoptosis depending on the stimulus or cell types, the contribution of caveolin-1 to doxorubicin-induced apoptosis remains unknown. This study was performed to identify the regulatory role of caveolin-1 on doxorubicin-induced apoptosis in H9c2 cardiac cells using a genetic approach. Caveolin-1 knockdown with a short hairpin (sh) RNA adenovirus, but not overexpression of wild-type caveolin-1, resulted in a marked inhibition of doxorubicin-induced caspase-3 cleavage. However, caveolin-1 knockdown tended to protect against doxorubicin-induced decrease in cell viability, but it did not significantly reverse cell death induced by doxorubicin. Doxorubicin stimulated the phosphorylation of p38 and extracellular signal regulated kinase (ERK). Doxorubicin-induced caspase-3 cleavage was inhibited by U0126, a MEK inhibitor or SB203580, a p38 inhibitor. Caveolin-1 knockdown markedly inhibited doxorubicin-induced p-38 phosphorylation but not ERK-mediated p-53 phosphorylation in H9c2 cardiac cells. Our results suggest that reduced caveolin-1 expression plays an anti-apoptotic role in doxorubicin-induced apoptosis but that it is insufficient to prevent such an apoptosis in H9c2 cardiac cells.

  7. Creatine supplementation reduces doxorubicin-induced cardiomyocellular injury.

    PubMed

    Santacruz, Lucia; Darrabie, Marcus D; Mantilla, Jose Gabriel; Mishra, Rajashree; Feger, Bryan J; Jacobs, Danny O

    2015-04-01

    Heart failure is a common complication of doxorubicin (DOX) therapy. Previous studies have shown that DOX adversely impacts cardiac energy metabolism, and the ensuing energy deficiencies antedate clinical manifestations of cardiac toxicity. Brief exposure of cultured cardiomyocytes to DOX significantly decreases creatine transport, which is the cell's sole source of creatine. We present the results of a study performed to determine if physiological creatine supplementation (5 mmol/L) could protect cardiomyocytes in culture from cellular injury resulting from exposure to therapeutic levels of DOX. Creatine supplementation significantly decreased cytotoxicity, apoptosis, and reactive oxygen species production caused by DOX. The protective effect was specific to creatine and depended on its transport into the cell.

  8. Cure of Xenografted Human Carcinomas by BR96-Doxorubicin Immunoconjugates

    NASA Astrophysics Data System (ADS)

    Trail, P. A.; Willner, D.; Lasch, S. J.; Henderson, A. J.; Hofstead, S.; Casazza, A. M.; Firestone, R. A.; Hellstrom, I.; Hellstrom, K. E.

    1993-07-01

    Immunoconjugates (BR96-DOX) were prepared between chimeric monoclonal antibody BR96 and the anticancer drug doxorubicin. The monoclonal antibody binds an antigen related to Lewis Y that is abundantly expressed at the surface of cells from many human carcinomas; it has a high degree of tumor selectivity and is internalized after binding. BR96-DOX induced complete regressions and cures of xenografted human lung, breast, and colon carcinomas growing subcutaneously in athymic mice and cured 70 percent of mice bearing extensive metastases of a human lung carcinoma. Also, BR96-DOX cured 94 percent of athymic rats with subcutaneous human lung carcinoma, even though the rats, like humans and in contrast to mice, expressed the BR96 target antigen in normal tissues.

  9. Efficient intravesical therapy of bladder cancer with cationic doxorubicin nanoassemblies.

    PubMed

    Jin, Xun; Zhang, Peilan; Luo, Li; Cheng, Hao; Li, Yunzu; Du, Ting; Zou, Bingwen; Gou, Maling

    Nanoparticles have promising applications in drug delivery for cancer therapy. Herein, we prepared cationic 1,2-dioleoyl-3-trimethylammonium propane/methoxypoly (ethyleneglycol) (DPP) nanoparticles to deliver doxorubicin (Dox) for intravesical therapy of bladder cancer. The DPP micelles have a mean dynamic diameter of 18.65 nm and a mean zeta potential of +19.6 mV. The DPP micelles could prolong the residence of Dox in the bladder, enhance the penetration of Dox into the bladder wall, and improve cellular uptake of Dox. The encapsulation by DPP micelles significantly improved the anticancer effect of Dox against orthotopic bladder cancer in vivo. This work described a Dox-loaded DPP nanoparticle with potential applications in intravesical therapy of bladder cancer.

  10. Fluorescence properties of several chemotherapy drugs: doxorubicin, paclitaxel and bleomycin

    PubMed Central

    Motlagh, Najme Sadat Hosseini; Parvin, Parviz; Ghasemi, Fatemah; Atyabi, Fatemeh

    2016-01-01

    Several chemo-drugs act as the biocompatible fluorophores. Here, the laser induced fluorescence (LIF) properties of doxorubicin, paclitaxel and bleomycin are investigated. The absorption lines mostly lie over UV range according to the UV-VIS spectra. Therefore, a single XeCl laser provokes the desired transitions of the chemo-drugs of interest at 308 nm. It is shown that LIF spectra are strongly dependent on the fluorophore concentration giving rise to the sensible red shift. This happens when large overlapping area appears between absorption and emission spectra accordingly. The red shift is taken into account as a characteristic parameter of a certain chemo-drug. The fluorescence extinction (α) and self-quenching (k) coefficients are determined based on the best fitting of the adopted Lambert-Beer equation over experimental data. The quantum yield of each chemo-drug is also measured using the linearity of the absorption and emission rates. PMID:27375954

  11. Organometallic Rhenium Complexes Divert Doxorubicin to the Mitochondria.

    PubMed

    Imstepf, Sebastian; Pierroz, Vanessa; Rubbiani, Riccardo; Felber, Michael; Fox, Thomas; Gasser, Gilles; Alberto, Roger

    2016-02-18

    Doxorubicin, a well-established chemotherapeutic agent, is known to accumulate in the cell nucleus. By using ICP-MS, we show that the conjugation of two small organometallic rhenium complexes to this structural motif results in a significant redirection of the conjugates from the nucleus to the mitochondria. Despite this relocation, the two bioconjugates display excellent toxicity toward HeLa cells. In addition, we carried out a preliminarily investigation of aspects of cytotoxicity and present evidence that the conjugates disrupt the mitochondrial membrane potential, are strong inhibitors of human Topoisomerase II, and induce apoptosis. Such derivatives may enhance the therapeutic index of the aggressive parent drug and overcome drug resistance by influencing nuclear and mitochondrial homeostasis.

  12. Quantitative imaging of light-triggered doxorubicin release

    PubMed Central

    Kress, Jeremy; Rohrbach, Daniel J.; Carter, Kevin A.; Luo, Dandan; Shao, Shuai; Lele, Shashikant; Lovell, Jonathan F.; Sunar, Ulas

    2015-01-01

    The efficacy of chemotherapy is related, in large part, to the concentration of drug that reaches tumor sites. Doxorubicin (DOX) is a common anti-cancer drug that is also approved for use in liposomal form for the treatment of ovarian cancer. We recently developed a porphyrin-phospholipid (PoP)-liposome system that enables on demand release of DOX from liposomes using near infrared irradiation to improve DOX bioavailability. Owing to its intrinsic fluorescence, it is possible, and desirable, to quantify DOX concentration and distribution, preferably noninvasively. Here we quantified DOX distribution following light-triggered drug release in phantoms and an animal carcass using spatial frequency domain imaging. This study demonstrates the feasibility of non-invasive quantitative mapping of DOX distributions in target areas. PMID:26417522

  13. Efficient intravesical therapy of bladder cancer with cationic doxorubicin nanoassemblies

    PubMed Central

    Jin, Xun; Zhang, Peilan; Luo, Li; Cheng, Hao; Li, Yunzu; Du, Ting; Zou, Bingwen; Gou, Maling

    2016-01-01

    Nanoparticles have promising applications in drug delivery for cancer therapy. Herein, we prepared cationic 1,2-dioleoyl-3-trimethylammonium propane/methoxypoly (ethyleneglycol) (DPP) nanoparticles to deliver doxorubicin (Dox) for intravesical therapy of bladder cancer. The DPP micelles have a mean dynamic diameter of 18.65 nm and a mean zeta potential of +19.6 mV. The DPP micelles could prolong the residence of Dox in the bladder, enhance the penetration of Dox into the bladder wall, and improve cellular uptake of Dox. The encapsulation by DPP micelles significantly improved the anticancer effect of Dox against orthotopic bladder cancer in vivo. This work described a Dox-loaded DPP nanoparticle with potential applications in intravesical therapy of bladder cancer. PMID:27660445

  14. Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer

    SciTech Connect

    Lee, Kwang-Hun; Liapi, Eleni A.; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A.; Ventura, Veronica Prieto; Geschwind, Jean-Francois H.

    2010-06-15

    The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

  15. Biodegradable pH/temperature-sensitive oligo(β-amino ester urethane) hydrogels for controlled release of doxorubicin.

    PubMed

    Huynh, Cong Truc; Nguyen, Minh Khanh; Lee, Doo Sung

    2011-08-01

    An injectable biodegradable pH/temperature-sensitive oligo(β-amino ester urethane) (OAEU) was synthesized. The OAEU was synthesized by addition polymerization between the isocyanate groups of 1,6-diisocyanato hexamethylene and the hydroxyl groups of a synthesized monomer piperazine dihydroxyl amino ester (monomer PDE) in chloroform in the presence of dibutyltin dilaurate as a catalyst. The synthesized OAEU was characterized by (1)H NMR spectroscopy, Fourier transform infrared spectroscopy and gel permeation chromatography. The aqueous solutions of OAEU showed a sol-to-gel-to-sol phase transition as a function of temperature and pH. The gel window covered the physiological conditions (37°C, pH 7.4) and could be controlled by changing the OAEU concentration. After a subcutaneous injection of the OAEU solution into Sprague-Dawley rats, a gel formed rapidly in situ and remained in the body for more than 2 weeks. The in vitro cytotoxicity test and in vitro degradation showed that the OAEU hydrogel was non-cytotoxic and biodegradable. The in vitro release of doxorubicin from this OAEU hydrogel was sustained for more than 10 days. This injectable biodegradable pH/temperature-sensitive OAEU hydrogel is a potential candidate as a drug/protein carrier and in biomedical applications.

  16. Modeling and Sensitivity Analysis of Acoustic Release of Doxorubicin from Unstabilized Pluronic P105 using an Artificial Neural Network Model

    PubMed Central

    Husseini, Ghaleb A.; Abdel-Jabbar, Nabil M.; Mjalli, Farouq S.; Pitt, William G.

    2007-01-01

    This paper models steady state acoustic release of Doxorubicin (Dox) from Pluronic P105 micelles using Artificial Neural Networks (ANN). Previously collected release data were compiled and used to train, validate, and test an ANN model. Sensitivity analysis was then performed on the following operating conditions: ultrasonic frequency, power density, Pluronic P105 concentration, and temperature. The model showed that drug release was most efficient at lower frequencies. The analysis also demonstrated that release increases as the power density increases. Sensitivity plots of ultrasound intensity revealed a drug release threshold of 0.015 W/cm2 and 0.38 W/cm2 at 20 and 70 kHz, respectively. The presence of a power density threshold provides strong evidence that cavitation plays an important role in acoustically activated drug release from polymeric micelles. Based on the developed model, Dox release is not a strong function of temperature, suggesting that thermal effects do not play a major role in the physical mechanism involved. Finally, sensitivity plots of P105 concentration indicated that higher release was observed at lower copolymer concentrations. PMID:17241100

  17. Preparation of polyelectrolyte complex nanoparticles of chitosan and poly(2-acry1amido-2-methylpropanesulfonic acid) for doxorubicin release.

    PubMed

    Zhang, Liping; Wang, Jie; Ni, Caihua; Zhang, Yanan; Shi, Gang

    2016-01-01

    A new kind of polyelectrolyte complex (PEC) based on cationic chitosan (CS) and anionic poly(2-acry1amido-2-methylpropanesulfonic acid) (PAMPS) was prepared using a polymer-monomer pair reaction system. Chitosan was mixed with 2-acry1amido-2-methylpropanesulfonic acid) (AMPS) in an aqueous solution, followed by polymerization of AMPS. The complex was formed by electrostatic interaction of NH3(+) groups of CS and SO3(-) groups of AMPS, leading to a formation of complex nanoparticles of CS-PAMPS. A series of nanoparticles were obtained by changing the weight ratio of CS to AMPS, the structure and properties of nanoparticles were investigated. It was observed that the nanoparticles possessed spherical morphologies with average diameters from 255 nm to 390 nm varied with compositions of the nanoparticles. The nanoparticles were used as drug vehicles for doxorubicin, displaying relative high drug loading rate and encapsulation rate. The vitro release profiles revealed that the drug release could be controlled by adjusting pH of the release media. The nanoparticles demonstrated apparent advantages such as simple preparation process, free of organic solvents, size controllable, good biodegradability and biocompatibility, and they could be potentially used in drug controlled release field.

  18. Rational design of multifunctional micelles against doxorubicin-sensitive and doxorubicin-resistant MCF-7 human breast cancer cells

    PubMed Central

    Hong, Wei; Shi, Hong; Qiao, Mingxi; Gao, Xiang; Yang, Jie; Tian, Chunlian; Zhang, Dexian; Niu, Shengli; Liu, Mingchun

    2017-01-01

    Even though a tremendous number of multifunctional nanocarriers have been developed to tackle heterogeneous cancer cells, little attention has been paid to elucidate how to rationally design a multifunctional nanocarrier. In this study, three individual functions (active targeting, stimuli-triggered release and endo-lysosomal escape) were evaluated in doxorubicin (DOX)-sensitive MCF-7 cells and DOX-resistant MCF-7/ADR cells by constructing four kinds of micelles with active-targeting (AT-M), passive targeting, pH-triggered release (pHT-M) and endo-lysosomal escape (endoE-M) function, respectively. AT-M demonstrated the strongest cytotoxicity against MCF-7 cells and the highest cellular uptake of DOX due to the folate-mediated endocytosis. However, AT-M failed to exhibit the best efficacy against MCF-7/ADR cells, while endoE-M exhibited the strongest cytotoxicity against MCF-7/ADR cells and the highest cellular uptake of DOX due to the lowest elimination of DOX from the cells. This was attributed to the carrier-facilitated endo-lysosomal escape of DOX, which avoided exocytosis by lysosome secretion, resulting in an effective accumulation of DOX in the cytoplasm. The enhanced elimination of DOX from the MCF-7/ADR cells also accounted for the remarkable decrease in cytotoxicity against the cells of AT-M. Three micelles were further evaluated with MCF-7 cells and MCF-7/ADR-resistant cells xenografted mice model. In accordance with the in vitro results, AT-M and endoE-M demonstrated the strongest inhibition on the MCF-7 and MCF-7/ADR xenografted tumor, respectively. Active targeting and active targeting in combination with endo-lysosomal escape have been demonstrated to be the primary function for a nanocarrier against doxorubicin-sensitive and doxorubicin-resistant MCF-7 cells, respectively. These results indicate that the rational design of multifunctional nanocarriers for cancer therapy needs to consider the heterogeneous cancer cells and the primary function needs

  19. Technetium-99m red blood cell labeling in patients treated with doxorubicin

    SciTech Connect

    Ballinger, J.R.; Gerson, B.; Gulenchyn, K.Y.; Ruddy, T.D.; Davies, R.A.

    1988-03-01

    Radionuclide angiography is useful in monitoring cardiotoxicity of doxorubicin, but in vivo RBC labeling in these patients is believed to be poorer than that in general patients. The left ventricle-to-background activity ratio (R) was not significantly lower in patients treated with doxorubicin (3.24 +/- 1.15, N = 13) than in control patients (3.89 +/- 1.60, N = 14). With both modified in vivo and in vitro labeling, R was significantly improved in patients treated with doxorubicin (4.37 +/- 0.91, N = 8, and 4.37 +/- 1.22, N = 13, respectively). However, with the modified in vivo method, labeling efficiency remained a function of hematocrit, whereas the in vitro method removed this dependency. Both modified in vivo and in vitro labeling result in improved image quality over in vivo labeling in patients treated with doxorubicin, and the choice of method can be based on other factors.

  20. Early downregulation of acute phase proteins after doxorubicin exposition in patients with breast cancer.

    PubMed

    Panis, Carolina; Pizzatti, Luciana; Bufalo, Aedra Carla; Herrera, Ana Cristina; Victorino, Vanessa Jacob; Cecchini, Rubens; Abdelhay, Eliana

    2016-03-01

    Chemotherapy remains the first-choice option for adjuvant therapy in breast cancer. Here, we investigated the impact of the first chemotherapic cycle of doxorubicin on the plasmatic-proteomic profiling of women diagnosed with breast cancer (n = 87). Blood samples were obtained from the same patient before and after doxorubicin infusion (1 h, 60 mg/m(2)) and processed for label-free LC-MS proteomic screening. A total of 80 proteins were downregulated after chemotherapy. In silico analysis revealed that the main biological process enrolled was inflammation and canonical pathways involving acute phase proteins. TNF-α, IL-1β, IL-12, TGF-β1, clusterin, and gelsolin were chosen as relevant for further validation. All selected targets presented reduced plasmatic levels after treatment. Our results indicate that doxorubicin downregulated acute phase proteins immediately after its infusion. Since such proteins are cancer promoting, its downregulation could support the effectiveness of doxorubicin along treatment.

  1. Prolonged pegylated liposomal doxorubicin treatment for recurrent pelvic cancers: a feasibility study.

    PubMed

    Rabinovich, Alex; Ramanakumar, Agnihotram V; Lau, Susie; Gotlieb, Walter H

    2015-07-01

    We conducted a proof of concept study evaluating prolonged treatment with pegylated liposomal doxorubicin for recurrent ovarian, tubal and peritoneal carcinoma. Thirteen consecutive patients received an average of 22.6 cycles of pegylated liposomal doxorubicin, with an average cumulative dose of 1409 mg/m(2) . Progression-free survival at 18 months was 61.5%, and was longer than the previous progression-free survival in 10 of the 13 patients. Overall 5-year survival was 78.8%. Despite prolonged use and relatively large cumulative doses of pegylated liposomal doxorubicin, most of the patients had mild to moderate side-effects, none of the patients had detectable cardio-toxic side-effects, and a positive impact on the performance status was noticed. Thus, in our group of patients, continued pegylated liposomal doxorubicin treatment was associated with a longer progression-free interval and allowed improved performance status with manageable toxicity.

  2. Conductometric, surface tension, and kinetic studies in mixed SDS-Tween 20 and SDS-SB3-12 micellar solutions.

    PubMed

    Muñoz, María; Rodríguez, Amalia; Graciani, María Del Mar; Moyá, María Luisa

    2004-12-07

    Micellization in sodium dodecyl sulfate (SDS)-N-dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate and SDS-polyoxyethylenesorbitan monolaurate binary surfactant solutions was studied by means of conductivity and surface tension measurements. These studies showed that two types of micellar aggregates are present in the mixed micellar solutions. Two reactions were investigated in these micellar media, the oxidation of 1-methoxy-4-(methylthio)benzene by IO(4)(-) and the spontaneous hydrolysis of phenyl chloroformate. Information on the distribution of reagents in the micellar reaction media was obtained through conductivity and spectroscopic measurements. Discussion of the kinetic data showed that the redox reaction takes place mainly in the aqueous phase of the mixed solutions, whereas hydrolysis occurs in the aqueous as well as in the micellar pseudophase. Variations in the observed rate constants of the two processes studied are gradual within the whole surfactant concentration range investigated, revealing little information about the mixed micellar medium.

  3. Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro.

    PubMed

    Spallarossa, Paolo; Garibaldi, Silvano; Altieri, Paola; Fabbi, Patrizia; Manca, Valeria; Nasti, Sabina; Rossettin, Pierfranco; Ghigliotti, Giorgio; Ballestrero, Alberto; Patrone, Franco; Barsotti, Antonio; Brunelli, Claudio

    2004-10-01

    The clinical use of doxorubicin, a highly active anticancer drug, is limited by its severe cardiotoxic side effects. Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity of doxorubicin. Carvedilol is an adrenergic blocking agent with potent anti-oxidant activity. In this study we investigated whether carvedilol has protective effects against doxorubicin-induced free radical production and apoptosis in cultured cardiac muscle cells, and we compared the effects of carvedilol to atenolol, a beta-blocker with no anti-oxidant activity. Reactive oxygen species (ROS) generation in cultured cardiac muscle cells (H9c2 cells) was evaluated by flow cytometry using dichlorofluorescein (DCF) and hydroethidine (HE). Apoptosis was assessed by measuring annexin V-FITC/propidium iodide double staining, DNA laddering, levels of expression of the pro-apoptotic protein Bax-alpha and the anti-apoptotic protein Bcl-2, and caspase-3 activity. Pre-treatment with carvedilol significantly attenuated the doxorubicin-induced increases in DCF (P < 0.001 compared to cells not pre-treated with carvedilol) and HE (P < 0.01) fluorescence. Doxorubicin increased the fraction of annexin V-FITC-positive fluorescent cells, while pre-treatment with carvedilol reduced the number of positive fluorescent cells (P < 0.01). Doxorubicin-induced DNA fragmentation to a clear ladder pattern, while carvedilol prevented DNA fragmentation. Doxorubicin-induced a fall in mRNA expression of the anti-apoptotic Bcl-2 and an increase in the expression of the pro-apoptotic Bax-alpha. Carvedilol pre-treatment blunted both the decrease of Bcl-2 (P < 0.01) and the increase of Bax-alpha mRNA expression (P < 0.01). Caspase-3 activity significantly increased after the addition of doxorubicin. Concurrently, carvedilol partially inhibited the doxorubicin-induced activation of caspase-3 (P < 0.01). Atenolol did not produce any effect in preventing doxorubicin-induced ROS generation and cardiac

  4. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    SciTech Connect

    Henninger, Christian; Huelsenbeck, Johannes; Huelsenbeck, Stefanie; Grösch, Sabine; Lackner, Karl J.; Kaina, Bernd; Fritz, Gerhard

    2012-05-15

    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by an attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  5. Decreased Soluble Guanylate Cyclase Contributes to Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice

    PubMed Central

    Vandenwijngaert, Sara; Swinnen, Melissa; Walravens, Ann-Sophie; Beerens, Manu; Gillijns, Hilde; Caluwé, Ellen; Tainsh, Robert E.; Nathan, Daniel I.; Allen, Kaitlin; Brouckaert, Peter; Bartunek, Jozef; Scherrer-Crosbie, Marielle; Bloch, Kenneth D.; Bloch, Donald B.; Janssens, Stefan P.

    2017-01-01

    Abstract Aims: The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity. Results: Doxorubicin administration (20 mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC α1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGCα1 allele [sGCα1−/−CM]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGCα1−/−CM than WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGCα1 mutant (DNsGCα1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGCα1tg/+, but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGCα1tg/+ and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGCα1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGCα1-deficient than WT hearts. Innovation and Conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use and may represent a promising approach to limit doxorubicin

  6. Conformational transition and mass transfer in extraction of proteins by AOT--alcohol--isooctane reverse micellar systems.

    PubMed

    Hong, D P; Lee, S S; Kuboi, R

    2000-06-23

    We examined quantitatively the effect of alcohols on protein and reverse micellar structure. We used circular dichroism (CD) to compare the effects of various alcohols on the protein structure, and percolation phenomena to evaluate the effects of various alcohols on reverse micellar structure. Upon the addition of alcohols to the bulk aqueous phase, proteins were denatured significantly, depending on the alcohol species and concentration, suggesting that use of alcohol directly to the stripping solution is not effective in back-extraction processes of proteins. In the present study, a new method, a small amount of alcohol is added to the surfactant-organic solution to improve the back-extraction behaviors of proteins. Practically, in the back-extraction process, the alcohols suppressing the cluster formation of reverse micelles (high value of beta1), remarkably improved the back-extraction behavior of proteins. In addition, the same alcohol molecules showed a positive effect on the rate and fraction of protein back-extraction. From a result of the CD measurement of the back-extracted proteins, it was known that the alcohols added to reverse micellar solution allowed the proteins to back-extract safely without causing structural changes. These results show that the values of beta(t), defined by the variation of percolation processes, and the back-extraction behaviors of proteins have a good relationship, suggesting that the back-extraction processes were controlled by the micellar-micellar and protein-micellar interactions.

  7. Kinetics and mechanism of bimolecular electron transfer reaction in quinone-amine systems in micellar solution

    SciTech Connect

    Kumbhakar, Manoj; Nath, Sukhendu; Mukherjee, Tulsi; Pal, Haridas

    2005-02-22

    Photoinduced electron transfer (ET) reactions between anthraquinone derivatives and aromatic amines have been investigated in sodium dodecyl sulphate (SDS) micellar solutions. Significant static quenching of the quinone fluorescence due to high amine concentration in the micellar phase has been observed in steady-state measurements. The bimolecular rate constants for the dynamic quenching in the present systems k{sub q}{sup TR}, as estimated from the time-resolved measurements, have been correlated with the free energy changes {delta}G{sup 0} for the ET reactions. Interestingly it is seen that the k{sub q}{sup TR} vs {delta}G{sup 0} plot displays an inversion behavior with maximum k{sub q}{sup TR} at around 0.7 eV, a trend similar to that predicted in Marcus ET theory. Like the present results, Marcus inversion in the k{sub q}{sup TR} values was also observed earlier in coumarin-amine systems in SDS and TX-100 micellar solutions, with maximum k{sub q}{sup TR} at around the same exergonicity. These results thus suggest that Marcus inversion in bimolecular ET reaction is a general phenomenon in micellar media. Present observations have been rationalized on the basis of the two-dimensional ET (2DET) theory, which seems to be more suitable for micellar ET reactions than the conventional ET theory. For the quinone-amine systems, it is interestingly seen that k{sub q}{sup TR} vs {delta}G{sup 0} plot is somewhat wider in comparison to that of the coumarin-amine systems, even though the maxima in the k{sub q}{sup TR} vs {delta}G{sup 0} plots appear at almost similar exergonicity for both the acceptor-donor systems. These observations have been rationalized on the basis of the differences in the reaction windows along the solvation axis, as envisaged within the framework of the 2DET theory, and arise due to the differences in the locations of the quinones and coumarin dyes in the micellar phase.

  8. Peroxisome Proliferator-Activated Receptor-α Inhibition Protects Against Doxorubicin-Induced Cardiotoxicity in Mice.

    PubMed

    Rahmatollahi, Mahdieh; Baram, Somayeh Mahmoodi; Rahimian, Reza; Saeedi Saravi, Seyed Soheil; Dehpour, Ahmad Reza

    2016-07-01

    Doxorubicin is an effective chemotherapeutic drug against a considerable number of malignancies. However, its toxic effects on myocardium are confirmed as major limit of utilization. PPAR-α is highly expressed in the heart, and its activation leads to an increased cardiac fatty acid oxidation and cardiomyocyte necrosis. This study was performed to adjust the hypothesis that PPAR-α receptor inhibition protects against doxorubicin-induced cardiac dysfunction in mice. Male Balb/c mice were used in this study. Left atria were isolated, and their contractility was measured in response to electrical field stimulation in a standard organ bath. PPAR-α activity was measured using specific PPAR-α antibody in an ELISA-based system coated with double-strand DNA containing PPAR-α response element sequence. Moreover, cardiac MDA and TNF-α levels were measured by ELISA method. Following incubation with doxorubicin (35 µM), a significant reduction in atrial contractility was observed (P < 0.001). Pretreatment of animals with a selective PPAR-α antagonist, GW6471, significantly improved doxorubicin-induced atrial dysfunction (P < 0.001). Furthermore, pretreatment of the mice with a non-selective cannabinoid agonist, WIN55212-2, significantly decreased PPAR-α activity in cardiac tissue, subsequently leading to significant improvement in doxorubicin-induced atrial dysfunction (P < 0.001). Also, GW6471 and WIN significantly reduced cardiac MDA and TNF-α levels compared with animals receiving doxorubicin (P < 0.001). The study showed that inhibition of PPAR-α is associated with protection against doxorubicin-induced cardiotoxicity in mice, and cannabinoids can potentiate the protection by PPAR-α blockade. Moreover, PPAR-α may be considered as a target to prevent cardiotoxicity induced by doxorubicin in patients undergoing chemotherapy.

  9. Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors.

    PubMed

    Yu, Man; Lee, Carol; Wang, Marina; Tannock, Ian F

    2015-10-01

    Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined the effects of the PPI lansoprazole to modify the activity of doxorubicin. To gain insight into its mechanisms, we studied the effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole showed concentration-dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances the therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors.

  10. Combined effects of zoledronic acid and doxorubicin on breast cancer cell invasion in vitro.

    PubMed

    Woodward, Julia K L; Neville-Webbe, Helen L; Coleman, Robert E; Holen, Ingunn

    2005-09-01

    The bisphosphonate zoledronic acid and the cytotoxic drug doxorubicin induce synergistic levels of apoptosis in breast cancer cells. As zoledronic acid and doxorubicin have been shown to reduce cell invasion and migration, we have investigated if these drugs also act synergistically on breast cancer invasion in vitro. MCF7 cells were treated with 0.05 microM doxorubicin/4 h followed by 1 or 10 microM zoledronic acid/24 h (or the reverse sequence). To study invasion, MCF7 cells were either grown on Transwell membranes coated with Matrigel or in a 24-well plate. Cells were treated sequentially using the above drug combinations, prior to starting the invasion assays for 48 h. Cell growth and death were also assessed under the same conditions. We found that invasion of MCF7 cells treated with zoledronic acid and doxorubicin was significantly reduced when compared with control, but the effect was dependent on drug sequence. At 1 microM, zoledronic acid significantly reduced invasion only if cells were pre-treated with doxorubicin, but cell growth was unaffected. For 10 microM zoledronic acid, invasion was reduced when administered before or after the doxorubicin, but this dose of zoledronic acid caused a significant reduction in MCF7 growth. Apoptosis was not induced by any of the drug doses and combinations. We conclude that pre-treatment with 0.05 microM doxorubicin followed by 1 microM zoledronic acid reduces invasion when cells were grown on Matrigel. For 10 microM zoledronic acid, pre- or post-doxorubicin also reduces invasion, but for this combination inhibition of cell growth may contribute to the reduction in invasion observed.

  11. High fat diet-fed obese rats are highly sensitive to doxorubicin-induced cardiotoxicity

    SciTech Connect

    Mitra, Mayurranjan S.; Donthamsetty, Shashikiran; White, Brent; Mehendale, Harihara M.

    2008-09-15

    Often, chemotherapy by doxorubicin (Adriamycin) is limited due to life threatening cardiotoxicity in patients during and posttherapy. Recently, we have shown that moderate diet restriction remarkably protects against doxorubicin-induced cardiotoxicity. This cardioprotection is accompanied by decreased cardiac oxidative stress and triglycerides and increased cardiac fatty-acid oxidation, ATP synthesis, and upregulated JAK/STAT3 pathway. In the current study, we investigated whether a physiological intervention by feeding 40% high fat diet (HFD), which induces obesity in male Sprague-Dawley rats (250-275 g), sensitizes to doxorubicin-induced cardiotoxicity. A LD{sub 10} dose (8 mg doxorubicin/kg, ip) administered on day 43 of the HFD feeding regimen led to higher cardiotoxicity, cardiac dysfunction, lipid peroxidation, and 80% mortality in the obese (OB) rats in the absence of any significant renal or hepatic toxicity. Doxorubicin toxicokinetics studies revealed no change in accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the normal diet-fed (ND) and OB hearts. Mechanistic studies revealed that OB rats are sensitized due to: (1) higher oxyradical stress leading to upregulation of uncoupling proteins 2 and 3, (2) downregulation of cardiac peroxisome proliferators activated receptor-{alpha}, (3) decreased plasma adiponectin levels, (4) decreased cardiac fatty-acid oxidation (666.9 {+-} 14.0 nmol/min/g heart in ND versus 400.2 {+-} 11.8 nmol/min/g heart in OB), (5) decreased mitochondrial AMP-{alpha}2 protein kinase, and (6) 86% drop in cardiac ATP levels accompanied by decreased ATP/ADP ratio after doxorubicin administration. Decreased cardiac erythropoietin and increased SOCS3 further downregulated the cardioprotective JAK/STAT3 pathway. In conclusion, HFD-induced obese rats are highly sensitized to doxorubicin-induced cardiotoxicity by substantially downregulating cardiac mitochondrial ATP generation, increasing oxidative stress and downregulating

  12. A unique squalenoylated and nonpegylated doxorubicin nanomedicine with systemic long-circulating properties and anticancer activity

    PubMed Central

    Maksimenko, Andrei; Dosio, Franco; Mougin, Julie; Ferrero, Annalisa; Wack, Severine; Reddy, L. Harivardhan; Weyn, Andrée-Anne; Lepeltier, Elise; Bourgaux, Claudie; Stella, Barbara; Cattel, Luigi; Couvreur, Patrick

    2014-01-01

    We identified that the chemical linkage of the anticancer drug doxorubicin onto squalene, a natural lipid precursor of the cholesterol’s biosynthesis, led to the formation of squalenoyl doxorubicin (SQ-Dox) nanoassemblies of 130-nm mean diameter, with an original “loop-train” structure. This unique nanomedicine demonstrates: (i) high drug payload, (ii) decreased toxicity of the coupled anticancer compound, (iii) improved therapeutic response, (iv) use of biocompatible transporter material, and (v) ease of preparation, all criteria that are not combined in the currently available nanodrugs. Cell culture viability tests and apoptosis assays showed that SQ-Dox nanoassemblies displayed comparable antiproliferative and cytotoxic effects than the native doxorubicin because of the high activity of apoptotic mediators, such as caspase-3 and poly(ADP-ribose) polymerase. In vivo experiments have shown that the SQ-Dox nanomedicine dramatically improved the anticancer efficacy, compared with free doxorubicin. Particularly, the M109 lung tumors that did not respond to doxorubicin treatment were found inhibited by 90% when treated with SQ-Dox nanoassemblies. SQ-Dox nanoassembly-treated MiaPaCa-2 pancreatic tumor xenografts in mice decreased by 95% compared with the tumors in the saline-treated mice, which was significantly higher than the 29% reduction achieved by native doxorubicin. Concerning toxicity, SQ-Dox nanoassemblies showed a fivefold higher maximum-tolerated dose than the free drug, and moreover, the cardiotoxicity study has evidenced that SQ-Dox nanoassemblies did not cause any myocardial lesions, such as those induced by the free doxorubicin treatment. Taken together, these findings demonstrate that SQ-Dox nanoassemblies make tumor cells more sensitive to doxorubicin and reduce the cardiac toxicity, thus providing a remarkable improvement in the drug’s therapeutic index. PMID:24385587

  13. Doxorubicin toxicity can be ameliorated during antioxidant L-carnitine supplementation.

    PubMed

    Alshabanah, Othman A; Hafez, Mohamed M; Al-Harbi, Mohamed M; Hassan, Zeinab K; Al Rejaie, Salim S; Asiri, Yosef A; Sayed-Ahmed, Mohamed M

    2010-01-01

    Doxorubicin is an antibiotic broadly used in treatment of different types of solid tumors. The present study investigates whether L-carnitine, antioxidant agent, can reduce the hepatic damage induced by doxorubicin. Male Wistar albino rats were divided into six groups: group 1 were intraperitoneal injected with normal saline for 10 consecutive days; group 2, 3 and 4 were injected every other day with doxorubicin (3 mg/kg, i.p.), to obtain treatments with cumulative doses of 6, 12, and 18 mg/kg. The fifth group was injected with L-carnitine (200 mg/kg, i.p.) for 10 consecutive days and the sixth group was received doxorubicin (18 mg/kg) and L-carnitine (200 mg/kg). High cumulative dose of doxorubicin (18 mg/kg) significantly increase the biochemical levels of alanine transaminase , alkaline phosphatase, total bilirubin, total carnitine, thiobarbituric acid reactive substances (TBARs), total nitrate/nitrite (NOx) p < 0.05 and decrease in glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GSHPx), glutathione-s-transferase (GST),glutathione reductase (GR) and catalase (CAT) activity p < 0.05. The effect of doxorubicin on the activity of antioxidant genes was confirmed by real time PCR in which the expression levels of these genes in liver tissue were significantly decrease compared to control p < 0.05. Interestingly, L-carnitine supplementation completely reverse the biochemical and gene expression levels induced by doxorubicin to the control values. In conclusion, data from this study suggest that the reduction of antioxidant defense during doxorubicin administration resulted in hepatic injury could be prevented by L-carnitine supplementation by decreasing the oxidative stress and preserving both the activity and gene expression level of antioxidant enzymes.

  14. Hyperthermic potentiation of doxorubicin and 4'-EPI-doxorubicin in a transplantable neurogenic rat tumor (BT/sub 4/A) in BD IX rats

    SciTech Connect

    Dahl, O.

    1983-02-01

    The combined effect of hyperthermia and doxorubicin on the neurogenic rat cell line BT/sub 4/C was found to be synergistic in vitro. The present investigation was initiated to study if this synergistic effect also could be obtained in vivo. An enhanced effect occurred when doxorubicin and 4'-epi-doxorubicin 7 mg/kg body weight were given 30 minutes prior to local water bath hyperthermia (one hour at 44.0 degrees C). The local side effects of the combined treatment did not increase above that of hyperthermia alone. Therefore, local hyperthermia may become a useful modality for enhancement of the effect of anthracyclines on tumors with marginal drug sensitivity or bulky tumors with poor drug penetration.

  15. Zero order delivery of itraconazole via polymeric micelles incorporated in situ ocular gel for the management of fungal keratitis.

    PubMed

    Jaiswal, Munmun; Kumar, Manish; Pathak, Kamla

    2015-06-01

    The aim of this article is to investigate the role of amphiphilic block copolymer-based polymeric micelles of itraconazole for the management of fungal keratitis to overcome the limitations of the conventional dosage form. The polymeric micelles were made using pluronics above critical micelle concentration. Itraconazole-loaded polymeric micelles prepared by rotary evaporation method were characterized and the optimized micellar formulation (M5) was selected on the basis of least micelle size (79.99 nm), maximum entrapment efficiency (91.32%±1.73%) and in vitro permeation (90.28%±0.31%) in 8h, that best fitted zero-order kinetics. M5 was developed as pH sensitive in situ gel and characterized for various parameters. The optimized in situ gel (F5) proved to be superior in its ex vivo transcorneal permeation when compared with Itral(®) eye drop and pure drug suspension, exhibiting 41.45%±0.87% permeation with zero-order kinetics (r(2)=0.994) across goat cornea. Transmission electron microscopy revealed spherical polymeric micelles entrapped in the gel matrix. A spectrum of tests revealed hydration capability, non-irritancy, and histologically safe gel formulation that had appropriate handling characteristics. Conclusively, a controlled release pH-sensitive ocular formulation capable of carrying drug to the anterior segment of the eye via topical delivery was successfully developed for the treatment of fungal keratitis.

  16. Kinetic study of the reaction *[Ru(bpy) 3] 2++S 2O 82- in solutions of Brij-35 at premicellar and micellar concentrations

    NASA Astrophysics Data System (ADS)

    López-Cornejo, P.; Mozo, J. D.; Roldán, E.; Domínguez, M.; Sánchez, F.

    2002-01-01

    The title reaction was studied in solutions of polyoxyethylene(23) lauryl ether (Brij-35) at premicellar and micellar concentrations. The reaction rate goes through a maximum, which appears at a concentration close to the critical micellar concentration (cmc). The results can be rationalized by an extension of previous models on premicellar and micellar effects on the kinetics of reactions. This model can explain similar results from other groups.

  17. Hypothalamic energy metabolism is impaired by doxorubicin independently of inflammation in non-tumour-bearing rats.

    PubMed

    Antunes, Barbara M M; Lira, Fabio Santos; Pimentel, Gustavo Duarte; Rosa Neto, José Cesar; Esteves, Andrea Maculano; Oyama, Lila Missae; de Souza, Cláudio Teodoro; Gonçalves, Cinara Ludvig; Streck, Emilio Luiz; Rodrigues, Bruno; dos Santos, Ronaldo Vagner; de Mello, Marco Túlio

    2015-08-01

    We sought to explore the effects of doxorubicin on inflammatory profiles and energy metabolism in the hypothalamus of rats. To investigate these effects, we formed two groups: a control (C) group and a Doxorubicin (DOXO) group. Sixteen rats were randomly assigned to either the control (C) or DOXO groups. The hypothalamus was collected. The levels of interleukin (IL)-1β, IL-6, IL-10, TNF-α and energy metabolism (malate dehydrogenase, complex I and III activities) were analysed in the hypothalamus. The DOXO group exhibited a decreased body weight (p < 0.01). Hypothalamic malate dehydrogenase activity was reduced when compared with control (p < 0.05). In addition, pro-inflammatory cytokine levels were unchanged. Therefore, our results demonstrate that doxorubicin leads to an impairment of \\hypothalamic energy metabolism, but do not affect the inflammatory pathway. SIGNIFICANCE PARAGRAPH: The hypothalamus is a central organ that regulates a great number of functions, such as food intake, temperature and energy expenditure, among others. Doxorubicin can lead to deep anorexia and metabolic chaos; thus, we observed the effect of this chemotherapeutic drug on the inflammation and metabolism in rats after the administration of doxorubicin in order to understand the central effect in the hypothalamus. Drug treatment by doxorubicin is used as a cancer therapy; however the use of this drug may cause harmful alterations to the metabolism. Thus, further investigations are needed on the impact of drug therapy over the long term.

  18. Enhancing Cellular Uptake and Doxorubicin Delivery of Mesoporous Silica Nanoparticles via Surface Functionalization: Effects of Serum.

    PubMed

    Shahabi, Shakiba; Döscher, Svea; Bollhorst, Tobias; Treccani, Laura; Maas, Michael; Dringen, Ralf; Rezwan, Kurosch

    2015-12-09

    In this study, we demonstrate how functional groups on the surface of mesoporous silica nanoparticles (MSNPs) can influence the encapsulation and release of the anticancer drug doxorubicin, as well as cancer cell response in the absence or presence of serum proteins. To this end, we synthesized four differently functionalized MSNPs with amine, sulfonate, polyethylene glycol, or polyethylene imine functional surface groups, as well as one type of antibody-conjugated MSNP for specific cellular targeting, and we characterized these MSNPs regarding their physicochemical properties, colloidal stability in physiological media, and uptake and release of doxorubicin in vitro. Then, the MSNPs were investigated for their cytotoxic potential on cancer cells. Cationic MSNPs could not be loaded with doxorubicin and did therefore not show any cytotoxic and antiproliferative potential on osteosarcoma cells, although they were efficiently taken up into the cells in the presence or absence of serum. In contrast, substantial amounts of doxorubicin were loaded into negatively charged and unfunctionalized MSNPs. Especially, sulfonate-functionalized doxorubicin-loaded MSNPs were efficiently taken up into the cells in the presence of serum and showed an accelerated toxic and antiproliferative potential compared to unfunctionalized MSNPs, antibody-conjugated MSNPs, and even free doxorubicin. These findings stress the high importance of the surface charge as well as of the protein corona for designing and applying nanoparticles for targeted drug delivery.

  19. High-intensity focused ultrasound-mediated doxorubicin delivery with thermosensitive liposomes

    NASA Astrophysics Data System (ADS)

    Escoffre, Jean-Michel; Mannaris, Christophoros; Novell, Anthony; Rioc, Laëtitia; Meyre, Marie-Edith; Germain, Matthieu; Averkiou, Michalakis; Bouakaz, Ayache

    2012-10-01

    Local drug delivery of doxorubicin holds promise to improve the therapeutic efficacy and to reduce toxicity profiles. Here, we investigated the release of doxorubicin from thermosensitive liposomes (Dox-TSL) into human glioblastoma (U-87MG) cells. Using Dox-TSL, experiments were carried out in a water bath and showed that 15 min incubation of TSL at 43°C induced the release of 80% doxorubicin loaded TSL compared to the release at 37°C. The cytotoxicity of a range of concentrations of Dox-TSL was also evaluated on U-87MG cells. At 37°C, no cytotoxicity was observed, whereas at 43°C the results showed that the cytotoxicity is dose dependent. At maximal dose of doxorubicin (30 μg/mL), the cell viability was less than 20%. Application of 15 min of HIFU at 1 MHz, 1.5 MPa and 50% duty cycle induced the release of 100% of doxorubicin from Dox-TSL. In the same experimental condition, the cell viability decreased to 40% and 20% at 12h and 48h, respectively, in comparison to that obtained during the incubation of cells with Dox-TSL alone without HIFU. In conclusion, a significant release of doxorubicin from temperature-sensitive liposomes can be achieved leading to an efficient treatment and cell death of tumor cells using HIFU.

  20. In vitro anti-cancer activity of doxorubicin against human RNA helicase, DDX3

    PubMed Central

    Botlagunta, Mahendran; Kollapalli, Bhulakshmi; Kakarla, Lavanya; Gajarla, Siva Priya; Gade, Sai Pujitha; Dadi, Chandra Lekha; Penumadu, Akhila; Javeed, Shaik

    2016-01-01

    RNA helicase, DDX3 is a multifunctional enzyme and is known to be associated with several diseases like HIV progression, brain and breast cancer. Some of the ring expanded nucleoside compounds such as REN: NZ51, fused di imidazodiazepine ring (RK33), (Z)-3-(5- (3-bromo benzylidene)-4-oxo-2-thioxothiazolidin-3-yl)-N-(2- hydroxy phenyl) propanamide compound (FE15) have been documented to inhibit DDX3 helicase activity. However, synthesis of these drugs is limited to few research groups. Prevalence of literature study, we found that doxorubicin form strong hydrogen bond interactions with crystallized form of DDX3 using in-silico molecular docking approach. To evaluate the biological inhibitory action of doxorubicin, we performed the ATPase activity assay and anti-cancer activity using H357 cancer cell lines. Results showed that doxorubicin continually declined the inorganic phosphate (Pi) release and inhibited the ATP hydrolysis by directly interacting with DDX3. Anticancer activity was detected by MTT assay. The half maximal inhibitory concentrations of doxorubicin (IC50) for H357 cancer cell line is 50 μM and also doxorubicin significantly down regulated the expression of DDX3. Taken together, our results demonstrate, that inhibition of DDX3 expression by using doxorubicin can be used as an ideal drug candidate to treat DDX3 associated cancer disorder by interacting with unique amino acid residues (Thr 198) and common amino acid residues (Tyr 200 and Thr 201). PMID:28246464

  1. A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence

    PubMed Central

    Ghosh, Asish K.; Rai, Rahul; Park, Kitae E.; Eren, Mesut; Miyata, Toshio; Wilsbacher, Lisa D.; Vaughan, Douglas E.

    2016-01-01

    Doxorubicin, an anthracycline antibiotic, is a commonly used anticancer drug. In spite of its widespread usage, its therapeutic effect is limited by its cardiotoxicity. On the cellular level, Doxorubicin-induced cardiotoxicity manifests as stress induced premature senescence. Previously, we demonstrated that plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of serine proteases, is an important biomarker and regulator of cellular senescence and aging. Here, we tested the hypothesis that pharmacological inhibition of cellular PAI-1 protects against stress- and aging-induced cellular senescence and delineated the molecular basis of protective action of PAI-1 inhibition. Results show that TM5441, a potent small molecule inhibitor of PAI-1, effectively prevents Doxorubicin-induced senescence in cardiomyocytes, fibroblasts and endothelial cells. TM5441 exerts its inhibitory effect on Doxorubicin-induced cellular senescence by decreasing reactive oxygen species generation, induction of antioxidants like catalase and suppression of stress-induced senescence cadre p53, p21, p16, PAI-1 and IGFBP3. Importantly, TM5441 also reduces replicative senescence of fibroblasts. Together these results for the first time demonstrate the efficacy of PAI-1 inhibitor in prevention of Doxorubicin-induced and replicative senescence in normal cells. Thus PAI-1 inhibitor may form an important adjuvant component of chemotherapy regimens, limiting not only Doxorubicin-induced cardiac senescence but also ameliorating the prothrombotic profile. PMID:27736799

  2. Local sequence requirements for DNA cleavage by mammalian topoisomerase II in the presence of doxorubicin.

    PubMed Central

    Capranico, G; Kohn, K W; Pommier, Y

    1990-01-01

    Doxorubicin, a DNA-intercalator, is one of several anti-cancer drugs that have been found to stabilizes topoisomerase II cleavage complexes at drug-specific DNA sites. The distribution and DNA sequence environments of doxorubicin-stabilized sites were determined in the SV40 genome. The sites were found to be most concentrated in the major nuclear matrix-associated region and nearly absent in the vicinity of the replication origin including the enhancer sequences in the 21-bp and 72-bp tandem repeats. Among 97 doxorubicin-stabilized sites that were localized at the DNA sequence level, none coincided with any of the 90 topoisomerase II cleavage sites detected in the same regions in the absence of drug. Cleavage at the 90 enzyme-only sites was inhibited by doxorubicin and never stimulated even at low drug concentrations. All of the doxorubicin-stabilized sites had an A at the 3' terminus of at least one member of each pair of strand breaks that would constitute a topoisomerase II double-strand scission. Conversely, none of the enzyme-only sites had an A simultaneously at the corresponding positions on opposite strands. The 3'-A requirement for doxorubicin-stabilized cleavage is therefore incompatible with enzyme-only cleavage and explains the mutual exclusivity of the two classes of sites. Images PMID:2174543

  3. Doxorubicin liposomes as an investigative model to study the skin permeation of nanocarriers.

    PubMed

    Boakye, Cedar H A; Patel, Ketan; Singh, Mandip

    2015-07-15

    The objectives of this study were to develop an innovative investigative model using doxorubicin as a fluorophore to evaluate the skin permeation of nanocarriers and the impact of size and surface characteristics on their permeability. Different doxorubicin-loaded liposomes with mean particle size <130 nm and different surface chemistry were prepared by ammonium acetate gradient method using DPPC, DOPE, Cholesterol, DSPE-PEG 2000 and 1,1-Di-((Z)-octadec-9-en-1-yl) pyrrolidin-1-ium chloride (CY5)/DOTAP/1,2-dioleoyl-sn-glycero-3-phosphate (DOPA) as the charge modifier. There was minimal release of doxorubicin from the liposomes up to 8h; indicating that fluorescence observed within the skin layers was due to the intact liposomes. Liposomes with particle sizes >600 nm were restricted within the stratum corneum. DOTAP (p<0.01) and CY5 (p<0.05) liposomes demonstrated significant permeation into the skin than DOPA and PEG liposomes. Tape stripping significantly (p<0.01) enhanced the skin permeation of doxorubicin liposomes but TAT-decorated doxorubicin liposomes permeated better (p<0.005). Blockage of the hair follicles resulted in significant reduction in the extent and intensity of fluorescence observed within the skin layers. Overall, doxorubicin liposomes proved to be an ideal fluorophore-based model. The hair follicles were the major route utilized by the liposomes to permeate skin. Surface charge and particle size played vital roles in the extent of permeation.

  4. Production of monodisperse, polymeric microspheres

    NASA Technical Reports Server (NTRS)

    Rembaum, Alan (Inventor); Rhim, Won-Kyu (Inventor); Hyson, Michael T. (Inventor); Chang, Manchium (Inventor)

    1990-01-01

    Very small, individual polymeric microspheres with very precise size and a wide variation in monomer type and properties are produced by deploying a precisely formed liquid monomer droplet, suitably an acrylic compound such as hydroxyethyl methacrylate into a containerless environment. The droplet which assumes a spheroid shape is subjected to polymerizing radiation such as ultraviolet or gamma radiation as it travels through the environment. Polymeric microspheres having precise diameters varying no more than plus or minus 5 percent from an average size are recovered. Many types of fillers including magnetic fillers may be dispersed in the liquid droplet.

  5. Melting line of polymeric nitrogen

    NASA Astrophysics Data System (ADS)

    Yakub, L. N.

    2013-05-01

    We made an attempt to predict location of the melting line of polymeric nitrogen using two equations for Helmholtz free energy: proposed earlier for cubic gauche-structure and developed recently for liquid polymerized nitrogen. The P-T relation, orthobaric densities and latent heat of melting were determined using a standard double tangent construction. The estimated melting temperature decreases with increasing pressure, alike the temperature of molecular-nonmolecular transition in solid. We discuss the possibility of a triple point (solid-molecular fluid-polymeric fluid) at ˜80 GPa and observed maximum of melting temperature of nitrogen.

  6. Organometallic Polymeric Conductors

    NASA Technical Reports Server (NTRS)

    Youngs, Wiley J.

    1997-01-01

    For aerospace applications, the use of polymers can result in tremendous weight savings over metals. Suitable polymeric materials for some applications like EMI shielding, spacecraft grounding, and charge dissipation must combine high electrical conductivity with long-term environmental stability, good processability, and good mechanical properties. Recently, other investigators have reported hybrid films made from an electrically conductive polymer combined with insulating polymers. In all of these instances, the films were prepared by infiltrating an insulating polymer with a precursor for a conductive polymer (either polypyrrole or polythiophene), and oxidatively polymerizing the precursor in situ. The resulting composite films have good electrical conductivity, while overcoming the brittleness inherent in most conductive polymers. Many aerospace applications require a combination of properties. Thus, hybrid films made from polyimides or other engineering resins are of primary interest, but only if conductivities on the same order as those obtained with a polystyrene base could be obtained. Hence, a series of experiments was performed to optimize the conductivity of polyimide-based composite films. The polyimide base chosen for this study was Kapton. 3-MethylThiophene (3MT) was used for the conductive phase. Three processing variables were identified for producing these composite films, namely time, temperature, and oxidant concentration for the in situ oxidation. Statistically designed experiments were used to examine the effects of these variables and synergistic/interactive effects among variables on the electrical conductivity and mechanical strength of the films. Multiple linear regression analysis of the tensile data revealed that temperature and time have the greatest effect on maximum stress. The response surface of maximum stress vs. temperature and time (for oxidant concentration at 1.2 M) is shown. Conductivity of the composite films was measured for

  7. High temperature structural, polymeric foams from high internal emulsion polymerization

    SciTech Connect

    Hoisington, M.A.; Duke, J.R.; Apen, P.G.

    1996-02-01

    In 1982, a high internal phase emulsion (HIPE) polymerization process to manufacture microcellular, polymeric foam systems was patented by Unilever. This patent discloses a polymerization process that occurs in a water-in-oil emulsion in which the water represents at least 76% of the emulsion by volume. The oil phase consists of vinyl monomers such as styrene and acrylates that are crosslinked by divinyl monomers during polymerization. After polymerization and drying to remove the water phase, the result is a crosslinked polymer foam with an open cell microstructure that is homogeneous throughout in terms of morphology, density, and mechanical properties. Since 1982, numerous patents have examined various HIPE polymerized foam processing techniques and applications that include absorbents for body fluids, cleaning materials, and ion exchange systems. All the published HIPE polymerized foams have concentrated on materials for low temperature applications. Copolymerization of styrene with maleic anhydride and N-substituted maleimides to produce heat resistant thermoplastics has been studied extensively. These investigations have shown that styrene will free radically copolymerize with N-substituted maleimides to create an alternating thermoplastic copolymer with a Tg of approximately 200{degrees}C. However, there are many difficulties in attempting the maleimide styrene copolymerization in a HIPE such as lower polymerization temperatures, maleimide solubility difficulties in both styrene and water, and difficulty obtaining a stable HIPE with a styrene/maleimide oil phase. This work describes the preparation of copolymer foams from N-ethylmaleimide and Bis(3-ethyl-5-methyl-4-maleimide-phenyl)methane with styrene based monomers and crosslinking agents.

  8. Mixed-micellar proliposomal systems for enhanced oral delivery of progesterone.

    PubMed

    Potluri, Praveen; Betageri, Guru V

    2006-01-01

    The objective of our study was to develop a mixed-micellar proliposomal formulation of poorly water-soluble drug progesterone and evaluate the dissolution profile and membrane transport. Several formulations of proliposomes were prepared by mixing different concentrations of lipid, progesterone, polysorbate 80, and microcrystalline cellulose. The mixed-micellar formulation of drug:dimyristoyl-phosphatidycholine:polysorbate 80 (1:20:3.3) exhibited the maximum dissolution (75.27%), while pure progesterone resulted in low dissolution. The above formulation showed a 4-fold increase in transport in Caco-2 cells and a 6-fold increase in transport across the everted rat intestinal sac experiments compared with control. Proliposomal formulations enhance the extent of dissolution and membrane transport of progesterone and serve as ideal carriers for oral delivery of drugs with low water solubility.

  9. Integrated extraction and purification of soy isoflavones by using aqueous micellar systems.

    PubMed

    Cordisco, Estefanía; Haidar, Carla N; Coscueta, Ezequiel R; Nerli, Bibiana B; Malpiedi, Luciana P

    2016-12-15

    In this work, an integration of solid-liquid and liquid-liquid extractions by using aqueous micellar two-phase systems was evaluated as potential tool to purify soy isoflavones. Additionally, the proposed methodology aimed to preserve the protein content of the processed soy flour. The extractive assays were performed in AMTPS formed by Triton X-114 and sodium tartrate. In order to optimize the purification process, temperature and time were evaluated as independent variables. Under optimal working conditions, i.e. 100min and 33°C of incubation, IF were purified with a recovery percentage of 93 and a purification factor of almost 10. More importantly, the obtained sample presented an aglycone proportion superior to the reported by other methodologies. These results open perspectives to the use of aqueous micellar two-phase systems as an integrative methodology to extract, concentrate and purify isoflavones.

  10. Sedimentary facies analysis, El Dorado Field, Kansas, micellar chemical pilot project

    SciTech Connect

    Tillman, R.W.; Jordan, D.W.

    1981-05-01

    The Permian 650-ft sand, one of several productive sands in the El Dorado Field, has yielded 36.5 million bbl by primary and secondary methods, with 71 million bbl remaining. During initial stages of the micellar-polymer tertiary recovery pilot project drilling in 1974, a phase I geologic analysis, using 7 cores, identified distributary channels and associated smaller splay channels as productive facies. The western edge of the pilot area was determined to have the best channel sandstone development. A 2-layer geologic facies model was proposed. Oriented cores were included in the drilling of 24 wells in Phase II. North and northeast flow directions were indicated for the channel sandstones. During Phase III four observation wells were cored. These wells were drilled at internals of 90ft (27 m) diagonally from earlier wells in the north and south block. Micellar injection for the pilot was completed in early 1979 and polmer injection followed.

  11. Laboratory core floods to support the El Dorado micellar/polymer project

    SciTech Connect

    Kellerhals, G.E.

    1982-06-01

    Two distinct micellar/polymer processes are being tested in the El Dorado project. In one pilot area, an oil-external micellar system followed by partically hydrolyzed polyacrylamide solution is being tested. In the north pattern, an aqueous surfactant system followed by xanthan gum solution is being implemented. From this work, the following conclusions are made. (1) Both the oleic and aqueous systems effectively displace residual oil from Berea sandstone. (2) Not surprisingly, oil recoveries with either the oil-external or the aqueous system were lower with stacked El Dorado cores than with Berea cores. (3) Higher concentrations of polymer in the polymer drive for the high-water content system appears to be more important to oil recovery than higher concentrations of surfactant in the surfactant slug. 27 refs.

  12. Application of micellar electrokinetic chromatography to the determination of sultamicillin in oral pharmaceutical preparations.

    PubMed

    Pajchel, Genowefa; Tyski, Stefan

    2002-12-06

    A micellar electrokinetic capillary electrophoretic method for determination of sultamicillin in Unasyn oral preparations--tablets and suspension--was evaluated. Phosphate-borate buffer at pH 7.0 containing 1.0% sodium dodecylsulfate was used as a mobile phase. The elaborated method ensures separation of sultamicillin from p-toluenesulfonic acid and the impurities, ampicillin, sulbactam and penicillamine. The method was validated for specificity, reproducibility, precision, accuracy and assay linearity (in a concentration range of sultamicillin of 0.05-1.5 mg/ml). Statistical analysis by Student's t-test showed no significant differences between the results obtained by micellar electrokinetic chromatography and HPLC, t(calculated) 0.519 for suspension assays and 0.284 for tablets assays were smaller then t(tabulated).

  13. On-line micellar electrokinetic chromatography-electrospray ionization mass spectrometry using anodically migrating micelles

    SciTech Connect

    Yang, L.; Harrata, A.K.; Lee, C.S. |

    1997-05-15

    On-line micellar electrokinetic chromatography (MEKC)-electrospray ionization mass spectrometry (ESIMS) is demonstrated for the analysis of chlorotriazine herbicides and barbiturates. In this study, the micellar velocity is directly manipulated by the adjustment of electroosmosis rather than the electrophoretic velocity of the micelle. The electroosmotic flow is adjusted against the electrophoretic velocity of the micelle by changing the solution pH in MEKC. The elimination of MEKC surfactant introduction into ESIMS is achieved with an anodically migrating micelle, moving away from the electrospray interface. The effects of moving surfactant boundary in the MEKC capillary on separation efficiency and resolution of triazine herbicides and barbiturates are investigated. The mass detection of herbicides and barbiturates sequentially eluted from the MEKC capillary is acquired using the positive and negative electrospray modes, respectively. 30 refs., 8 figs., 3 tabs.

  14. Analysis of different beta-lactams antibiotics in pharmaceutical preparations using micellar electrokinetic capillary chromatography.

    PubMed

    Pérez, M I Bailón; Rodríguez, L Cuadros; Cruces-Blanco, C

    2007-01-17

    The potential of micellar electrokinetic capillary chromatography (MEKC) for analyzing nine beta-lactams antibiotics (cloxacillin, dicloxacillin, oxacillin, penicillin G, penicillin V, ampicillin, nafcillin, piperacillin, amoxicillin) in different pharmaceutical preparations, have been demonstrated. An experimental design strategy has been applied to optimize the main variables: pH and buffer concentration, concentration of the micellar medium, separation voltage and capillary temperature. Borate buffer (26mM) at pH 8.5 containing 100mM sodium dodecyl sulphate (SDS) was used as the background electrolyte. The method was validated. Linearity, limit of detection and quantitation and precision were established for each compound. The analysis of some of the beta-lactams in Orbenin capsules, Britapen tables and in Veterin-Micipen injectable, all used in human and veterinary medicine, have demonstrated the applicability of these technique for quality control in the pharmaceutical industry.

  15. Light-induced redox reactions of proflavin in aqueous and micellar solution

    SciTech Connect

    Pileni, M.P.; Graetzel, M.

    1980-09-18

    Primary photoprocesses and photochemical behavior of proflavin (PF) were investigated in aqueous and anionic micellar solution. Micellar effects are noted in the pK of the singlet and triplet excited states, which are due to differences in surface and bulk pH. The photoredox behavior is distinguished by (1) a monophotonic photoionization process and T-T annihilation leading to production of oxidized and reduced proflavin radicals in water solution, and (2) a biphotonic photoionization process in NaLS solution. Because of strong adsorption of PF on the surface of anionic micelles, the T-T annihilation is impaired in the surfactant solutions. Reduced PF radicals are also produced in aqueous solution in the presence of triethanolamine, where reductive quenching of the triplet states is dominant. They are distinguished by a long lifetime and a high reactivity toward colloidal platinum. The kinetics of intervention of this catalyst in the radical reaction is illustrated directly. 8 figures.

  16. Epigallocatechin gallate decreases the micellar solubility of cholesterol via specific interaction with phosphatidylcholine.

    PubMed

    Kobayashi, Makoto; Nishizawa, Masato; Inoue, Nao; Hosoya, Takahiro; Yoshida, Masahito; Ukawa, Yuichi; Sagesaka, Yuko M; Doi, Takayuki; Nakayama, Tsutomu; Kumazawa, Shigenori; Ikeda, Ikuo

    2014-04-02

    The mechanisms underlying the effect of epigallocatechin gallate (EGCG) on the micellar solubility of cholesterol were examined. EGCG eliminated both cholesterol and phosphatidylcholine (PC) from bile salt micelles in a dose-dependent manner in vitro. When the bile salt micelles contained a phospholipid other than PC, neither cholesterol nor the phospholipid was eliminated following the addition of EGCG. When vesicles comprised of various phospholipids were prepared and, EGCG was added to the vesicles, EGCG effectively and exclusively eliminated only PC. An intermolecular nuclear Overhauser effect (NOE) was observed between PC and EGCG in bile salt micelles with EGCG added, but not between cholesterol and EGCG, by using a NOE-correlated spectroscopy nuclear magnetic resonance method. The results of binding analyses using surface plasmon resonance (SPR) showed that EGCG did not bind to cholesterol. These observations strongly suggest that EGCG decreases the micellar solubility of cholesterol via specific interaction with PC.

  17. Akt Rescue in Cardiomyocytes but not Breast Cancer Cells After Doxorubicin and Anti-erB2 Treatment

    DTIC Science & Technology

    2006-05-01

    creating a useful in- vivo model for investigation of cardiotoxicity. Both doxorubicin administration and presence of indwelling venous catheters have... catheterized group (87.5%) achieved cardiotoxicity relative to the doxorubicin treated/venotomy group (28.6%). This was reflected by an earlier and more...precipitous decline in fractional shortening demonstrated by the doxorubicin treated/ catheterized rats. Despite this, rats from catheterized groups

  18. Huisgen cycloaddition reaction of C-alkynyl ribosides under micellar catalysis: synthesis of ribavirin analogues.

    PubMed

    Youcef, Ramzi Aït; Dos Santos, Mickaël; Roussel, Sandrine; Baltaze, Jean-Pierre; Lubin-Germain, Nadège; Uziel, Jacques

    2009-06-05

    Carbonated analogues of ribavirin were synthesized from ethyl C-ribosylpropiolate obtained by an alkynylation reaction mediated by indium(0). The C-ribosides were then engaged in a Huisgen 1,3-dipolar cycloaddition reaction under a micellar catalysis. In these conditions, formation of 1,2,3-triazoles with control of the regioselectivity was observed. The regiochemistry of the adducts was determined by HMBC 2D-NMR analysis.

  19. Temperature-dependent hydration at micellar surface: activation energy barrier crossing model revisited.

    PubMed

    Mitra, Rajib Kumar; Sinha, Sudarson Sekhar; Pal, Samir Kumar

    2007-07-05

    In recent years, the validity of the activation energy barrier crossing model at the micellar surface brings notable controversy (Sen, P.; Mukherjee, S.; Halder, A.; Bhattacharyya, K. Chem. Phys. Lett. 2004, 385, 357-361. Kumbhakar, M.; Goel, T.; Mukherjee, T.; Pal, H. J. Phys. Chem. B 2004, 108, 19246-19254.) in the literature. In order to check the validity of the model by time-resolved solvation of a probe fluorophore, a wider range of temperature must be considered. At the same time, spatial heterogeneity (solubilization) of the probe and structural perturbation of the host micelle should carefully be avoided, which was not strictly maintained in the earlier studies. We report here the solvation dynamics of 4-(dicyanomethylene)-2-methyl-6(p-dimethylamino-styryl) 4H-pyran (DCM) in the SDS micelle at 298, 323, and 348 K. The probe DCM is completely insoluble in bulk water in this wide range of temperature. The size of the micelle at different temperatures using the dynamic light scattering (DLS) technique is found to have insignificant change. The hydration number of the micelle, determined by sound velocity measurements, decreases with increasing temperature. Time-resolved fluorescence anisotropy reveals the retention of the probe in the micellar interface within the temperature range. The average solvation time decreases with increasing temperature. The result of the solvation study has been analyzed in the light of energetics of bound to free water conversion at a constant size and decreasing hydration number at the micellar surface. The solvation process at the micellar surface has been found to be the activation energy barrier crossing type, in which interfacially bound type water molecules get converted into free type molecules. We have calculated Ea to be 3.5 kcal mol-1, which is in good agreement with that obtained by molecular dynamics simulation studies.

  20. Transepithelial Transport of Curcumin in Caco-2 Cells Is significantly Enhanced by Micellar Solubilisation.

    PubMed

    Frank, Jan; Schiborr, Christina; Kocher, Alexa; Meins, Jürgen; Behnam, Dariush; Schubert-Zsilavecz, Manfred; Abdel-Tawab, Mona

    2017-03-01

    Curcumin, the active constituent of Curcuma longa L. (family Zingiberaceae), has gained increasing interest because of its anti-cancer, anti-inflammatory, anti-diabetic, and anti-rheumatic properties associated with good tolerability and safety up to very high doses of 12 g. Nanoscaled micellar formulations on the base of Tween 80 represent a promising strategy to overcome its low oral bioavailability. We therefore aimed to investigate the uptake and transepithelial transport of native curcumin (CUR) vs. a nanoscaled micellar formulation (Sol-CUR) in a Caco-2 cell model. Sol-CUR afforded a higher flux than CUR (39.23 vs. 4.98 μg min(-1) cm(-2), respectively). This resulted in a higher Papp value of 2.11 × 10(-6) cm/s for Sol-CUR compared to a Papp value of 0.56 × 10(-6) cm/s for CUR. Accordingly a nearly 9.5 fold higher amount of curcumin was detected on the basolateral side at the end of the transport experiments after 180 min with Sol-CUR compared to CUR. The determined 3.8-fold improvement in the permeability of curcumin is in agreement with an up to 185-fold increase in the AUC of curcumin observed in humans following the oral administration of the nanoscaled micellar formulation compared to native curcumin. The present study demonstrates that the enhanced oral bioavailability of micellar curcumin formulations is likely a result of enhanced absorption into and increased transport through small intestinal epithelial cells.

  1. HER2-targeted liposomal doxorubicin displays enhanced anti-tumorigenic effects without associated cardiotoxicity

    SciTech Connect

    Reynolds, Joseph G.; Geretti, Elena; Hendriks, Bart S.; Lee, Helen; Leonard, Shannon C.; Klinz, Stephan G.; Noble, Charles O.; Lücker, Petra B.; Zandstra, Peter W.; Drummond, Daryl C.; Olivier, Kenneth J.; Nielsen, Ulrik B.; Niyikiza, Clet; Agresta, Samuel V.; Wickham, Thomas J.

    2012-07-01

    Anthracycline-based regimens are a mainstay of early breast cancer therapy, however their use is limited by cardiac toxicity. The potential for cardiotoxicity is a major consideration in the design and development of combinatorial therapies incorporating anthracyclines and agents that target the HER2-mediated signaling pathway, such as trastuzumab. In this regard, HER2-targeted liposomal doxorubicin was developed to provide clinical benefit by both reducing the cardiotoxicity observed with anthracyclines and enhancing the therapeutic potential of HER2-based therapies that are currently available for HER2-overexpressing cancers. While documenting the enhanced therapeutic potential of HER2-targeted liposomal doxorubicin can be done with existing models, there has been no validated human cardiac cell-based assay system to rigorously assess the cardiotoxicity of anthracyclines. To understand if HER2-targeting of liposomal doxorubicin is possible with a favorable cardiac safety profile, we applied a human stem cell-derived cardiomyocyte platform to evaluate the doxorubicin exposure of human cardiac cells to HER2-targeted liposomal doxorubicin. To the best of our knowledge, this is the first known application of a stem cell-derived system for evaluating preclinical cardiotoxicity of an investigational agent. We demonstrate that HER2-targeted liposomal doxorubicin has little or no uptake into human cardiomyocytes, does not inhibit HER2-mediated signaling, results in little or no evidence of cardiomyocyte cell death or dysfunction, and retains the low penetration into heart tissue of liposomal doxorubicin. Taken together, this data ultimately led to the clinical decision to advance this drug to Phase I clinical testing, which is now ongoing as a single agent in HER2-expressing cancers. -- Highlights: ► Novel approach using stem cell-derived cardiomyocytes to assess preclinical safety. ► HER2-targeted liposomal doxorubicin has improved safety profile vs free doxorubicin

  2. Boswellic acids synergize antitumor activity and protect against the cardiotoxicity of doxorubicin in mice bearing Ehrlich's carcinoma.

    PubMed

    Ali, Shimaa A; Zaitone, Sawsan A; Moustafa, Yasser M

    2015-08-01

    This study aimed to test whether boswellic acids add to the antitumor effects of doxorubicin against solid tumors of Ehrlich's ascites carcinoma (EAC) grown in mice, and to investigate the protective effects of boswellic acids against doxorubicin-induced cardiotoxicity. Sixty-four female Swiss albino mice bearing EAC solid tumors were distributed among 8 groups as follows: group 1, EAC control group; group 2, doxorubicin treatment group [mice were injected with doxorubicin (6 mg·(kg body mass)(-1)·week(-1)) for 3 weeks]; groups 3-5, these mice were treated with boswellic acids (125, 250, or 500 mg·kg(-1)·day(-1)), respectively; groups 6-8, these mice were treated with a combination of doxorubicin and boswellic acids (125, 250, or 500 mg·kg(-1)·day(-1)), respectively, for 3 weeks. The results indicated that boswellic acids synergized the antitumor activity of doxorubicin. Doxorubicin-treated mice showed elevated serum activities of lactate dehydrogenase and creatine kinase isoenzyme MB as well as cardiac malondialdehyde. Further, decreases in cardiac levels of reduced glutathione, superoxide dismutase, and catalase activities were observed. These effects were accompanied by an increase in cardiac expression of caspase 3. Thus, treatment with boswellic acids attenuated doxorubicin-evoked disturbances in the above-mentioned parameters, highlighting antioxidant and antiapoptotic activities. Therefore, boswellic acids could be potential candidates for ameliorating the cardiotoxicity of doxorubicin.

  3. Hydrophobically modified inulin as an amphiphilic carbohydrate polymer for micellar delivery of paclitaxel for intravenous route.

    PubMed

    Muley, Pratik; Kumar, Sunny; El Kourati, Fadoua; Kesharwani, Siddharth S; Tummala, Hemachand

    2016-03-16

    Micellization offers several advantages for the delivery of water insoluble drugs including a nanoparticulate 'core-shell' delivery system for drug targeting. Recently, hydrophobically modified polysaccharides (HMPs) are gaining recognition as micelle forming polymers to encapsulate hydrophobic drugs. In this manuscript, for the first time, we have evaluated the self-assembling properties of a lauryl carbamate derivative of the poly-fructose natural polymer inulin (Inutec SP1(®) (INT)) to form paclitaxel (PTX) loaded micelles. INT self-assembled into well-defined micellar structures in aqueous environment with a low critical micellar concentration of 27.8 μg/ml. INT micelles exhibited excellent hemocompatibility and low toxicity to cultured cells. PTX loaded INT micelles exhibited a mean size of 256.37 ± 10.45 nm with excellent drug encapsulation efficiency (95.66 ± 2.25%) and loading (8.69 ± 0.22%). PTX loaded micelles also displayed sustained release of PTX and enhanced anti-cancer efficacy in-vitro in mouse melanoma cells (B16F10) compared to Taxol formulation with Cremophor EL as solvent. In addition, PTX loaded INT micelles exhibited comparable in-vivo antitumor activity in B16F10 allograft mouse model at half the dose of Taxol. In conclusion, INT offers safe, inexpensive and natural alternative to widely used PEG-modified polymers for the formulation of micellar delivery systems for paclitaxel.

  4. Study of complex micellar systems by static and dynamic light scattering

    NASA Astrophysics Data System (ADS)

    Khlebtsov, Boris N.; Chumakov, Eugene M.; Semyonov, Sergei V.; Chumakov, Mikhail I.; Khlebtsov, Nikolai G.

    2004-07-01

    The static and dynamic light scattering (DLS) methods were applied to study the thermodynamic properties and disperse structure of water+surfactant+solubilizer systems. It is supposed that such systems possess a micellar structure that can be used to develop new effective forms of veterinary drugs. For preparation of drugs (antibiotics) in micellar form, water solutions of the surfactant Cremafor-EL (CR) with the co-solvent dimethylacetamide (DMA) were used. To evaluate the stability of micellar solutions, we measured the light scattering intensity at 90 degrees as a function of temperature (20-80° C) in a water+CR+DMA system. The size distribution of micelles was determined by DLS measurements followed by DynaLS software processing. As thermodynamic characteristics of solutions, the so-called cloud point temperatures (CPT) and absolute instability temperatures (AIT) were used. Specifically, the CPT was determined as the intersection point of two linear fittings for scattering intensity vs temperature plots. AIT was determined using the inverse light scattering intensity data plotted vs temperature and then extrapolated to zero. The micelle-size distributions were measured for three types of surfactants (CR, Tween-80, and Tween-20), as well as for water+CR+DMA systems.

  5. Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy

    NASA Astrophysics Data System (ADS)

    Chung, Joo Eun; Tan, Susi; Gao, Shu Jun; Yongvongsoontorn, Nunnarpas; Kim, Soon Hee; Lee, Jeong Heon; Choi, Hak Soo; Yano, Hirohisa; Zhuo, Lang; Kurisawa, Motoichi; Ying, Jackie Y.

    2014-11-01

    When designing drug carriers, the drug-to-carrier ratio is an important consideration, because the use of high quantities of carriers can result in toxicity as a consequence of poor metabolism and elimination of the carriers. However, these issues would be of less concern if both the drug and carrier had therapeutic effects. (-)-Epigallocatechin-3-O-gallate (EGCG), a major ingredient of green tea, has been shown, for example, to possess anticancer effects, anti-HIV effects, neuroprotective effects and DNA-protective effects. Here, we show that sequential self-assembly of the EGCG derivative with anticancer proteins leads to the formation of stable micellar nanocomplexes, which have greater anticancer effects in vitro and in vivo than the free protein. The micellar nanocomplex is obtained by complexation of oligomerized EGCG with the anticancer protein Herceptin to form the core, followed by complexation of poly(ethylene glycol)-EGCG to form the shell. When injected into mice, the Herceptin-loaded micellar nanocomplex demonstrates better tumour selectivity and growth reduction, as well as longer blood half-life, than free Herceptin.

  6. Study of the dehydrochlorination of DDT in basic media in sulfobetaine aqueous micellar solutions

    SciTech Connect

    Rodriguez, A.; Mar Graciani, M. del; Guinda, A.; Munoz, M.; Moya, M.L.

    2000-04-04

    The reaction of dehydrochlorination of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, DDT, with hydroxide ions has been studied in aqueous micellar solutions of N-tetradecyl-N,N-dimethyl-3-ammino-1-propane-sulfonate, SB3-14, and N-hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate, SB3-16. A simple expression for the observed rate constant, k{sub obs}, based on the pseudophase model, could explain the influence of changes in the surfactant concentration on k{sub obs}. The kinetic effects of added electrolytes (NaF, NaCl, NaBr, and NaNO{sub 3}) on the reaction rate in SB3-14 micellar media have also been studied. They were rationalized by considering the binding of the anions, which come from the added salt, to the sulfobetaine micelles and their competition with the reactive hydroxide ions for the micellar surface. Conductivity measurements have been a helpful tool in the discussion of the kinetic effects of added salts and permitted the estimation of equilibrium constants for the distribution of the anions between the zwitterionic micelles and the aqueous phase.

  7. Physicochemical assessment of dextran-g-poly (ɛ-caprolactone) micellar nanoaggregates as drug nanocarriers.

    PubMed

    Saldías, César; Velásquez, Luis; Quezada, Caterina; Leiva, Angel

    2015-03-06

    Self-assembling polymers in aqueous solution have attracted significant attention with recent research efforts focused on the development of new strategies to design devices useful in the field of controlled drug delivery. In this context, amphiphilic copolymers having specific structural features and self-assembling behaviors in aqueous media that would enable controlled drug release over longer time periods. In this work, we report on the synthesis and characterization of a Poly (ɛ-caprolactone)-grafted Dextran copolymer and its use in the preparation of micellar nanoaggregates. The characterization and study of the morphology, topography, size distribution and stability of micellar nanoaggregates by Transmission Electron Microscopy (TEM), Atomic Force Microscopy (AFM), Dynamic Light Scattering (DLS) and Zeta Potential (ζ), respectively, were carried out. Spherical-shaped morphologies and an average size of approximately 83 nm, for drug-free nanoaggregates, were observed. In addition, Zeta Potential studies showed that drug-free nanoaggregates are more stable than drug-loaded structures measured in a phosphate buffer (pH 7.2) medium. UV-vis spectrophotometry of both the drug entrapment efficiency (EE%) and in vitro drug release behavior were assessed. The EE% was determined to be 78% (w/w), and a combination of diffusion and eroding polymer matrix mechanisms for drug release were established. Finally, these results indicate that Dx-g-PCL micellar nanoaggregates are suitable for use as a potential nanocarrier having both biodegradable and biocompatible properties.

  8. Characterization of chemical selectivity in micellar electrokinetic chromatography. 4. Effect of surfactant headgroup.

    PubMed

    Trone, M D; Khaledi, M G

    1999-04-01

    The influence of surfactant headgroups on migration behavior in micellar electrokinetic chromatography is examined. Using linear solvation energy relationships (LSER) and functional group selectivity studies, the effect of six anionic headgroups on chemical selectivity is characterized. The sodium dodecyl surfactants of the sulfate [SO4-], sulfonate [SO3-], carboxylate [CO2-], carbonyl valine [OC(O)NHCH(CH(CH3)2)CO2-], and sulfoacetate [OC(O)CH2SO3-] anions are investigated. Solute size and the hydrogen-bond-donating ability of the micellar phase play the most significant roles in solute retention in all of the surfactants studied. While solute-micelle hydrogen bonding plays a dominant role in the observed selectivity, the dipolarity and polarizability of the micellar phase also have a small influence. The results also suggest that the hydrogen-bond-accepting ability for surfactants is inversely proportional to the proton acidity (pKa) of its headgroup. The observed hydrogen-bond-donating ability and dipolarity of surfactant systems are believed to be a result of the water that resides near the micelle surface.

  9. Development of a 2-D large-scale micellar/polymer simulator

    SciTech Connect

    Wang, B.

    1982-01-01

    A large-scale, two-dimensional, multicomponent, multiphase, compositional simulator for micellar/polymer flooding has been developed and applied. It can be used to calculate the areal sweep with any well pattern and any irregular reservoir boundary. This model involves both streamline and finite-difference techniques. Time invariant streamlines without transverse dispersion are assumed. The change in the flow rates into each streamline is accounted for as a function of mobility ratio. The sensitivity of the oil recovery for micellar/polymer flood to several reservoir and process variables was investigated. The reservoir variables included the well spacing, pattern type, pattern orientation in an anisotropic reservoir, and degree of confinement. The process variables included the salinity gradient, surfactant content of the slug, slug and polymer bank sizes, mobility ratio of polymer drive to oil bank, and polymer shear thinning effect. In order to demonstrate that this model is capable of handling large field problems, a large-scale simulation of the north lease of the El Dorado micellar/polymer pilot test was made. The simulated final oil recovery and the production histories of each producer are illustrated.

  10. Role of the surfactant structure in the behavior of hydrophobic ionic liquids within aqueous micellar solutions.

    PubMed

    Behera, Kamalakanta; Kumar, Vinod; Pandey, Siddharth

    2010-04-06

    The behavior of an ionic liquid (IL) within aqueous micellar solutions is governed by its unique property to act as both an electrolyte and a cosolvent. The influence of the surfactant structure on the properties of aqueous micellar solutions of zwitterionic SB-12, nonionic Brij-35 and TX-100, and anionic sodium dodecyl sulfate (SDS) in the presence of the "hydrophobic" IL 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF(6)]) is assessed along with the possibility of forming oil-in-water microemulsions in which the IL acts as the "oil" phase. The solubility of [bmim][PF(6)] within aqueous micellar solutions increases with increasing surfactant concentration. In contrast to anionic SDS, the zwitterionic and nonionic surfactant solutions solubilize more [bmim][PF(6)] at higher concentrations and the average aggregate size remains almost unchanged. The formation of IL-in-water microemulsions when the concentration of [bmim][PF(6)] is above its aqueous solubility is suggested for nonionic Brij-35 and TX-100 aqueous surfactant solutions.

  11. Use of micellar liquid chromatography to analyze darunavir, ritonavir, emtricitabine, and tenofovir in plasma.

    PubMed

    Peris-Vicente, Juan; Villarreal-Traver, Mónica; Casas-Breva, Inmaculada; Carda-Broch, Samuel; Esteve-Romero, Josep

    2014-10-01

    Danuravir, ritonavir, emtricitabine, and tenofovir are together prescribed against AIDS as a highly active antiretroviral therapy regimen. Micellar liquid chromatography has been applied to determine these four antiretroviral drugs in plasma. The sample preparation is shortened to the dilution of the sample in a micellar solution, filtration, and injection. Clean-up steps are avoided, due to the solubilization of plasma matrix in micellar media. The drugs were analyzed in <20 min using a mobile phase of 0.06 M sodium dodecyl sulfate/2.5% 1-pentanol (pH 7) running under isocratic mode through a C18 column at 1 mL/min at room temperature. Absorbance wavelength detection was set at 214 nm. The method was successfully validated following the ICH Harmonized Tripartite Guideline in terms of selectivity, limit of detection (0.080-0.110 μg/mL), limit of quantification (0.240-0.270 μg/mL), linearity between 0.25 and 25 μg/mL (r(2) > 0.995), accuracy (89.3-103.2%), precision (<8.2%) and robustness (<7.5%). Real plasma sample from patients taking this therapy were analyzed. This is the first paper showing the simultaneous detection of this four drugs. Therefore, the methodology was proven useful for the routine analysis of these samples in a hospital laboratory for clinical purposes.

  12. Can neutral analytes be concentrated by transient isotachophoresis in micellar electrokinetic chromatography and how much?

    PubMed

    Matczuk, Magdalena; Foteeva, Lidia S; Jarosz, Maciej; Galanski, Markus; Keppler, Bernhard K; Hirokawa, Takeshi; Timerbaev, Andrei R

    2014-06-06

    Transient isotachophoresis (tITP) is a versatile sample preconcentration technique that uses ITP to focus electrically charged analytes at the initial stage of CE analysis. However, according to the ruling principle of tITP, uncharged analytes are beyond its capacity while being separated and detected by micellar electrokinetic chromatography (MEKC). On the other hand, when these are charged micelles that undergo the tITP focusing, one can anticipate the concentration effect, resulting from the formation of transient micellar stack at moving sample/background electrolyte (BGE) boundary, which increasingly accumulates the analytes. This work expands the enrichment potential of tITP for MEKC by demonstrating the quantitative analysis of uncharged metal-based drugs from highly saline samples and introducing to the BGE solution anionic surfactants and buffer (terminating) co-ions of different mobility and concentration to optimize performance. Metallodrugs of assorted lipophilicity were chosen so as to explore whether their varying affinity toward micelles plays the role. In addition to altering the sample and BGE composition, optimization of the detection capability was achieved due to fine-tuning operational variables such as sample volume, separation voltage and pressure, etc. The results of optimization trials shed light on the mechanism of micellar tITP and render effective determination of selected drugs in human urine, with practical limits of detection using conventional UV detector.

  13. Simultaneous isocratic separation of phenolic acids and flavonoids using micellar liquid chromatography.

    PubMed

    Hadjmohammadi, Mohammad Reza; Nazari, S Saman S J

    2013-12-01

    The simultaneous isocratic separation of a mixture of five phenolic acids and four flavonoids (two important groups of natural polyphenolic compounds with very different polarities) was investigated in three different RPLC modes using a hydro-organic mobile phase, and mobile phases containing SDS at concentrations below and above the critical micellar concentration (submicellar LC and micellar LC (MLC), respectively). In the hydro-organic mode, methanol and acetonitrile; in the submicellar mode methanol; and in the micellar mode, methanol and 1-propanol were examined individually as organic modifiers. Regarding the other modes, MLC provided more appropriate resolutions and analysis time and was preferred for the separation of the selected compounds. Optimization of separation in MLC was performed using an interpretative approach for each alcohol. In this way, the retention of phenolic acids and flavonoids were modeled using the retention factors obtained from five different mobile phases, then the Pareto optimality method was applied to find the best compatibility between analysis time and quality of separation. The results of this study showed some promising advantages of MLC for the simultaneous separation of phenolic acids and flavonoids, including low consumption of organic solvent, good resolution, short analysis time, and no requirement of gradient elution.

  14. Isocratic and gradient elution in micellar liquid chromatography with Brij-35.

    PubMed

    Peris-García, Ester; Ortiz-Bolsico, Casandra; Baeza-Baeza, Juan José; García-Alvarez-Coque, María Celia

    2015-06-01

    Polyoxyethylene(23)lauryl ether (known as Brij-35) is a nonionic surfactant, which has been considered as an alternative to the extensively used in micellar liquid chromatography anionic surfactant sodium lauryl (dodecyl) sulfate, for the analysis of drugs and other types of compounds. Brij-35 is the most suitable nonionic surfactant for micellar liquid chromatography, owing to its commercial availability, low cost, low toxicity, high cloud temperature, and low background absorbance. However, it has had minor use. In this work, we gather and discuss some results obtained in our laboratory with several β-blockers, sulfonamides, and flavonoids, concerning the use of Brij-35 as mobile phase modifier in the isocratic and gradient modes. The chromatographic performance for purely micellar eluents (with only surfactant) and hybrid eluents (with surfactant and acetonitrile) is compared. Brij-35 increases the polarity of the alkyl-bonded stationary phase and its polyoxyethylene chain with the hydroxyl end group allows hydrogen-bond interactions, especially for phenolic compounds. This offers the possibility of using aqueous solutions of Brij-35 as mobile phases with sufficiently short retention times. The use of gradients of acetonitrile to keep the concentration of Brij-35 constant is another interesting strategy that yields a significant reduction in the peak widths, which guarantee high resolution.

  15. Micellar Packing in Aqueous Solutions of As-Received and Pure Pluronic Block Copolymers

    NASA Astrophysics Data System (ADS)

    Ryu, Chang; Park, Han Jin

    2013-03-01

    Pluronic block copolymers (Pluronics) are produced on a commercial scale to enable wide range of novel applications from emulsification and colloidal stabilization as nonionic surfactants. While the Pluronic block copolymers offer the advantages of being readily available for such applications, it contains non-micellizable low molecular weight (MW) impurities that would interfere with the self-assembly and micellar packing of PEO-PPO-PEO triblock copolymers in aqueous solutions. The impacts of the low MW impurities will be discussed on the micellar packing of Pluronics F108 and F127 solutions, which form BCC and FCC. While as-received Pluronic samples typically contain about 20 wt.% low MW impurities, we were able to reduce the impurity level to less than 2 wt.% using our large scale purification technique. Comparative studies on small angle x-ray scattering (SAXS) experiments on as-received and purified Pluronics solutions revealed that the contents of triblock copolymers in solutions essentially governs the inter-micellar distance of Pluronic cubic structures. A universal relationship between triblock copolymer concentration and SAXS-based domain spacing has been finally discussed. Funding from Agency for Defense Development, Korea.

  16. Kinetics of silica polymerization

    SciTech Connect

    Weres, O.; Yee, A.; Tsao, L.

    1980-05-01

    The polymerization of silicic acid in geothermal brine-like aqueous solutions to produce amorphous silica in colloidal form has been studied experimentally and theoretically. A large amount of high quality experimental data has been generated over the temperature rang 23 to 100{sup 0}C. Wide ranges of dissolved silica concentration, pH, and sodium chloride concentration were covered. The catalytic effects of fluoride and the reaction inhibiting effects of aluminum and boron were studied also. Two basic processes have been separately studied: the formation of new colloidal particles by the homogeneous nucleation process and the deposition of dissolved silica on pre-existing colloidal particles. A rigorous theory of the formation of colloidal particles of amorphous silica by homogeneous nucleation was developed. This theory employs the Lothe-Pound formalism, and is embodied in the computer code SILNUC which quantitatively models the homogeneous nucleation and growth of colloidal silica particles in more than enough detail for practical application. The theory and code were extensively used in planning the experimental work and analyzing the data produced. The code is now complete and running in its final form. It is capable of reproducing most of the experimental results to within experimental error. It is also capable of extrapolation to experimentally inaccessible conditions, i.e., high temperatures, rapidly varying temperature and pH, etc.

  17. Nanomicelles loaded with doxorubicin and curcumin for alleviating multidrug resistance in lung cancer

    PubMed Central

    Gu, Yue; Li, Jing; Li, Yang; Song, Lei; Li, Dan; Peng, Liping; Wan, Ying; Hua, Shucheng

    2016-01-01

    Purpose A new type of polymeric micelle (PM) was assembled using a polyethylene glycol (PEG)-linked (PEGylated) amphiphilic copolymer and d-tocopheryl PEG1000 succinate (TPGS1000). The micelles were used to deliver doxorubicin (DOX) and curcumin (CUR) for alleviating multidrug resistance (MDR) in lung cancer cells while enhancing the therapeutic efficacy of DOX. Methods Micelles loaded with DOX and CUR were assembled using a film-forming technique. Micelles were used to treat A549/Adr cells to find out whether micelles had the ability to reverse the MDR of A549/Adr cells. Some investigations were conducted using tumor-bearing mice to assess whether these micelles had enhanced antitumor efficacy as compared to DOX alone or the combination of DOX and CUR. Results Some micelles (DOX + CUR)–PMs had a small average size of about 17 nm and showed definite ability to deliver both DOX and CUR into DOX-resistant A549/Adr cells. The PMs had high cytotoxicity toward A549/Adr cells when the applied equivalent DOX dose was 1 µg/mL or higher. The cellular uptake of (DOX + CUR)–PMs into A549/Adr cells was found to be associated with an energy-dependent, caveolae-mediated, and clathrin-independent mechanism. (DOX + CUR)–PMs helped to prolong the circulation of DOX or CUR as compared to the individual administration of DOX or CUR, and they exhibited high inhibiting efficiency against the growth of tumors and were able to reduce the side effects of DOX. Conclusion TPGS1000 and CUR could synergistically reverse DOX-resistance of A549/Adr cells. In vivo examinations confirmed that the micelles had the capability to increase the plasma concentration of DOX or CUR, as well as to prolong their respective blood circulation. These micelles were able to significantly inhibit tumor growth in Lewis lung carcinoma tumor-bearing mice while reducing the side effects of DOX. The micelles showed potential in the treatment of lung cancer. PMID:27843316

  18. Preparation and evaluation of poly (caprolactone fumarate) nanoparticles containing doxorubicin HCI

    PubMed Central

    Shokri, N.; Akbari Javar, H.; Fouladdel, Sh.; Khalaj, A.; Khoshayand, MR.; Dinarvand, R.; Atyabi, F.; Nomani, A.; Azizi, E.

    2011-01-01

    Background and the purpose of the study Biodegradable Poly(caprolactone fumarate) (PCLF) has been used as bioresorbable sutures. In this study, doxorubicin HCl (Dox) loaded PCLF nanoparticles were prepared and characterized. Material and methods PCLFs were synthesized by polycondensation of PCL diols (Mws of 530, 1250 and 2000) with fumaryl chloride. The degradation of PCLF in NaOH, water and phosphate buffer saline (PBS), was determined in terms of changes in Mw. Nanoparticles (NPs) were prepared by two methods. In microemulsion polymerization method, dichloromethane containing PCLF and photoinitiator were combined with the water containing surfactants and then the mixture was placed under light for crosslinking. In nanoprecipitation method, the organic solvent containing PCLF was poured into the stirring water. The effect of several variables including concentration of PCLF, polyvinyl alcohol (PVA), Dox and Trypan blue (Trb) and the Mw of PCLF and PVA on NP size and loading were evaluated. Result PCLF 530, 1250 and 2000 in PBS or water were not degraded over 28 days. Nanoprecipitaion method gave spherical (revealed by SEM images) stable NPs of about 225 with narrow size distribution and a zeta potential of −43 mV. The size of NP increased significantly by increase in Mw or concentration of PCLF. Although PVA was not necessary for formation of NPs, but it decreased with NP size. Dox loading and EE were 2.5–6.8% and 15–20%, respectively. Increasing the drug concentration increased the drug loading (DL) and NP size. The entrapment efficiency (EE) for Trb ranged from 1% for PCLF530 to 6% for PCLF2000. An increase in PCLF concentration resulted in an increase in EE. Dox and Trb release showed a burst followed by 80% and 78% release during 3 and 4 days respectively. Conclusion PCLF possessed suitable characteristics for preparation of nanoparticulate drug delivery system such as desired NP size, stability and degradation time. Although PCLF530 NPs were the

  19. Coaxial electrohydrodynamic atomization process for production of polymeric composite microspheres

    PubMed Central

    Xu, Qingxing; Qin, Hao; Yin, Zhenyuan; Hua, Jinsong; Pack, Daniel W.; Wang, Chi-Hwa

    2013-01-01

    Polymeric composite microspheres consisting of a poly(D,L-lactic-co-glycolic acid) (PLGA) core surrounded by a poly(D,L-lactic acid) (PDLLA) shell layer were successfully fabricated by coaxial electrohydrodynamic atomization (CEHDA) process. Process conditions, including nozzle voltage and polymer solution flow rates, as well as solution parameters, such as polymer concentrations, were investigated to ensure the formation of composite microspheres with a doxorubicin-loaded PLGA core surrounded by a relatively drug-free PDLLA shell layer. Various microsphere formulations were fabricated and characterized in terms of their drug distribution, encapsulation efficiency and in vitro release. Numerical simulation of CEHDA process was performed based on a computational fluid dynamics (CFD) model in Fluent by employing the process conditions and fluid properties used in the experiments. The simulation results were compared with the experimental work to illustrate the capability of the CFD model to predict the production of consistent compound droplets, and hence, the expected core-shell structured microspheres. PMID:24347672

  20. Coaxial electrohydrodynamic atomization process for production of polymeric composite microspheres.

    PubMed

    Xu, Qingxing; Qin, Hao; Yin, Zhenyuan; Hua, Jinsong; Pack, Daniel W; Wang, Chi-Hwa

    2013-12-18

    Polymeric composite microspheres consisting of a poly(D,L-lactic-co-glycolic acid) (PLGA) core surrounded by a poly(D,L-lactic acid) (PDLLA) shell layer were successfully fabricated by coaxial electrohydrodynamic atomization (CEHDA) process. Process conditions, including nozzle voltage and polymer solution flow rates, as well as solution parameters, such as polymer concentrations, were investigated to ensure the formation of composite microspheres with a doxorubicin-loaded PLGA core surrounded by a relatively drug-free PDLLA shell layer. Various microsphere formulations were fabricated and characterized in terms of their drug distribution, encapsulation efficiency and in vitro release. Numerical simulation of CEHDA process was performed based on a computational fluid dynamics (CFD) model in Fluent by employing the process conditions and fluid properties used in the experiments. The simulation results were compared with the experimental work to illustrate the capability of the CFD model to predict the production of consistent compound droplets, and hence, the expected core-shell structured microspheres.

  1. Comparison of micellar isotherms of benzene determined by headspace gas chromatography and micellar electrokinetic chromatography. Assessment on impact of buffer and solubilization-induced conductivity change.

    PubMed

    Liu, Siyuan; Davis, Joe M

    2007-04-13

    The possibility is discussed that micellar isotherms determined by vacancy-micellar electrokinetic chromatography (vacancy-MEKC) differ from isotherms in electrolyte-free surfactants due to thermodynamic effects of buffer. Also discussed is the possibility that they are biased at high solute concentrations by solubilization-induced changes of electrical conductivity. Such bias could invalidate a theory on peak asymmetry of neutral solutes in MEKC that is based on thermodynamic interpretation of the isotherms. To evaluate these possibilities, the nonlinear concave upward isotherm of benzene in a pH 7.0, 0.0060 M sodium phosphate buffer containing 50 mM sodium dodecyl sulfate (SDS) was measured by headspace gas chromatography. Of interest is the finding that benzene is more stable in the surfactant-free buffer than in water. The isotherm was compared to that previously measured by vacancy-MEKC in the same buffer and 10, 30, or 50 mM SDS. No difference was found between the isotherms. However, the isotherm indeed differed from that of benzene in buffer-free 50 mM SDS, which was also determined and agreed favorably with previous results. A partial explanation is given for the independence of the vacancy-MEKC isotherm of solubilization-induced conductivity changes.

  2. Polymerized supramolecular assemblies and biocompatibility

    NASA Astrophysics Data System (ADS)

    O'Brien, David F.

    2001-03-01

    The creation of durable, biomembrane-mimetic coatings for inorganic and polymeric surfaces that are biocompatible, i.e. resistant to nonspecific protein adsorption, remains an important goal that is expected to impact numerous fields. It has already been shown that the physical stability of lipid bilayer vesicles can be dramatically enhanced by cross-linking polymerization of reactive lipids, such as phosphatidylcholines. Bilayers of these same lipids on clean silicon dioxide surfaces can be formed by fusion of small bilayer vesicles with the surface. Radical initiated polymerization of these supported bilayers yields a stable poly(lipid) film that is not perturbed upon exposure to surfactant. Moreover, the cross-linked bilayer film can be removed from water into air with retention of the poly(lipid) bilayer structure. These polymerized bilayer films could be repeatedly transferred from water to air to water with no obvious change in their biocompatibility. The supported bilayer films were equally resistant to non-specific protein adsorption before and after polymerization. This indicates that biocompatible nature of the phosphorylcholine head group of the lipids was not compromised by polymerization of the lipids. The ability to maintain surface biocompatibility of membranes while substantially increasing their stability would appear to extend the technological uses of supramolecular assemblies of lipids.

  3. Oxygen radical detoxification enzymes in doxorubicin-sensitive and -resistant P388 murine leukemia cells

    SciTech Connect

    Ramu, A.; Cohen, L.; Glaubiger, D.

    1984-05-01

    One of the proposed mechanisms for the cytotoxic effects of anthracycline compounds suggests that the effect is mediated through the formation of intracellular superoxide radicals. It is therefore possible that doxorubicin resistance is associated with increased intracellular enzyme capacity to convert these superoxide radicals to inactive metabolites. We have measured the relative activities of superoxide dismutase, glutathione peroxidase, and catalase in P388 mouse leukemia cells and in a doxorubicin-resistant subline. Since oxygen-reactive metabolites also play a role in mediating the cytotoxicity of ionizing radiation, the radiosensitivity of both cell lines was also studied. No significant differences in superoxide dismutase activity between these cell lines was observed, indicating that they have a similar capacity to convert superoxide anion radicals to hydrogen peroxide. P388 cells that are resistant to doxorubicin have 1.5 times the glutathione content and 1.5 times the activity of glutathione peroxidase measured in drug-sensitive P388 cells. However, incubation with 1-chloro-2,4-dinitrobenzene, which covalently binds glutathione, had no effect on the sensitivity of either cell line to doxorubicin. Measured catalase activity in drug-resistant P388 cells was one-third of the activity measured in doxorubicin-sensitive P388 cells. The activity of this enzyme was much higher than that of glutathione peroxidase in terms of H/sub 2/O/sub 2/ deactivation in both cell lines. It is therefore unlikely that doxorubicin-resistant P388 cells have an increased ability to detoxify reactive oxygen metabolites when compared to drug-sensitive cells. Doxorubicin-resistant P388 cells were significantly more sensitive to X-irradiation than were drug-sensitive P388 cells. These observations suggest that the difference in catalase activity in these cell lines may be associated with the observed differences in radiosensitivity.

  4. Optimization of Doxorubicin Loading for Superabsorbent Polymer Microspheres: in vitro Analysis

    SciTech Connect

    Liu, David M.; Kos, Sebastian; Buczkowski, Andrzej; Kee, Stephen; Wasan, Ellen

    2012-04-15

    Purpose: This study was designed to establish the ability of super-absorbent polymer microspheres (SAP) to actively uptake doxorubicin and to establish the proof of principle of SAP's ability to phase transfer doxorubicin onto the polymer matrix and to elute into buffer with a loading method that optimizes physical handling and elution characteristics. Methods: Phase I: 50-100 {mu}m SAP subject to various prehydration methods (normal saline 10 cc, hypertonic saline 4 cc, iodinated contrast 10 cc) or left in their dry state, and combined with 50 mg of clinical grade lyophilized doxorubicin reconstituted with various methods (normal saline 10 cc and 25 cc, sterile water 4 cc, iodinated contrast 5 cc) were placed in buffer and assessed based on loading, handling, and elution utilizing high-performance liquid chromatography (HPLC). Phase II: top two performing methods were subject to loading of doxorubicin (50, 75, 100 mg) in a single bolus (group A) or as a serial loading method (group B) followed by measurement of loading vs. time and elution vs. time. Results: Phase I revealed the most effective loading mechanisms and easiest handling to be dry (group A) vs. normal saline prehydrated (group B) SAP with normal saline reconstituted doxorubicin (10 mg/mL) with loading efficiencies of 83.1% and 88.4%. Phase II results revealed unstable behavior of SAP with 100 mg of doxorubicin and similar loading/elution profiles of dry and prehydrated SAP, with superior handling characteristics of group B SAP at 50 and 75 mg. Conclusions: SAP demonstrates the ability to load and bulk phase transfer doxorubicin at 50 and 75 mg with ease of handling and optimal efficiency through dry loading of SAP.

  5. Inhibition of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin

    SciTech Connect

    Wang, Feng; Yang, Yong

    2014-11-21

    Highlights: • Suppression of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin. • Repression of PKM2 affects the glycolysis and decreases ATP production. • Downregulation of PKM2 increases the intracellular accumulation of doxorubicin. • Inhibition of PKM2 enhances the antitumor efficacy of doxorubicin in vivo. - Abstract: Cancer cells alter regular metabolic pathways in order to sustain rapid proliferation. One example of metabolic remodeling in cancerous tissue is the upregulation of pyruvate kinase isoenzyme M2 (PKM2), which is involved in aerobic glycolysis. Indeed, PKM2 has previously been identified as a tumor biomarker and as a potential target for cancer therapy. Here, we examined the effects of combined treatment with doxorubicin and anti-PKM2 small interfering RNA (siRNA) on triple-negative breast cancer (TNBC). The suppression of PKM2 resulted in changes in glucose metabolism, leading to decreased synthesis of adenosine triphosphate (ATP). Reduced levels of ATP resulted in the intracellular accumulation of doxorubicin, consequently enhancing the therapeutic efficacy of this drug in several triple-negative breast cancer cell lines. Furthermore, the combined effect of PKM2 siRNA and doxorubicin was evaluated in an in vivo MDA-MB-231 orthotopic breast cancer model. The siRNA was systemically administered through a polyethylenimine (PEI)-based delivery system that has been extensively used. We demonstrate that the combination treatment showed superior anticancer efficacy as compared to doxorubicin alone. These findings suggest that targeting PKM2 can increase the efficacy of chemotherapy, potentially providing a new approach for improving the outcome of chemotherapy in patients with TNBC.

  6. Polymeric materials for neovascularization

    NASA Astrophysics Data System (ADS)

    DeVolder, Ross John

    Revascularization therapies have emerged as a promising strategy to treat various acute and chronic wounds, cardiovascular diseases, and tissue defects. It is common to either administer proangiogenic growth factors, such as vascular endothelial growth factor (VEGF), or transplant cells that endogenously express multiple proangiogenic factors. Additionally, these strategies utilize a wide variety of polymeric systems, including hydrogels and biodegradable plastics, to deliver proangiogenic factors in a sophisticated manner to maintain a sustained proangiogenic environment. Despite some impressive results in rebuilding vascular networks, it is still a challenging task to engineer mature and functional neovessels in target tissues, because of the increasing complexities involved with neovascularization applications. To resolve these challenges, this work aims to design a wide variety of proangiogenic biomaterial systems with tunable properties used for neovascularization therapies. This thesis describes the design of several biomaterial systems used for the delivery of proangiogenic factors in neovascularization therapies, including: an electrospun/electrosprayed biodegradable plastic patch used for directional blood vessel growth (Chapter 2), an alginate-g-pyrrole hydrogel system that biochemically stimulates cellular endogenous proangiogenic factor expression (Chapter 3), an enzyme-catalyzed alginate-g-pyrrole hydrogel system for VEGF delivery (Chapter 4), an enzyme-activated alginate-g-pyrrole hydrogel system with systematically controllable electrical and mechanical properties (Chapter 5), and an alginate-g-pyrrole hydrogel that enables the decoupled control of electrical conductivity and mechanical rigidity and is use to electrically stimulate cellular endogenous proangiogenic factor expression (Chapter 6). Overall, the biomaterial systems developed in this thesis will be broadly useful for improving the quality of a wide array of molecular and cellular based

  7. Polymeric materials in Space

    NASA Astrophysics Data System (ADS)

    Skurat, Vladimir

    Paper of short review type. It is the continuation of and addition to previous review papers "V. E. Skurat. Polymers in Space. In: Encyclopedia of aerospace engineering, vol. 4, Wiley and sons, 2010; Ibid., 2012 (on line)". Following topics are considered: (1) Destruction of polymers by solar radiation with various wavelengths in different spectral regions (visible-UV, vacuum UV (VUV), deep UV, soft and hard X-rays) are discussed. In difference with common polymer photochemistry induced by UV radiation, directions of various routs of polymer phototransformations and their relative yields are greatly dependent on wavelength of light (photon energy) during illuminations in VUV, deep UV and X-ray regions. During last twenty years, intensive spacecraft investigations of solar spectrum show great periodic and spontaneous variations of radiation intensities in short-wavelengths regions - up to one - two decimal orders of magnitude for X-rays. As a result, during solar flares the absorbed dose on the polymer surfaces from X-rays can be compared with absorbed dose from VUV radiation. (2) Some new approaches to predictions of reaction efficiencies of fast orbital atomic oxygen in their interaction with polymeric materials are considered. (3) Some aspects of photocatalitic destruction of polymers in vacuum conditions by full-spectrum solar radiation are discussed. This process can take place in enamels containing semiconducting particles (TiO2, ZnO) as pigments. (4) Contamination of spacecraft surfaces from intrinsic outer atmosphere play important role not only from the point of view of deterioration of optical and thermophysical properties. Layers of SiO2 contaminations with nanometer thicknesses can greatly diminish mass losses from perfluorinated polymers under VUV irradiation.

  8. Pegylated liposomal-encapsulated doxorubicin in cutaneous composite lymphoma

    PubMed Central

    Wollina, Uwe; Langner, Dana; Hansel, Gesina; Haroske, Gunter

    2016-01-01

    Abstract Background: Cutaneous composite lymphomas are very rare. Their treatment depends upon the different contributing lymphoma entities. Peripheral T-cell lymphoma, not otherwise specified, (PTCL-NOS) represents an aggressive lymphoma subtype. Follicular cutaneous B-cell lymphoma (FCBCL) runs an indolent course. Treatment with pegylated liposomal encapsulated doxorubicin (PLE-DOXO) has yet not been reported in this entity. Case presentation: A 73-year-old male patient presented with 3 rapidly growing, painful nodules on his left leg. He was diagnosed as composite cutaneous lymphoma consisting of PTCL-NOS and FCBCL. All lesions had been surgically removed. Staging was unremarkable. After 4 months a relapse occurred with involvement of inguinal lymph nodes and systemic treatment with PEL-DOXO 20 mg/ m2 every 3 weeks was initiated. After 6 cycles PLE-DOXO, which were well tolerated without grade 3 or 4 toxicities, a mixed response was obtained with complete remission of cutaneous lesions. Lymph nodes were treated by radiotherapy. A second relapse occurred after 8 months and various polychemotherapy regimens were applied without remission. The overall survival was 28 months. Conclusion: PEL-DOXO is a possible initial systemic treatment in case of PCTL-NOS. Whether polychemotherapy offers an advantage for survival remains questionable but further investigations are needed. PMID:27787356

  9. Novel proteasome inhibitor ixazomib sensitizes neuroblastoma cells to doxorubicin treatment

    PubMed Central

    Li, Haoyu; Chen, Zhenghu; Hu, Ting; Wang, Long; Yu, Yang; Zhao, Yanling; Sun, Wenijing; Guan, Shan; Pang, Jonathan C.; Woodfield, Sarah E.; Liu, Qing; Yang, Jianhua

    2016-01-01

    Neuroblastoma (NB) is the most common extracranial malignant solid tumor seen in children and continues to lead to the death of many pediatric cancer patients. The poor outcome in high risk NB is largely attributed to the development of chemoresistant tumor cells. Doxorubicin (dox) has been widely employed as a potent anti-cancer agent in chemotherapeutic regimens; however, it also leads to chemoresistance in many cancer types including NB. Thus, developing novel small molecules that can overcome dox-induced chemoresistance is a promising strategy in cancer therapy. Here we show that the second generation proteasome inhibitor ixazomib (MLN9708) not only inhibits NB cell proliferation and induces apoptosis in vitro but also enhances dox-induced cytotoxicity in NB cells. Ixazomib inhibits dox-induced NF-κB activity and sensitizes NB cells to dox-induced apoptosis. More importantly, ixazomib demonstrated potent anti-tumor efficacy in vivo by enhancing dox-induced apoptosis in an orthotopic xenograft NB mouse model. Collectively, our study illustrates the anti-tumor efficacy of ixazomib in NB both alone and in combination with dox, suggesting that combination therapy including ixazomib with traditional therapeutic agents such as dox is a viable strategy that may achieve better outcomes for NB patients. PMID:27687684

  10. A mouse model for juvenile doxorubicin-induced cardiac dysfunction.

    PubMed

    Zhu, Wuqiang; Shou, Weinian; Payne, R Mark; Caldwell, Randall; Field, Loren J

    2008-11-01

    Doxorubicin (DOX) is a potent antitumor agent. DOX can also induce cardiotoxicity, and high cumulative doses are associated with recalcitrant heart failure. Children are particularly sensitive to DOX-induced heart failure. The ability to genetically modify mice makes them an ideal experimental system to study the molecular basis of DOX-induced cardiotoxicity. However, most mouse DOX studies rely on acute drug administration in adult animals, which typically are analyzed within 1 wk. Here, we describe a juvenile mouse model of chronic DOX-induced cardiac dysfunction. DOX treatment was initiated at 2 wk of age and continued for a period of 5 wk (25 mg/kg cumulative dose). This resulted in a decline in cardiac systolic function, which was accompanied by marked atrophy of the heart, low levels of cardiomyocyte apoptosis, and decreased growth velocity. Other animals were allowed to recover for 13 wk after the final DOX injection. Cardiac systolic function improved during this recovery period but remained depressed compared with the saline injected controls, despite the reversal of cardiac atrophy. Interestingly, increased levels of cardiomyocyte apoptosis and concomitant myocardial fibrosis were observed after DOX withdrawal. These data suggest that different mechanisms contribute to cardiac dysfunction during the treatment and recovery phases.

  11. DNA-doxorubicin interaction: New insights and peculiarities.

    PubMed

    Silva, E F; Bazoni, R F; Ramos, E B; Rocha, M S

    2017-03-01

    We have investigated the interaction of the DNA molecule with the anticancer drug doxorubicin (doxo) by using three different experimental techniques: single molecule stretching, single molecule imaging, and dynamic light scattering. Such techniques allowed us to get new insights on the mechanical behavior of the DNA-doxo complexes as well as on the physical chemistry of the interaction. First, the contour length data obtained from single molecule stretching were used to extract the physicochemical parameters of the DNA-doxo interaction under different buffer conditions. This analysis has proven that the physical chemistry of such interaction can be modulated by changing the ionic strength of the surrounding buffer. In particular we have found that at low ionc strengths doxo interacts with DNA by simple intercalation (no aggregation) and/or by forming bound dimers. For high ionic strengths, otherwise, doxo-doxo self-association is enhanced, giving rise to the formation of bound doxo aggregates composed by 3 to 4 molecules along the double-helix. On the other hand, the results obtained for the persistence length of the DNA-doxo complexes is strongly force-dependent, presenting different behaviors when measured with stretching or non-stretching techniques.

  12. Roles of oxidative stress and Akt signaling in doxorubicin cardiotoxicity

    SciTech Connect

    Ichihara, Sahoko . E-mail: saho@gene.mie-u.ac.jp; Yamada, Yoshiji; Kawai, Yoshichika; Osawa, Toshihiko; Furuhashi, Koichi; Duan Zhiwen; Ichihara, Gaku

    2007-07-20

    Cardiotoxicity is a treatment-limiting side effect of the anticancer drug doxorubicin (DOX). We have now investigated the roles of oxidative stress and signaling by the protein kinase Akt in DOX-induced cardiotoxicity as well as the effects on such toxicity both of fenofibrate, an agonist of peroxisome proliferator-activated receptor-{alpha}, and of polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), an antioxidant. Mice injected intraperitoneally with DOX were treated for 4 days with fenofibrate or PEG-SOD. Fenofibrate and PEG-SOD each prevented the induction of cardiac dysfunction by DOX. Both drugs also inhibited the activation of the transcription factor NF-{kappa}B and increase in lipid peroxidation in the left ventricle induced by DOX, whereas only PEG-SOD inhibited the DOX-induced activation of Akt and Akt-regulated gene expression. These results suggest that fenofibrate and PEG-SOD prevented cardiac dysfunction induced by DOX through normalization of oxidative stress and redox-regulated NF-{kappa}B signaling.

  13. Adsorption and desorption of doxorubicin on oxidized carbon nanotubes.

    PubMed

    Wang, Yunxia; Yang, Sheng-Tao; Wang, Yanli; Liu, Yuanfang; Wang, Haifang

    2012-09-01

    Carbon nanotubes (CNTs) show promise as nano-drug carriers. To develop the CNT-based drug delivery systems, drug loading and release are two major issues. In this study, we systematically evaluated the adsorption and desorption of doxorubicin (DOX) on oxidized multi-walled CNTs (O-MWCNTs). Our results indicated that O-MWCNTs possessed a huge adsorption capacity for DOX (9.45×10(3) mg/g). Although the adsorption process was quite slow, the adsorption capacity kept high enough for the therapy while shortening the incubation time to 2h (1.03×10(3) mg/g). The desorption of DOX from O-MWCNTs scarcely occurred while incubated in buffer solution at both pH 7.4 and pH 5.5, however, the lower pH did benefit the desorption. The presence of serum proteins facilitated the desorption of DOX significantly, because these proteins bound strongly to O-MWCNTs resulting in the partial surface of O-MWNCTs being occupied. Moreover, the adsorption time also affected the release of DOX from O-MWCNTs. Shortening the incubation time benefited the release of DOX. The implications to the drug loading and therapeutics of the CNT-based drug delivery systems are discussed.

  14. Development and characterization of liposomal doxorubicin hydrochloride with palm oil.

    PubMed

    Sabeti, Bahareh; Noordin, Mohamed Ibrahim; Mohd, Shaharuddin; Hashim, Rosnani; Dahlan, Afendi; Javar, Hamid Akbari

    2014-01-01

    The usage of natural products in pharmaceuticals has steadily seen improvements over the last decade, and this study focuses on the utilization of palm oil in formulating liposomal doxorubicin (Dox). The liposomal form of Dox generally minimizes toxicity and enhances target delivery actions. Taking into account the antiproliferative and antioxidant properties of palm oil, the aim of this study is to design and characterize a new liposomal Dox by replacing phosphatidylcholine with 5% and 10% palm oil content. Liposomes were formed using the freeze_thaw method, and Dox was loaded through pH gradient technique and characterized through in vitro and ex vivo terms. Based on TEM images, large lamellar vesicles (LUV) were formed, with sizes of 438 and 453 nm, having polydispersity index of 0.21 ± 0.8 and 0.22 ± 1.3 and zeta potentials of about -31 and -32 mV, respectively. In both formulations, the entrapment efficiency was about 99%, and whole Dox was released through 96 hours in PBS (pH = 7.4) at 37°C. Comparing cytotoxicity and cellular uptake of LUV with Caelyx(R) on MCF7 and MDA-MBA 231 breast cancer cell lines indicated suitable uptake and lower IC50 of the prepared liposomes.

  15. Development and Characterization of Liposomal Doxorubicin Hydrochloride with Palm Oil

    PubMed Central

    Sabeti, Bahareh; Noordin, Mohamed Ibrahim; Mohd, Shaharuddin; Hashim, Rosnani; Akbari Javar, Hamid

    2014-01-01

    The usage of natural products in pharmaceuticals has steadily seen improvements over the last decade, and this study focuses on the utilization of palm oil in formulating liposomal doxorubicin (Dox). The liposomal form of Dox generally minimizes toxicity and enhances target delivery actions. Taking into account the antiproliferative and antioxidant properties of palm oil, the aim of this study is to design and characterize a new liposomal Dox by replacing phosphatidylcholine with 5% and 10% palm oil content. Liposomes were formed using the freeze_thaw method, and Dox was loaded through pH gradient technique and characterized through in vitro and ex vivo terms. Based on TEM images, large lamellar vesicles (LUV) were formed, with sizes of 438 and 453 nm, having polydispersity index of 0.21 ± 0.8 and 0.22 ± 1.3 and zeta potentials of about −31 and −32 mV, respectively. In both formulations, the entrapment efficiency was about 99%, and whole Dox was released through 96 hours in PBS (pH = 7.4) at 37°C. Comparing cytotoxicity and cellular uptake of LUV with CaelyxR on MCF7 and MDA-MBA 231 breast cancer cell lines indicated suitable uptake and lower IC50 of the prepared liposomes. PMID:24795894

  16. Biocompatible microemulsion modifies the tissue distribution of doxorubicin.

    PubMed

    Candido, Caroline Damico; Campos, Michel Leandro; Correa Vidigal Assumpção, Juliana Uruguay; Pestana, Kelly Chrystina; Padilha, Elias Carvalho; Carlos, Iracilda Zeppone; Peccinini, Rosângela Gonçalves

    2014-10-01

    The incorporation of doxorubicin (DOX) in a microemulsion (DOX-ME) has shown beneficial consequences by reducing the cardiotoxic effects of DOX. The aim of this study was to determine the distribution of DOX-ME in Ehrlich solid tumor (EST) and the heart, and compare it with that of free DOX. The distribution study was conducted with female Swiss mice with EST (n = 7 per group; 20-25 g). Animals received a single dose (10 mg/kg, i.p.) of DOX or DOX-ME 7 days after tumor inoculation. Fifteen minutes after administration, the animals were sacrificed, and the tumor and heart tissues were taken for immediate analysis by ultra-performance liquid chromatography. No difference was observed in DOX concentration in tumor tissue between DOX and DOX-ME administration. However, the most remarkable result in this study was the statistically significant reduction in DOX concentration in heart tissue of animals given DOX-ME. Mean DOX concentration in heart tissue was 0.92 ± 0.54 ng mg(-1) for DOX-ME and 1.85 ± 0.34 ng mg(-1) for free DOX. In conclusion, DOX-ME provides a better tissue distribution profile, with a lower drug concentration in heart tissue but still comparable tumor drug concentration, which indicates that antitumor activity would not be compromised.

  17. Gamma irradiation reduces the immunological toxicity of doxorubicin, anticancer drug

    NASA Astrophysics Data System (ADS)

    Kim, Jae-Hun; Sung, Nak-Yun; Raghavendran, H. Balaji; Yoon, Yohan; Song, Beom-Seok; Choi, Jong-il; Yoo, Young-Choon; Byun, Myung-Woo; Hwang, Young-Jeong; Lee, Ju-Woon

    2009-07-01

    Doxorubicin (DOX) is a widely used anticancer agent, but exhibits some immunological toxicity to patients during chemotherapy. The present study was conducted to evaluate the effect of gamma irradiation on the immunological response and the inhibition activity on in vivo tumor mass of DOX. The results showed that DOX irradiated at 10 and 20 kGy reduce the inhibition of mouse peritoneal macrophage proliferation and induce the release of cytokines (TNF-α and IL-6) when compared with non-irradiated DOX. The cytotoxicity against human breast (MCF-7), murine colon adenocarcinoma (Colon 26) and human monocytic (THP-1) tumor cell were not significantly different between non-irradiated and irradiated DOX ( P<0.05). In vivo study on the tumor mass inhibition, gamma-irradiated DOX showed a considerable inhibition of tumor mass and this effect was statistically non-significant as compared with non-irradiated DOX. In conclusion, gamma irradiation could be regarded as a potential method for reducing the immunological toxicity of DOX. Further researches is needed to reveal the formation and activity of radiolysis products by gamma irradiation.

  18. Doxorubicin-induced alopecia is associated with sebaceous gland degeneration.

    PubMed

    Selleri, Silvia; Seltmann, Holger; Gariboldi, Silvia; Shirai, Yuri F; Balsari, Andrea; Zouboulis, Christos C; Rumio, Cristiano

    2006-04-01

    Alopecia, accompanied by skin dryness, is one of the distressing side effects often occurring in chemotherapy-treated cancer patients. Little is known of the effects of chemotherapy on sebaceous glands, despite their importance in hair follicle homeostasis. This study investigates sebaceous gland morphology and the response of SZ95 sebaceous gland cell line to doxorubicin (DXR) treatment. The morphology of sebaceous glands during intraperitoneal DXR treatment was investigated by optical and electron microscopy in a 7-day-old rat model and further confirmed in an adult mouse model. Moreover, in vitro studies using the SZ95 sebaceous gland cell line were performed to assess the response of sebocytes to DXR in terms of cell proliferation, apoptosis, and necrosis. DXR treatment induced sebaceous gland regression and occasionally caused their complete disappearance. This observed damage and disappearance preceded DXR-induced hair loss. In vitro experiments using the SZ95 sebaceous gland cell line indicated that DXR treatment induced a differentiation process leading to premature sebocytes apoptosis. Owing to the importance of the sebaceous gland in hair follicle homeostasis, DXR-induced involution of this gland might be related to subsequent hair loss.

  19. Interactions of human serum albumin with doxorubicin in different media

    NASA Astrophysics Data System (ADS)

    Gun'ko, Vladimir M.; Turov, Vladimir V.; Krupska, Tetyana V.; Tsapko, Magdalina D.

    2017-02-01

    Interactions of human serum albumin (10 wt% H2O and 0.3 wt% sodium caprylate) with doxorubicin hydrochloride (1 wt%) were studied alone or with addition of HCl (3.6 wt% HCl) using 1H NMR spectroscopy. A model of hydrated HSA/12DOX was calculated using PM7 method with COSMO showing large variations in the binding constant depending on structural features of DOX/HSA complexes. DOX molecules/ions displace bound water from narrow intramolecular voids in HSA that leads to diminution of freezing-melting point depression of strongly bound water (SBW). Structure of weakly bound water (WBW) depends much weaker on the presence of DOX than SBW because a major fraction of DOX is bound to adsorption sites of HSA. Addition of HCl results in strong changes in structure of macromolecules and organization of water in hydration shells of HSA (i.e., mainly SBW) and in the solution (i.e., WBW + non-bound bulk water).

  20. Erdosteine prevents doxorubicin-induced cardiotoxicity in rats.

    PubMed

    Yagmurca, Murat; Fadillioglu, Ersin; Erdogan, Hasan; Ucar, Muharrem; Sogut, Sadik; Irmak, M Kemal

    2003-10-01

    The clinical use of doxorubicin (Dxr) is limited by its cardiotoxic effects which are mediated by oxygen radicals. The purpose of this study was to investigate in vivo protective effects of erdosteine, an antioxidant agent because of its secondary active metabolites in vivo, against the cardiotoxicity induced by Dxr in rats. Three groups of male Sprague-Dawley rats (60 days old) were used. Group 1 was untreated group used as control; the other groups were treated with Dxr (single i.p. dosage of 20 mg kg(-1) b.wt.) or Dxr plus erdosteine (10 mg kg(-1) day(-1), orally), respectively. Erdosteine or oral saline treatment was done starting 2 days before Dxr for 12 days. The analyses were done at the 10th day of Dxr treatment. The protein carbonyl content, the activities of myeloperoxidase, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine kinase (CK) as well as heart rate and blood pressures were significantly increased in Dxr group in comparison with the other groups. However, pulse pressure was decreased in Dxr group. The body and heart weights were decreased in both Dxr administered groups in comparison with control group. Disorganization of myocardial histology, picnotic nuclei, edema, and increase in collagen content around vessels were seen in the slides of Dxr group, whereas normal myocardial microscopy was preserved in Dxr plus erdosteine group. Collectively, these in vivo hemodynamic, enzymatic and morphologic studies provide an evidence for a possible prevention of cardiac toxicity in Dxr-treated patients.

  1. A sensitive high performance liquid chromatography assay for the quantification of doxorubicin associated with DNA in tumor and tissues.

    PubMed

    Lucas, Andrew T; O'Neal, Sara K; Santos, Charlene M; White, Taylor F; Zamboni, William C

    2016-02-05

    Doxorubicin, a widely used anticancer agent, exhibits antitumor activity against a wide variety of malignancies. The drug exerts its cytotoxic effects by binding to and intercalating within the DNA of tumor and tissue cells. However, current assays are unable to accurately determine the concentration of the intracellular active form of doxorubicin. Thus, the development of a sample processing method and a high-performance liquid chromatography (HPLC) methodology was performed in order to quantify doxorubicin that is associated with DNA in tumors and tissues, which provided an intracellular cytotoxic measure of doxorubicin exposure after administration of small molecule and nanoparticle formulations of doxorubicin. The assay uses daunorubicin as an internal standard; liquid-liquid phase extraction to isolate drug associated with DNA; a Shimadzu HPLC with fluorescence detection equipped with a Phenomenex Luna C18 (2μm, 2.0×100mm) analytical column and a gradient mobile phase of 0.1% formic acid in water or acetonitrile for separation and quantification. The assay has a lower limit of detection (LLOQ) of 10ng/mL and is shown to be linear up to 3000ng/mL. The intra- and inter-day precision of the assay expressed as a coefficient of variation (CV%) ranged from 4.01 to 8.81%. Furthermore, the suitability of this assay for measuring doxorubicin associated with DNA in vivo was demonstrated by using it to quantify the doxorubicin concentration within tumor samples from SKOV3 and HEC1A mice obtained 72h after administration of PEGylated liposomal doxorubicin (Doxil(®); PLD) at 6mg/kg IV x 1. This HPLC assay allows for sensitive intracellular quantification of doxorubicin and will be an important tool for future studies evaluating intracellular pharmacokinetics of doxorubicin and various nanoparticle formulations of doxorubicin.

  2. Multiscale Modeling of the Effects of Salt and Perfume Raw Materials on the Rheological Properties of Commercial Threadlike Micellar Solutions.

    PubMed

    Tang, Xueming; Zou, Weizhong; Koenig, Peter H; McConaughy, Shawn D; Weaver, Mike R; Eike, David M; Schmidt, Michael J; Larson, Ronald G

    2017-03-23

    We link micellar structures to their rheological properties for two surfactant body-wash formulations at various concentrations of salts and perfume raw materials (PRMs) using molecular simulations and micellar-scale modeling, as well as traditional surfactant packing arguments. The two body washes, namely, BW-1EO and BW-3EO, are composed of sodium lauryl ethylene glycol ether sulfate (SLEnS, where n is the average number of ethylene glycol repeat units), cocamidopropyl betaine (CAPB), ACCORD (which is a mixture of six PRMs), and NaCl salt. BW-3EO is an SLE3S-based body wash, whereas BW-1EO is an SLE1S-based body wash. Additional PRMs are also added into the body washes. The effects of temperature, salt, and added PRMs on micellar lengths, breakage times, end-cap free energies, and other properties are obtained from fits of the rheological data to predictions of the "Pointer Algorithm" [ Zou , W. ; Larson , R.G. J. Rheol. 2014 , 58 , 1 - 41 ], which is a simulation method based on the Cates model of micellar dynamics. Changes in these micellar properties are interpreted using the Israelachvili surfactant packing argument. From coarse-grained molecular simulations, we infer how salt modifies the micellar properties by changing the packing between the surfactant head groups, with the micellar radius remaining nearly constant. PRMs do so by partitioning to different locations within the micelles according to their octanol/water partition coefficient POW and chemical structures, adjusting the packing of the head and/or tail groups, and by changing the micelle radius, in the case of a large hydrophobic PRM. We find that relatively hydrophilic PRMs with log POW < 2 partition primarily to the head group region and shrink micellar length, decreasing viscosity substantially, whereas more hydrophobic PRMs, with log POW between 2 and 4, mix with the hydrophobic surfactant tails within the micellar core and slightly enhance the viscosity and micelle length, which is

  3. Solubilization sites and acid-base forms of dibucaine-hydrochloride in neutral and charged micellar solutions.

    PubMed

    Mertz, C J; Lin, C T

    1991-03-01

    Steady-state and time-resolved emission spectroscopic techniques have been employed to characterize the drug species of dibucaine and to identify its location in micellar Triton X-100 (neutral), hexadecyltrimethyl ammonium bromide (cationic) and lithium dodecyl sulfate (anionic) solutions at 77 K. Under physiological conditions, the dibucaine is shown to exist in the free base form (D) while solubilized in the hydrocarbon core of neutral micelles. In cationic micellar solution, dibucaine exists as the monocation species (DH+) where the anesthetic is solubilized in the extramicellar aqueous solution and D is solubilized in the hydrophobic region with close proximity to the micellar interface. In the anionic micelles, interfacial solubilization is most consistent with a site in which the tertiary amino group of the monocation dibucaine (DH+) is anchored at the micellar interface with its quinoline analog penetrating the hydrophobic region. The distinct properties observed for the drug species (i.e. D and DH+) and their solubilization sites in micelles are consistent with a balance between hydrophobic forces, surface polarity and the interfacial electrostatic potential present in the micellar solubilization sites. These observations could lend insight into the molecular basis of pharmacological action, in particular the mechanism of local anesthetic drug transport across membranes.

  4. Study of monoprotic acid-base equilibria in aqueous micellar solutions of nonionic surfactants using spectrophotometry and chemometrics.

    PubMed

    Babamoradi, Hamid; Abdollahi, Hamid

    2015-10-05

    Many studies have shown the distribution of solutes between aqueous phase and micellar pseudo-phase in aqueous micellar solutions. However, spectrophotometric studies of acid-base equilibria in these media do not confirm such distribution because of the collinearity between concentrations of chemical species in the two phases. The collinearity causes the number of detected species to be equal to the number of species in a homogenous solution that automatically misinterpreted as homogeneity of micellar solutions, therefore the collinearity is often neglected. This interpretation is in contradiction to the distribution theory in micellar media that must be avoided. Acid-base equilibrium of an indicator was studied in aqueous micellar solutions of a nonionic surfactant to address the collinearity using UV/Visible spectrophotometry. Simultaneous analysis (matrix augmentation) of the equilibrium and solvation data was applied to eliminate the collinearity from the equilibrium data. A model was then suggested for the equilibrium that was fitted to the augmented data to estimate distribution coefficients of the species between the two phases. Moreover, complete resolution of concentration and spectral profiles of species in each phase was achieved.

  5. Magnetic nanoparticle-conjugated polymeric micelles for combined hyperthermia and chemotherapy

    NASA Astrophysics Data System (ADS)

    Kim, Hyun-Chul; Kim, Eunjoo; Jeong, Sang Won; Ha, Tae-Lin; Park, Sang-Im; Lee, Se Guen; Lee, Sung Jun; Lee, Seung Woo

    2015-10-01

    Magnetic nanoparticle-conjugated polymeric micelles (MNP-PMs) consisting of poly(ethylene glycol)-poly(lactide) (PEG-PLA) and iron oxide nanoparticles were prepared and used as nanocarriers for combined hyperthermia and chemotherapy. Doxorubicin (DOX) was encapsulated in MNP-PMs, and an alternating magnetic field (AMF) resulted in an increase to temperature within a suitable range for inducing hyperthermia and a higher rate of drug release than observed without AMF. In vitro cytotoxicity and hyperthermia experiments were carried out using human lung adenocarcinoma A549 cells. When MNP-PMs encapsulated with an anticancer drug were used to treat A549 cells in combination with hyperthermia under AMF, 78% of the cells were killed by the double effects of heat and the drug, and the combination was more effective than either chemotherapy or hyperthermia treatment alone. Therefore, MNP-PMs encapsulated with an anticancer drug show potential for combined chemotherapy and hyperthermia.Magnetic nanoparticle-conjugated polymeric micelles (MNP-PMs) consisting of poly(ethylene glycol)-poly(lactide) (PEG-PLA) and iron oxide nanoparticles were prepared and used as nanocarriers for combined hyperthermia and chemotherapy. Doxorubicin (DOX) was encapsulated in MNP-PMs, and an alternating magnetic field (AMF) resulted in an increase to temperature within a suitable range for inducing hyperthermia and a higher rate of drug release than observed without AMF. In vitro cytotoxicity and hyperthermia experiments were carried out using human lung adenocarcinoma A549 cells. When MNP-PMs encapsulated with an anticancer drug were used to treat A549 cells in combination with hyperthermia under AMF, 78% of the cells were killed by the double effects of heat and the drug, and the combination was more effective than either chemotherapy or hyperthermia treatment alone. Therefore, MNP-PMs encapsulated with an anticancer drug show potential for combined chemotherapy and hyperthermia. Electronic

  6. Precision synthesis of functional materials via RAFT polymerization and click-type chemical reactions

    NASA Astrophysics Data System (ADS)

    Flores, Joel Diez

    2011-12-01

    achieved via reaction with model amine, thiol and alcohol compounds yielding urea, thiourethane and urethane derivatives, respectively. Reactions with amines and thiols (in the presence of base) were rapid, quantitative and efficient. However, the reaction with alcohols catalyzed by dibutyltin dilaurate (DBTDL) was relatively slow but proceeded to completion. Selective reaction pathways for the addition of difunctional ethanolamine and mercaptoethanol were also investigated. A related strategy is described in Section II wherein a hydroxyl-containing diblock copolymer precursor was transformed into a library of functional copolymers via two sequential post-polymerization modification reactions. A diblock copolymer scaffold, poly[(N,N-dimethylacrylamide)-b-( N-(2-hydroxyethyl)acrylamide] (PDMA-b-PHEA) was first prepared. The hydroxyl groups of the HEA block were then reacted with 2-(acryloyloxy)ethylisocyanate (AOI) and allylisocyanate (AI) resulting in acrylate- and allyl-functionalized copolymer precursors, respectively. The efficiencies of Michael-type and free radical thiol addition reactions were investigated using selected thiols having alkyl, aryl, hydroxyl, carboxylic acid, amine and amino acid functionalities. The steps of RAFT polymerization, isocyanate-hydroxyl coupling and thiol-ene addition are accomplished under mild conditions, thus offering facile and modular routes to synthesize functional copolymers. The synthesis and solution studies of pH- and salt-responsive triblock copolymer are described in Section III. This system is capable of forming self-locked micellar structures which may be controlled by changing solution pH as well as ionic strength. A triblock copolymer containing a permanently hydrophilic poly(N,N-dimethylacrylamide) (PDMA) outer block, a salt-sensitive zwitterionic poly(3[2-(N-methylacrylamido)ethyl dimethylammonio]propanesulfonate) (PMAEDAPS) middle block and a pH-responsive 3-acrylamido-3-methylbutanoic acid (PAMBA) core block was

  7. Nanocarriers Enhance Doxorubicin Uptake in Drug-Resistant Ovarian Cancer Cells

    PubMed Central

    Arora, Hans C; Jensen, Mark P; Yuan, Ye; Wu, Aiguo; Vogt, Stefan; Paunesku, Tatjana; Woloschak, Gayle E

    2012-01-01

    Resistance to anthracyclines and other chemotherapeutics due to P-glycoprotein (PGP)-mediated export is a frequent problem in cancer treatment. Here we report that iron oxide-titanium dioxide core-shell nanocomposites can serve as efficient carriers for doxorubicin to overcome this common mechanism of drug resistance in cancer cells. Doxorubicin nanocarriers (DNCs) increased effective drug uptake in drug-resistant ovarian cells. Mechanistically, doxorubicin bound to the TiO2 surface by a labile bond that was severed upon acidification within cell endosomes. Upon its release doxorubicin traversed the intracellular milieu and entered the cell nucleus by a route that evaded PGP-mediated drug export. Confocal and x-ray fluorescence microscopy with flow cytometry were used to demonstrate the ability of DNC to modulate transferrin uptake and distribution in cells. Increased transferrin uptake occurred through clathrin-mediated endocytosis, indicating that nanocomposites and DNCs may both interfere with removal of transferrin from cells. Together, our findings show that DNCs not only provide an alternative route of delivery of doxorubicin to PGP-over-expressing cancer cells, but may also boost the uptake of transferrin-tagged therapeutic agents. PMID:22158944

  8. MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity.

    PubMed

    Holmgren, Gustav; Synnergren, Jane; Andersson, Christian X; Lindahl, Anders; Sartipy, Peter

    2016-08-01

    Anthracyclines, such as doxorubicin, are well-established, highly efficient anti-neoplastic drugs used for treatment of a variety of cancers, including solid tumors, leukemia, lymphomas, and breast cancer. The successful use of doxorubicin has, however, been hampered by severe cardiotoxic side-effects. In order to prevent or reverse negative side-effects of doxorubicin, it is important to find early biomarkers of heart injury and drug-induced cardiotoxicity. The high stability under extreme conditions, presence in various body fluids, and tissue-specificity, makes microRNAs very suitable as clinical biomarkers. The present study aimed towards evaluating the early and late effects of doxorubicin on the microRNA expression in cardiomyocytes derived from human pluripotent stem cells. We report on several microRNAs, including miR-34a, miR-34b, miR-187, miR-199a, miR-199b, miR-146a, miR-15b, miR-130a, miR-214, and miR-424, that are differentially expressed upon, and after, treatment with doxorubicin. Investigation of the biological relevance of the identified microRNAs revealed connections to cardiomyocyte function and cardiotoxicity, thus supporting the findings of these microRNAs as potential biomarkers for drug-induced cardiotoxicity.

  9. Molecular dynamics simulation of doxorubicin adsorption on a bundle of functionalized CNT.

    PubMed

    Izadyar, Akram; Farhadian, Nafiseh; Chenarani, Naser

    2016-08-01

    In this study, molecular dynamics simulation is used to investigate the adsorption of an anticancer drug, doxorubicin, on bundles of functionalized single-walled carbon nanotubes (SWNTs) in an aqueous solution. Carboxylic group has been selected as the functional group. Molecular dynamics (MD) simulations are performed for both separated systems containing a SWNT bundle and a functionalized carbon nanotube bundle, and results are compared with existing experimental data. MD results show that doxorubicin can be adsorbed on CNTs using different methods such as entrapment within CNT bundle, attachment to the side wall of the CNT, and adsorption on the CNT inner cavity. For functionalized CNT, the adsorption of drugs on the functional groups is essential for predicting the enhancement of drug loading on the functionalized nanotubes. Furthermore, the adsorption behavior of doxorubicin on CNTs is fitted with Langmuir and Freundlich isotherm models. The results show that Langmuir model can predict the adsorption behavior of doxorubicin on CNTs more accurately than Freundlich model does. As predicted by this isotherm model, the adsorption process of doxorubicin on CNTs is relatively difficult, but it can be improved by increasing the functional groups on the CNTs surface.

  10. α-Tocopherol succinate improves encapsulation and anticancer activity of doxorubicin loaded in solid lipid nanoparticles.

    PubMed

    Oliveira, Mariana S; Mussi, Samuel V; Gomes, Dawidson A; Yoshida, Maria Irene; Frezard, Frederic; Carregal, Virgínia M; Ferreira, Lucas A M

    2016-04-01

    This work aimed to develop solid lipid nanoparticles (SLN) co-loaded with doxorubicin and α-tocopheryl succinate (TS), a succinic acid ester of α-tocopherol that exhibits anticancer actions, evaluating the influence of TS on drug encapsulation efficiency. The SLN were characterized for size, zeta potential, entrapment efficiency (EE), and drug release. Studies of in vitro anticancer activity were also conducted. The EE was significantly improved from 30 ± 1% to 96 ± 2% for SLN without and with TS at 0.4%, respectively. In contrast, a reduction in particle size from 298 ± 1 to 79 ± 1 nm was observed for SLN without and with TS respectively. The doxorubicin release data show that SLN provide a controlled drug release. The in vitro studies showed higher cytotoxicity for doxorubicin-TS-loaded SLN than for free doxorubicin in breast cancer cells. These findings suggest that TS-doxorubicin-loaded SLN is a promising alternative for the treatment of cancer.

  11. Tumor Cells Upregulate Normoxic HIF-1α in Response to Doxorubicin

    PubMed Central

    Cao, Yiting; Eble, Joseph M.; Moon, Ejung; Yuan, Hong; Weitzel, Douglas H.; Landon, Chelsea D.; Nien, Charleen Yu-Chih; Hanna, Gabi; Rich, Jeremy N.; Provenzale, James M.; Dewhirst, Mark W.

    2013-01-01

    Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor that controls cellular homeostasis. While its activation benefits normal tissue, HIF-1 activation in tumors is a major risk factor for angiogenesis, therapeutic resistance and poor prognosis. HIF-1 activity is usually suppressed under normoxic conditions because of rapid oxygen-dependent degradation of HIF-1α. Here we show that under normoxic conditions HIF-1α is upregulated in tumor cells in response to doxorubicin, a chemotherapy used to treat many cancers. Doxorubicin also enhanced VEGF secretion by normoxic tumor cells and stimulated tumor angiogenesis. Doxorubicin-induced accumulation of HIF-1α in normoxic cells was caused by increased expression and activation of STAT1, the activation of which stimulated expression of iNOS and its synthesis of NO in tumor cells. Mechanistic investigations established that blocking NO synthesis or STAT1 activation was sufficient to attenuate the HIF-1α accumulation induced by doxorubicin in normoxic cancer cells. To our knowledge, this is the first report that a chemotherapeutic drug can induce HIF-1α accumulation in normoxic cells, an efficacy-limiting activity. Our results argue that HIF-1α targeting strategies may enhance doxorubicin efficacy. More generally, they suggest a broader perspective on the design of combination chemotherapy approaches with immediate clinical impact. PMID:23959856

  12. Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin

    PubMed Central

    Xu, Xiao Dong; Zhao, Yan; Zhang, Min; He, Rui Zhi; Shi, Xiu Hui; Guo, Xing Jun; Shi, Cheng Jian; Peng, Feng; Wang, Min; Shen, Min; Wang, Xin; Li, Xu; Qin, Ren Yi

    2017-01-01

    Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer. PMID:28208617

  13. Mitochondrial catastrophe during doxorubicin-induced cardiotoxicity: a review of the protective role of melatonin.

    PubMed

    Govender, Jenelle; Loos, Ben; Marais, Erna; Engelbrecht, Anna-Mart

    2014-11-01

    Anthracyclines, such as doxorubicin, are among the most valuable treatments for various cancers, but their clinical use is limited due to detrimental side effects such as cardiotoxicity. Doxorubicin-induced cardiotoxicity is emerging as a critical issue among cancer survivors and is an area of much significance to the field of cardio-oncology. Abnormalities in mitochondrial functions such as defects in the respiratory chain, decreased adenosine triphosphate production, mitochondrial DNA damage, modulation of mitochondrial sirtuin activity and free radical formation have all been suggested as the primary causative factors in the pathogenesis of doxorubicin-induced cardiotoxicity. Melatonin is a potent antioxidant, is nontoxic, and has been shown to influence mitochondrial homeostasis and function. Although a number of studies support the mitochondrial protective role of melatonin, the exact mechanisms by which melatonin confers mitochondrial protection in the context of doxorubicin-induced cardiotoxicity remain to be elucidated. This review focuses on the role of melatonin on doxorubicin-induced bioenergetic failure, free radical generation, and cell death. A further aim is to highlight other mitochondrial parameters such as mitophagy, autophagy, mitochondrial fission and fusion, and mitochondrial sirtuin activity, which lack evidence to support the role of melatonin in the context of cardiotoxicity.

  14. Fulvestrant reverses doxorubicin resistance in multidrug-resistant breast cell lines independent of estrogen receptor expression.

    PubMed

    Huang, Yuan; Jiang, Donghai; Sui, Meihua; Wang, Xiaojia; Fan, Weimin

    2017-02-01

    Drug resistance, a major obstacle to successful cancer chemotherapy, frequently occurs in recurrent or metastatic breast cancer and results in poor clinical response. Fulvestrant is a new type of selective estrogen receptor (ER) downregulator and a promising endocrine therapy for breast cancer. In this study, we evaluated the combination treatment of fulvestrant and doxorubicin in ER-negative multidrug-resistant (MDR) breast cancer cell lines Bads‑200 and Bats‑72. Fulvestrant potentiated doxorubicin-induced cytotoxicity, apoptosis and G2/M arrest with upregulation of cyclin B1. It functioned as a substrate for P-glycoprotein (P-gp) without affecting its expression. Furthermore, fulvestrant not only restored the intracellular accumulation of doxorubicin but also relocalized it to the nuclei in Bats‑72 and Bads‑200 cells, which may be another potential mechanism of reversal of P-gp mediated doxorubicin resistance. These results indicated that the combination of fulvestrant and doxorubicin-based chemotherapy may be feasible and effective for patients with advanced breast cancer.

  15. Fluorescence resonance energy transfer between green fluorescent protein and doxorubicin enabled by DNA nanotechnology.

    PubMed

    Heger, Zbynek; Kominkova, Marketa; Cernei, Natalia; Krejcova, Ludmila; Kopel, Pavel; Zitka, Ondrej; Adam, Vojtech; Kizek, Rene

    2014-12-01

    DNA nanotechnology is a rapidly growing research area, where DNA may be used for wide range of applications such as construction of nanodevices serving for large scale of diverse purposes. Likewise a panel of various purified fluorescent proteins is investigated for their ability to emit their typical fluorescence spectra under influence of particular excitation. Hence these proteins may form ideal donor molecules for assembly of fluorescence resonance emission transfer (FRET) constructions. To extend the application possibilities of fluorescent proteins, while using DNA nanotechnology, we developed nanoconstruction comprising green fluorescent protein (GFP) bound onto surface of surface active nanomaghemite and functionalized with gold nanoparticles. We took advantage of natural affinity between gold and thiol moieties, which were modified to bind DNA fragment. Finally we enclosed doxorubicin into fullerene cages. Doxorubicin intercalated in DNA fragment bound on the particles and thus we were able to connect these parts together. Because GFP behaved as a donor and doxorubicin as an acceptor using excitation wavelength for GFP (395 nm) in emission wavelength of doxorubicin (590 nm) FRET was observed. This nanoconstruction may serve as a double-labeled transporter of doxorubicin guided by force of external magnetic force owing to the presence of nanomaghemite. Further nanomaghemite offers the possibility of using this technology for thermotherapy.

  16. A Flow Cytometric Clonogenic Assay Reveals the Single-Cell Potency of Doxorubicin.

    PubMed

    Maass, Katie F; Kulkarni, Chethana; Quadir, Mohiuddin A; Hammond, Paula T; Betts, Alison M; Wittrup, Karl Dane

    2015-12-01

    Standard cell proliferation assays use bulk media drug concentration to ascertain the potency of chemotherapeutic drugs; however, the relevant quantity is clearly the amount of drug actually taken up by the cell. To address this discrepancy, we have developed a flow cytometric clonogenic assay to correlate the amount of drug in a single cell with the cell's ability to proliferate using a cell tracing dye and doxorubicin, a naturally fluorescent chemotherapeutic drug. By varying doxorubicin concentration in the media, length of treatment time, and treatment with verapamil, an efflux pump inhibitor, we introduced 10(5) -10(10) doxorubicin molecules per cell; then used a dye-dilution assay to simultaneously assess the number of cell divisions. We find that a cell's ability to proliferate is a surprisingly conserved function of the number of intracellular doxorubicin molecules, resulting in single-cell IC50 values of 4-12 million intracellular doxorubicin molecules. The developed assay is a straightforward method for understanding a drug's single-cell potency and can be used for any fluorescent or fluorescently labeled drug, including nanoparticles or antibody-drug conjugates.

  17. Stereospecific olefin polymerization catalysts

    DOEpatents

    Bercaw, John E.; Herzog, Timothy A.

    1998-01-01

    A metallocene catalyst system for the polymerization of .alpha.-olefins to yield stereospecific polymers including syndiotactic, and isotactic polymers. The catalyst system includes a metal and a ligand of the formula ##STR1## wherein: R.sup.1, R.sup.2, and R.sup.3 are independently selected from the group consisting of hydrogen, C.sub.1 to C.sub.10 alkyl, 5 to 7 membered cycloalkyl, which in turn may have from 1 to 3 C.sub.1 to C.sub.10 alkyls as a substituent, C.sub.6 to C.sub.15 aryl or arylalkyl in which two adjacent radicals may together stand for cyclic groups having 4 to 15 carbon atoms which in turn may be substituted, or Si(R.sup.8).sub.3 where R.sup.8 is selected from the group consisting of C.sub.1 to C.sub.10 alkyl, C.sub.6 to C.sub.15 aryl or C.sub.3 to C.sub.10 cycloalkyl; R.sup.4 and R.sup.6 are substituents both having van der Waals radii larger than the van der Waals radii of groups R.sup.1 and R.sup.3 ; R.sup.5 is a substituent having a van der Waals radius less than about the van der Waals radius of a methyl group; E.sup.1, E.sup.2 are independently selected from the group consisting of Si(R.sup.9).sub.2, Si(R.sup.9).sub.2 --Si(R.sup.9).sub.2, Ge(R.sup.9).sub.2, Sn(R.sup.9).sub.2, C(R.sup.9).sub.2, C(R.sup.9).sub.2 --C(R.sup.9).sub.2, where R.sup.9 is C.sub.1 to C.sub.10 alkyl, C.sub.6 to C.sub.15 aryl or C.sub.3 to C.sub.10 cycloalkyl; and the ligand may have C.sub.S or C.sub.1 -symmetry. Preferred metals are selected from the group consisting of group III, group IV, group V or lanthanide group elements. The catalysts are used to prepare stereoregular polymers including polypropylene from .alpha.-olefin monomers.

  18. Stereospecific olefin polymerization catalysts

    DOEpatents

    Bercaw, J.E.; Herzog, T.A.

    1998-01-13

    A metallocene catalyst system is described for the polymerization of {alpha}-olefins to yield stereospecific polymers including syndiotactic, and isotactic polymers. The catalyst system includes a metal and a ligand of the formula shown wherein: R{sup 1}, R{sup 2}, and R{sup 3} are independently selected from the group consisting of hydrogen, C{sub 1} to C{sub 10} alkyl, 5 to 7 membered cycloalkyl, which in turn may have from 1 to 3 C{sub 1} to C{sub 10} alkyls as a substituent, C{sub 6} to C{sub 15} aryl or arylalkyl in which two adjacent radicals may together stand for cyclic groups having 4 to 15 carbon atoms which in turn may be substituted, or Si(R{sup 8}){sub 3} where R{sup 8} is selected from the group consisting of C{sub 1} to C{sub 10} alkyl, C{sub 6} to C{sub 15} aryl or C{sub 3} to C{sub 10} cycloalkyl; R{sup 4} and R{sup 6} are substituents both having van der Waals radii larger than the van der Waals radii of groups R{sup 1} and R{sup 3}; R{sup 5} is a substituent having a van der Waals radius less than about the van der Waals radius of a methyl group; E{sup 1}, E{sup 2} are independently selected from the group consisting of Si(R{sup 9}){sub 2}, Si(R{sup 9}){sub 2}--Si(R{sup 9}){sub 2}, Ge(R{sup 9}){sub 2}, Sn(R{sup 9}){sub 2}, C(R{sup 9}){sub 2}, C(R{sup 9}){sub 2}--C(R{sup 9}){sub 2}, where R{sup 9} is C{sub 1} to C{sub 10} alkyl, C{sub 6} to C{sub 15} aryl or C{sub 3} to C{sub 10} cycloalkyl; and the ligand may have C{sub S} or C{sub 1}-symmetry. Preferred metals are selected from the group consisting of group III, group IV, group V or lanthanide group elements. The catalysts are used to prepare stereoregular polymers including polypropylene from {alpha}-olefin monomers.

  19. Mechanically controlled radical polymerization initiated by ultrasound

    NASA Astrophysics Data System (ADS)

    Mohapatra, Hemakesh; Kleiman, Maya; Esser-Kahn, Aaron Palmer

    2016-10-01

    In polymer chemistry, mechanical energy degrades polymeric chains. In contrast, in nature, mechanical energy is often used to create new polymers. This mechanically stimulated growth is a key component of the robustness of biological materials. A synthetic system in which mechanical force initiates polymerization will provide similar robustness in polymeric materials. Here we show a polymerization of acrylate monomers initiated and controlled by mechanical energy provided by ultrasonic agitation. The activator for an atom-transfer radical polymerization is generated using piezochemical reduction of a Cu(II) precursor complex, which thus converts a mechanical activation of piezoelectric particles to the synthesis of a new material. This polymerization reaction has some characteristics of controlled radical polymerization, such as narrow molecular-weight distribution and linear dependence of the polymeric chain length on the time of mechanical activation. This new method of controlled radical polymerization complements the existing methods to synthesize commercially useful well-defined polymers.

  20. Core-Shell Silver/Polymeric Nanoparticles-Based Combinatorial Therapy against Breast Cancer In-vitro

    NASA Astrophysics Data System (ADS)

    Elbaz, Nancy M.; Ziko, Laila; Siam, Rania; Mamdouh, Wael

    2016-08-01

    The current study aimed at preparing AgNPs and three different core-shell silver/polymeric NPs composed of Ag core and three different polymeric shells: polyvinyl alcohol (PVA), polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP). Thereafter, the core/shell NPs were loaded with a chemotherapeutic agent doxorubicin (DOX). Finally, the cytotoxic effects of the different core-shell Ag/polymeric NPs-based combinatorial therapeutics were tested in-vitro against breast cancer (MCF-7) and human fibroblast (1BR hTERT) cell lines. AgNPs, Ag/PVA and Ag/PVP NPs were more cytotoxic to MCF-7 cells than normal fibroblasts, as well as DOX-Ag, DOX-Ag/PVA, DOX-Ag/PEG and DOX-Ag/PVP nanocarriers (NCs). Notably, low dosage of core-shell DOX-loaded Ag/polymeric nanocarriers (NCs) exhibited a synergic anticancer activity, with DOX-Ag/PVP being the most cytotoxic. We believe that the prepared NPs-based combinatorial therapy showed a significant enhanced cytotoxic effect against breast cancer cells. Future studies on NPs-based combinatorial therapy may aid in formulating a novel and more effective cancer therapeutics.

  1. Core-Shell Silver/Polymeric Nanoparticles-Based Combinatorial Therapy against Breast Cancer In-vitro

    PubMed Central

    Elbaz, Nancy M.; Ziko, Laila; Siam, Rania; Mamdouh, Wael

    2016-01-01

    The current study aimed at preparing AgNPs and three different core-shell silver/polymeric NPs composed of Ag core and three different polymeric shells: polyvinyl alcohol (PVA), polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP). Thereafter, the core/shell NPs were loaded with a chemotherapeutic agent doxorubicin (DOX). Finally, the cytotoxic effects of the different core-shell Ag/polymeric NPs-based combinatorial therapeutics were tested in-vitro against breast cancer (MCF-7) and human fibroblast (1BR hTERT) cell lines. AgNPs, Ag/PVA and Ag/PVP NPs were more cytotoxic to MCF-7 cells than normal fibroblasts, as well as DOX-Ag, DOX-Ag/PVA, DOX-Ag/PEG and DOX-Ag/PVP nanocarriers (NCs). Notably, low dosage of core-shell DOX-loaded Ag/polymeric nanocarriers (NCs) exhibited a synergic anticancer activity, with DOX-Ag/PVP being the most cytotoxic. We believe that the prepared NPs-based combinatorial therapy showed a significant enhanced cytotoxic effect against breast cancer cells. Future studies on NPs-based combinatorial therapy may aid in formulating a novel and more effective cancer therapeutics. PMID:27491622

  2. Role of the aclacinomycin A--doxorubicin association in reversal of doxorubicin resistance in K562 tumour cells.

    PubMed Central

    Millot, J. M.; Rasoanaivo, T. D.; Morjani, H.; Manfait, M.

    1989-01-01

    Acquired resistance to anthracyclines is characterised by a lower sensitivity to these agents, associated with impaired accumulation of drug. We have examined the ability of aclacinomycin A (ACM) associated with doxorubicin (DOX), to increase intranuclear DOX concentrations and, consequently, to enhance cytotoxic effects against drug resistant cells in vitro. A recently developed microspectrofluorometric technique is used to measure intranuclear DOX concentrations in sensitive and DOX-resistant K562 cells treated with DOX and ACM. Fluorescence emission spectra are collected from a microvolume of single living cell nuclei. From both DOX and ACM model fluorescence spectra (free, DNA-bound and metabolites), the intranuclear spectral profile is analysed according to the amount of each component. This quantitative analysis determines intranuclear DOX concentrations with an error of 10%. Non-cytotoxic doses of ACM, in combination with DOX, increase cytotoxic activity of DOX against K562 resistant cells. When DOX-resistant cells are exposed simultaneously to ACM and DOX, significant increases in intranuclear DOX concentrations are found compared with the case of exposure to DOX alone. The measure of the intranuclear retention of DOX shows that ACM partly blocks the DOX efflux in resistant cell nuclei, resulting in enhanced accumulation of DOX. These data lead us to conclude that ACM-DOX association partly reverses the DOX resistance at clinically achievable concentrations. PMID:2803945

  3. miR-145 sensitizes breast cancer to doxorubicin by targeting multidrug resistance-associated protein-1

    PubMed Central

    Gao, Man; Miao, Lingling; Liu, Mingxia; Li, Chenggang; Yu, Cunzhi; Yan, Hong; Yin, Yongxiang; Wang, Yizheng; Qi, Xinming; Ren, Jin

    2016-01-01

    Multidrug resistance-associated protein 1 (MRP1) is an important efflux transporter and overexpression of MRP1 usually leads to chemoresistance in breast cancer. Here, we found MRP1 overexpressed in human breast cancer tissues and breast cancer cell lines (compared with normal breast tissues and cell line, respectively). And MRP1 level increased in doxorubicin resistant MCF-7 cells compared with parental MCF-7 cells. Increasing evidences suggest microRNAs (miRNAs) influence chemotherapy response. We found miR-145 level decreased in human breast cancer tissues, breast cancer cell lines and doxorubicin resistant MCF-7 cells, and inversely correlated with MRP1 expression level. In the process of constructing MCF-7 doxorubicin resistant cell line, escalating doxorubicin markedly decreased miR-145 level, following by increased MRP1 level. Further study showed, miR-145 suppressed MRP1 expression by directly targeting MRP1 3′-untranslated regions. Overexpression of miR-145 sensitized breast cancer cells to doxorubicin in vitro and enhanced to doxorubicin chemotherapy in vivo through inducing intracellular doxorubicin accumulation via inhibiting MRP1. Taken together, our study revealed miR-145 sensitizes breast cancer to doxorubicin by targeting MRP1 and indicated the potential application in developing MRP1 inhibitor. PMID:27487127

  4. Pulsed Electromagnetic Field Stimulation Promotes Anti-cell Proliferative Activity in Doxorubicin-treated Mouse Osteosarcoma Cells

    PubMed Central

    MURAMATSU, YOSHITAKA; MATSUI, TAKUYA; DEIE, MASATAKA; SATO, KEIJI

    2017-01-01

    Aim: We aimed to investigate the synergistic effects of pulsed electromagnetic field (PEMF) and doxorubicin therapy in a mouse osteosarcoma cell line (LM8 cells) in vitro. Materials and Methods: The effects of PEMF (5 mT, 200 Hz) of different durations and doxorubicin on the proliferative activity of LM8 cells were measured by the MTT assay. Apoptotic-related factors such as cell-cycle phase, mitochondrial membrane potential, and caspase 3/7 activity were investigated using 4’,6-diamidino-2-phenylindole staining and apoptosis kits. Identification of intracellular signaling molecules induced by the combination was comprehensively explored using a stress and apoptosis-related protein array kit. Results: PEMF enhanced the inhibition of cell proliferation mediated by doxorubicin but did not affect the cell cycle, mitochondrial membrane potential, or doxorubicin-induced G2/M arrest. The combination of PEMF and doxorubicin altered a few signaling molecules. PEMF tended to reduce the doxorubicin-induced decrease of phosphorylated BAD, while reducing the increased expression of total IĸB and phosphorylated-CHK1 induced by doxorubicin. Conclusion: Our results indicate that combination of PEMF and doxorubicin could be a novel chemotherapeutic strategy. PMID:28064222

  5. An Efficient Templating Approach for the Synthesis of Redispersible Size-Controllable Carbon Quantum Dots from Graphitic Polymeric Micelles.

    PubMed

    Zhang, Jianming; Abbasi, Farshad; Claverie, Jerome

    2015-10-19

    Access to high-quality, easily dispersible carbon quantum dots (CQDs) is essential in order to fully exploit their desirable properties. Copolymers based on N-acryloyl-D-glucosamine and acrylic acid prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization are self-assembled into micelle-like nanoreactors. After a facile graphitization process (170 °C, atmospheric pressure), each micellar template is transformed into a CQD through a 1:1 copy process. These high-quality CQDs (quantum yield=22 %) with tunable sizes (2-5 nm) are decorated by carboxylic acid moieties and can be spontaneously redispersed in water and polar organic solvents. This preparation method renders the mass production of multifunctional CQDs possible. To demonstrate the versatility of this approach, CQDs hybridized TiO2 nanoparticles with enhanced photocatalytic activity under visible-light have been prepared.

  6. Doxorubicin induced myocardial injury is exacerbated following ischaemic stress via opening of the mitochondrial permeability transition pore

    SciTech Connect

    Gharanei, M.; Hussain, A.; Janneh, O.; Maddock, H.L.

    2013-04-15

    Chemotherapeutic agents such as doxorubicin are known to cause or exacerbate cardiovascular cell death when an underlying heart condition is present. However, the mechanism of doxorubicin-induced cardiotoxicity is unclear. Here we assess the cardiotoxic effects of doxorubicin in conditions of myocardial ischaemia reperfusion and the mechanistic basis of protection, in particular the role of the mitochondrial permeability transition pore (mPTP) in such protection. The effects of doxorubicin (1 μM) ± cyclosporine A (CsA, 0.2 μM; inhibits mPTP) were investigated in isolated male Sprague–Dawley rats using Langendorff heart and papillary muscle contraction models subjected to simulated ischaemia and reperfusion injury. Isolated rat cardiac myocytes were used in an oxidative stress model to study the effects of drug treatment on mPTP by confocal microscopy. Western blot analysis evaluated the effects of drug treatment on p-Akt and p-Erk 1/2 levels. Langendorff and the isometric contraction models showed a detrimental effect of doxorubicin throughout reperfusion/reoxygenation as well as increased p-Akt and p-Erk levels. Interestingly, CsA not only reversed the detrimental effects of doxorubicin, but also reduced p-Akt and p-Erk levels. In the sustained oxidative stress assay to study mPTP opening, doxorubicin decreased the time taken to depolarization and hypercontracture, but these effects were delayed in the presence of CsA. Collectively, our data suggest for the first that doxorubicin exacerbates myocardial injury in an ischaemia reperfusion model. If the inhibition of mPTP ameliorates the cardiotoxic effects of doxorubicin, then more selective inhibitors of mPTP should be further investigated for their utility in patients receiving doxorubicin. - Highlights: ► Doxorubicin exacerbates myocardial ischaemia reperfusion injury. ► Co-treatment with CsA protects against doxorubicin induced myocardial injury. ► CsA delays doxorubicin induced mPTP opening in laser

  7. Effect of the salt-induced micellar microstructure on the nonlinear shear flow behavior of ionic cetylpyridinium chloride surfactant solutions

    NASA Astrophysics Data System (ADS)

    Gaudino, D.; Pasquino, R.; Kriegs, H.; Szekely, N.; Pyckhout-Hintzen, W.; Lettinga, M. P.; Grizzuti, N.

    2017-03-01

    The shear flow dynamics of linear and branched wormlike micellar systems based on cetylpyridinium chloride and sodium salicylate in brine solution is investigated through rheometric and scattering techniques. In particular, the flow and the structural flow response are explored via velocimetry measurements and rheological and rheometric small-angle neutron scattering (SANS) experiments, respectively. Although all micellar solutions display a similar shear thinning behavior in the nonlinear regime, the experimental results show that shear banding sets in only when the micelle contour length L ¯ is sufficiently long, independent of the nature of the micellar connections (either linear or branched micelles). Using rheometric SANS, we observe that the shear banding systems both show very similar orientational ordering as a function of Weissenberg number, while the short branched micelles manifest an unexpected increase of ordering at very low Weissenberg numbers. This suggests the presence of an additional flow-induced relaxation process that is peculiar for branched systems.

  8. Separation of cationic analytes by nonionic micellar electrokinetic chromatography using polyoxyethylene lauryl ether surfactants with different polyoxyethylene length.

    PubMed

    Quirino, Joselito P; Kato, Masaru

    2014-09-01

    Although nonionic micellar electrokinetic chromatography is used for the separation of charged compounds that are not easily separated by capillary zone electrophoresis, the effect of the hydrophilic moiety of the nonionic surfactant has not been studied well. In this study, the separation of ultraviolet-absorbing amino acids was studied in electrokinetic chromatography using neutral polyoxyethylene lauryl ether surfactants (Adekatol) in the separation solution. The effect of the polyethylene moiety (the number of repeating units was from 6.5 to 50) of the hydrophobic test amino acids (methionine, tryptophan, and tysorine) was studied using a 10 cm effective length capillary. The separation mechanism was based on hydrophobic as well as hydrogen bonding interactions at the micellar surface, which was made of the polyoxyethylene moiety. The length of the polyoxyethylene moiety of the surfactants was not important in nonionic micellar electrokinetic chromatography mode.

  9. Atrophic nerve fibers in regions of reduced MIBG uptake in doxorubicin cardiomyopathy

    SciTech Connect

    Takano, Hajime; Ozawa Hideyuki; Kobayashi, Isao

    1995-11-01

    A myocardial MIBG-SPECT examination was conducted 2 wk after doxorubicin chemotherapy on a 52-yr-old woman without cardiac symptoms. Despite normal {sup 201}Tl scintigraphy, reduced MIBG uptake was detected in the apical anterior, inferior and lateral segments of the left ventricle. The patient died of congestive heart failure due to doxorubicin-induced cardiomyopathy 10 mo later. At necropsy, the left ventricle was markedly dilated and the apical anterior, inferior and lateral walls were thin, stiff and whitish. Nerve fibers in the apical inferior wall were atrophic and markedly fibrotic where MIBG uptake was most reduced. Nerve fibers in the septum were normal where MIBG uptake had remained normal. The histologic findings correspond with the findings on the MIBG image. MIBG imaging may detect cardiac sympathetic denervation in doxorubicin-induced cardiomyopathy before cardiac symptoms are manifest and cardiac function deteriorates. 5 refs., 2 figs.

  10. Sensitization of K562 Leukemia Cells to Doxorubicin by the Viscum album Extract.

    PubMed

    Srdic-Rajic, Tatjana; Tisma-Miletic, Nevena; Cavic, Milena; Kanjer, Ksenija; Savikin, Katarina; Galun, Danijel; Konic-Ristic, Aleksandra; Zoranovic, Tamara

    2016-03-01

    Toxicity of conventional chemotherapeutics highlights the requirement for complementary or alternative medicines that would reduce side effects and improve their anticancer effectiveness. European mistletoe (Viscum album) has long been used as a complementary and alternative medicine supporting cancer therapy. The aim of this study was to investigate synergistic antitumor action of V. album extract and doxorubicin during co-treatment of chemoresistant chronic myelogenic leukemia K562 cells. Combined treatment of leukemia cells led to inhibitory synergism at sub-apoptotic doxorubicin concentrations and multifold reduction of cytotoxic effects in healthy control cells. Prolonged co-treatment was associated with reduced G2/M accumulation and increased expression of early and late apoptotic markers. Our data indicate that V. album extract increases antileukemic effectiveness of doxorubicin against resistant K562 cells by preventing G2/M arrest and inducing apoptosis.

  11. Magnetic controllable biorecognition process of doxorubicin detected by electrochemical contact angle measurement.

    PubMed

    Zhou, Jian; Zhang, Renyun; Li, Xiaomao; Gutmann, Sebastian; Lv, Gang; Wang, Xuemei

    2007-08-01

    Fe3O4 nanoparticles are the most commonly used magnetic materials with promising applications in biomedical and biochemical engineering. In this study, a novel application of the tetraheptylammonium capped Fe3O4 nanoparticles in controllable biorecognition process of anticancer drug doxorubicin through combination with external static magnetic field has been demonstrated. Our AFM and electrochemical studies illustrate that the presence of the tetraheptylammonium capped Fe3O4 nanoparticles could promote the binding behavior of doxorubicin to DNA. And the results of the electrochemical contact angle measurements indicate that the controllable biomolecular recognition of doxorubicin could be readily achieved by combining these functionalized Fe3O4 nanoparticles with changing the positions of external magnetic field.

  12. Solute-solvent interactions in micellar electrokinetic chromatography. Characterization of sodium dodecyl sulfate-Brij 35 micellar systems for quantitative structure-activity relationship modelling.

    PubMed

    Rosés, M; Ràfols, C; Bosch, E; Martínez, A M; Abraham, M H

    1999-06-11

    The solvation parameter model has been applied to the characterization of micellar electrokinetic chromatographic (MEKC) systems with mixtures of sodium dodecyl sulfate and Brij 35 as surfactant. The variation in MEKC surfactant composition results in changes in the coefficients of the correlation equation, which in turns leads to information on solute-solvent and solute-micelle interactions. Since the same solvation model can be used to describe many biological processes, particular MEKC surfactant compositions can be selected that model the solute-solvent interactions of some of these processes. Two different MEKC systems have been selected to model the solute-solvent interactions of two processes of biological interest (octanol-water partition and tadpole narcosis).

  13. Cryoprotection–lyophilization and physical stabilization of rifampicin-loaded flower-like polymeric micelles

    PubMed Central

    Moretton, Marcela A.; Chiappetta, Diego A.; Sosnik, Alejandro

    2012-01-01

    Rifampicin-loaded poly(ε-caprolactone)–b-poly(ethylene glycol)–poly(ε-caprolactone) flower-like polymeric micelles display low aqueous physical stability over time and undergo substantial secondary aggregation. To improve their physical stability, the lyoprotection–lyophilization process was thoroughly characterized. The preliminary cryoprotectant performance of mono- and disaccharides (e.g. maltose, glucose), hydroxypropyl-β-cyclodextrin (HPβCD) and poly(ethylene glycol) (PEG) of different molecular weights was assessed in freeze–thawing assays at −20°C, −80°C and −196°C. The size and size distribution of the micelles at the different stages were measured by dynamic light scattering (DLS). A cryoprotectant factor (fc) was determined by taking the ratio between the size immediately after the addition of the cryoprotectant and the size after the preliminary freeze–thawing assay. The benefit of a synergistic cryoprotection by means of saccharide/PEG mixtures was also assessed. Glucose (1 : 20), maltose (1 : 20), HPβCD (1 : 5) and glucose or maltose mixtures with PEG3350 (1 : 20) (copolymer:cryoprotectant weight ratio) were the most effective systems to protect 1 per cent micellar systems. Conversely, only HPβCD (1 : 5) cryoprotected more concentrated drug-loaded micelles (4% and 6%). Then, those micelle/cryoprotectant systems that displayed fc values smaller than 2 were freeze-dried. The morphology of freeze-dried powders was characterized by scanning electron microscopy and atomic force microscopy and the residual water content analysed by the Karl Fisher method. The HPβCD-added lyophilisates were brittle porous cakes (residual water was between 0.8% and 3%), easily redispersable in water to form transparent systems with a minimal increase in the micellar size, as determined by DLS. PMID:21865255

  14. Sulforaphane protects the heart from doxorubicin-induced toxicity

    PubMed Central

    Singh, Preeti; Sharma, Rajendra; McElhanon, Kevin; Allen, Charles D.; Megyesi, Judit K.; Beneš, Helen; Singh, Sharda P.

    2015-01-01

    Cardiotoxicity is one of the major side effects encountered during cancer chemotherapy with doxorubicin (DOX) and other anthracyclines. Previous studies have shown that oxidative stress caused by DOX is one of the primary mechanisms for its toxic effects on the heart. Since the redox-sensitive transcription factor, Nrf2, plays a major role in protecting cells from the toxic metabolites generated during oxidative stress, we examined the effects of the phytochemical sulforaphane (SFN), a potent Nrf2-activating agent, on DOX-induced cardiotoxicity. These studies were carried out both in vitro and in vivo using rat H9c2 cardiomyoblast cells and wild type 129/sv mice, and involved SFN pretreatment followed by SFN administration during DOX exposure. SFN treatment protected H9c2 cells from DOX cytotoxicity and also resulted in restored cardiac function and a significant reduction in DOX-induced cardiomyopathy and mortality in mice. Specificity of SFN induction of Nrf2 and protection of H9c2 cells was demonstrated in Nrf2 knockdown experiments. Cardiac accumulation of 4-hydroxynonenal (4-HNE) protein adducts, due to lipid peroxidation following DOX-induced oxidative stress, was significantly attenuated by SFN treatment. The respiratory function of cardiac mitochondria isolated from mice exposed to DOX alone was repressed, while SFN treatment with DOX significantly elevated mitochondrial respiratory complex activities. Co-administration of SFN reversed the DOX-associated reduction in nuclear Nrf2 binding activity and restored cardiac expression of Nrf2-regulated genes, at both the RNA and protein levels. Together, our results demonstrate for the first time that the Nrf2 inducer, SFN, has the potential to provide protection against DOX-mediated cardiotoxicity. PMID:26025579

  15. Protective effects of Terminalia arjuna against Doxorubicin-induced cardiotoxicity.

    PubMed

    Singh, Gurvinder; Singh, Anu T; Abraham, Aji; Bhat, Beena; Mukherjee, Ashok; Verma, Ritu; Agarwal, Shiv K; Jha, Shivesh; Mukherjee, Rama; Burman, Anand C

    2008-04-17

    Terminalia arjuna has been marked as a potential cardioprotective agent since vedic period. The present study was aimed to investigate the effects of butanolic fraction of Terminalia arjuna bark (TA-05) on Doxorubicin (Dox)-induced cardiotoxicity. Male wistar rats were used as in vivo model for the study. TA-05 was administered orally to Wistar rats at different doses (0.42 mg/kg, 0.85 mg/kg, 1.7 mg/kg, 3.4 mg/kg and 6.8 mg/kg) for 6 days/week for 4 weeks. Thereafter, all the animals except saline and TA-05-treated controls were administered 20 mg/kg Dox intraperitonially. There was a significant decrease in myocardial superoxide dismutase (38.94%) and reduced glutathione (23.84%) in animals treated with Dox. Concurrently marked increase in serum creatine kinase-MB (CKMB) activity (48.11%) as well as increase in extent of lipid peroxidation (2.55-fold) was reported. Co-treatment of TA-05 and Dox resulted in an increase in the cardiac antioxidant enzymes, decrease in serum CKMB levels and reduction in lipid peroxidation as compared to Dox-treated animals. Electron microscopic studies in Dox-treated animals revealed mitochondrial swelling, Z-band disarray, focal dilatation of smooth endoplasmic reticulum (SER) and lipid inclusions, whereas the concurrent administration of TA-05 led to a lesser degree of Dox-induced histological alterations. These findings suggest that butanolic fraction of Terminalia arjuna bark has protective effects against Dox-induced cardiotoxicity and may have potential as a cardioprotective agent.

  16. Doxorubicin decreases paraquat accumulation and toxicity in Caco-2 cells.

    PubMed

    Silva, Renata; Carmo, Helena; Vilas-Boas, Vânia; de Pinho, Paula Guedes; Dinis-Oliveira, Ricardo Jorge; Carvalho, Félix; Silva, Isabel; Correia-de-Sá, Paulo; Bastos, Maria de Lourdes; Remião, Fernando

    2013-02-13

    P-glycoprotein (P-gp) is an efflux pump belonging to the ATP-binding cassette transporter superfamily expressed in several organs. Considering its potential protective effects, the induction of de novo synthesis of P-gp could be used therapeutically in the treatment of intoxications by its substrates. The herbicide paraquat (PQ) is a P-gp substrate responsible for thousands of fatal intoxications worldwide that still lacks an effective antidote. The aim of the present work was to evaluate the effectiveness of such an antidote by testing whether doxorubicin (DOX), a known P-gp inducer, could efficiently protect Caco-2 cells against PQ cytotoxicity, 6 h after the incubation with the herbicide, reflecting a real-life intoxication scenario. Cytotoxicity was evaluated by the MTT assay and PQ intracellular concentrations were measured by gas chromatography-ion trap-mass spectrometry (GC-IT-MS). Also, the DOX modulatory effect on choline uptake transport system was assessed by measuring the uptake of [³H]-choline. The results show that DOX exerts protective effects against PQ cytotoxicity, preventing the intracellular accumulation of the herbicide. These protective effects were not completely prevented by the incubation with the UIC2 antibody, a specific P-gp inhibitor, suggesting the involvement of alternative protection mechanisms. In fact, DOX also efficiently inhibited the choline transport system that influences PQ cellular uptake. In conclusion, in this cellular model, DOX effectively protects against PQ toxicity by inducing P-gp and through the interaction with the choline transporter, suggesting that compounds presenting this double feature of promoting the efflux and limiting the uptake of PQ could be used as effective antidotes to treat intoxications.

  17. Stimuli-responsive PEGylated prodrugs for targeted doxorubicin delivery.

    PubMed

    Xu, Minghui; Qian, Junmin; Liu, Xuefeng; Liu, Ting; Wang, Hongjie

    2015-05-01

    In recent years, stimuli-sensitive prodrugs have been extensively studied for the rapid "burst" release of antitumor drugs to enhance chemotherapeutic efficiency. In this study, a novel stimuli-sensitive prodrug containing galactosamine as a targeting moiety, poly(ethylene glycol)-doxorubicin (PEG-DOX) conjugate, was developed for targeting HepG2 human liver cancer cells. To obtain the PEG-DOX conjugate, both galactosamine-decorated poly(ethylene glycol) aldehyde (Gal-PEG-CHO) and methoxy poly(ethylene glycol) aldehyde (mPEG-CHO) were firstly synthesized and functionalized with dithiodipropionate dihydrazide (TPH) through direct reductive amination via Schiff's base formation, and then DOX molecules were chemically conjugated to the hydrazide end groups of TPH-functionalized Gal-/m-PEG chains via pH-sensitive hydrazone linkages. The chemical structures of TPH-functionalized PEG and PEG-DOX prodrug were confirmed by (1)H NMR analysis. The PEG-DOX conjugate could self-assemble into spherical nanomicelles with a mean diameter of 140 nm, as indicated by transmission electron microscopy and dynamic light scattering. The drug loading content and loading efficiency in the prodrug nanomicelles were as high as 20 wt.% and 75 wt.%, respectively. In vitro drug release studies showed that DOX was released rapidly from the prodrug nanomicelles at the intracellular levels of pH and reducing agent. Cellular uptake and MTT experiments demonstrated that the galactosamine-decorated prodrug nanomicelles were more efficiently internalized into HepG2 cells via a receptor-mediated endocytosis process and exhibited a higher toxicity, compared with pristine prodrug nanomicelles. These results suggest that the novel Gal-PEG-DOX prodrug nanomicelles have tremendous potential for targeted liver cancer therapy.

  18. On-demand photoinitiated polymerization

    SciTech Connect

    Boydston, Andrew J; Grubbs, Robert H; Daeffler, Chris; Momcilovic, Nebojsa

    2015-01-13

    Compositions and methods for adjustable lenses are provided. In some embodiments, the lenses contain a lens matrix material, a masking compound, and a prepolymer. The lens matrix material provides structure to the lens. The masking compound is capable of blocking polymerization or crosslinking of the prepolymer, until photoisomerization of the compound is triggered, and the compound is converted from a first isomer to a second isomer having a different absorption profile. The prepolymer is a composition that can undergo a polymerization or crosslinking reaction upon photoinitiation to alter one or more of the properties of the lenses.

  19. On-demand photoinitiated polymerization

    DOEpatents

    Boydston, Andrew J; Grubbs, Robert H; Daeffler, Chris; Momcilovic, Nebojsa

    2013-12-10

    Compositions and methods for adjustable lenses are provided. In some embodiments, the lenses contain a lens matrix material, a masking compound, and a prepolymer. The lens matrix material provides structure to the lens. The masking compound is capable of blocking polymerization or crosslinking of the prepolymer, until photoisomerization of the compound is triggered, and the compound is converted from a first isomer to a second isomer having a different absorption profile. The prepolymer is a composition that can undergo a polymerization or crosslinking reaction upon photoinitiation to alter one or more of the properties of the lenses.

  20. The effects of thymoquinone and Doxorubicin on leukemia and cardiomyocyte cell lines.

    PubMed

    Brown, R Keith; Wilson, Gerri; Tucci, Michelle A; Benghuzzi, Hamed A

    2014-01-01

    Acute Lymphoblastic Leukemia remains the most common cancer for children, and if left untreated is rapidly fatal. The gold standard for treatment of ALL in children is with a class of drugs known as the antracyclines. Long term outcomes following treatment of leukemia with antracylines can result in cardiac abnormalities including arrhythmias, congestive heart failure, myocardial infarction, hypertension and left ventricular failure. Thymoquinone is a natural product that has demonstrated anti-proliferative, anti-inflammatory, anti-cancer, and chemo-protective effects in control trials as well as a reduction in cardiotoxicity in antracyline treated rats. The aims of the study were to determine if thymoqunione could be used to reduce leukemia cell viability without injuring primary cardiomyocyte, and to determine its effects if used in conjunction with a known chemotherapeutic agent. Cellular viability and morphological changes were observed in the, RAW leukemia cells and cardiac myocytes following treatment with thymoquinone, antracyline (doxorubicin), alone and in combination for 24, 48 and 72 hours. The results suggest that thymoquinone treatment in RAW leukemia cells reduced the cell number without altering the morphology, while doxorubicin reduced cell number and induced spindle cell formation and increased cellular damage. Findings also suggest RAW cell apoptosis increased in combination therapy with thymoquinone and doxorubicin. Thymoquinone administered to cardiomyocytes showed similar morphological changes as control over time in culture; whereas doxorubicin treated cells showed evidence of loss of connectivity and disruption of cell membranes. Combination treatment with doxorubicin and thymoquinone demonstrated significant cardiac myocyte survival at concentrations when used alone were able to reduce the leukemia cells. Overall, the data is promising and may provide a treatment regime to protect the heart tissue. Additional work is warrant to understand

  1. Doxorubicin inhibits E. coli division by interacting at a novel site in FtsZ.

    PubMed

    Panda, Pragnya; Taviti, Ashoka Chary; Satpati, Suresh; Kar, Mitali Madhusmita; Dixit, Anshuman; Beuria, Tushar Kant

    2015-11-01

    The increase in antibiotic resistance has become a major health concern in recent times. It is therefore essential to identify novel antibacterial targets as well as discover and develop new antibacterial agents. FtsZ, a highly conserved bacterial protein, is responsible for the initiation of cell division in bacteria. The functions of FtsZ inside cells are tightly regulated and any perturbation in its functions leads to inhibition of bacterial division. Recent reports indicate that small molecules targeting the functions of FtsZ may be used as leads to develop new antibacterial agents. To identify small molecules targeting FtsZ and inhibiting bacterial division, we screened a U.S. FDA (Food and Drug Administration)-approved drug library of 800 molecules using an independent computational, biochemical and microbial approach. From this screen, we identified doxorubicin, an anthracycline molecule that inhibits Escherichia coli division and forms filamentous cells. A fluorescence-binding assay shows that doxorubicin interacts strongly with FtsZ. A detailed biochemical analysis demonstrated that doxorubicin inhibits FtsZ assembly and its GTPase activity through binding to a site other than the GTP-binding site. Furthermore, using molecular docking, we identified a probable doxorubicin-binding site in FtsZ. A number of single amino acid mutations at the identified binding site in FtsZ resulted in a severalfold decrease in the affinity of FtsZ for doxorubicin, indicating the importance of this site for doxorubicin interaction. The present study suggests the presence of a novel binding site in FtsZ that interacts with the small molecules and can be targeted for the screening and development of new antibacterial agents.

  2. Targeted delivery of doxorubicin to breast cancer cells by aptamer functionalized DOTAP/DOPE liposomes.

    PubMed

    Song, Xingli; Ren, Yi; Zhang, Jing; Wang, Gang; Han, Xuedong; Zheng, Wei; Zhen, Linlin

    2015-10-01

    Doxorubicin is used to treat numerous types of tumors including breast cancer, yet dose-associated toxicities limit its clinical application. Here, we demonstrated a novel strategy by which to deliver doxorubicin to breast cancer cells by conjugating cancer cell-specific single-strand DNA aptamers with doxorubicin-encapsulated DOTAP:DOPE nanoparticles (NPs). We utilizing a whole-cell-SELEX strategy, and 4T1 cells with high invasive and metastatic potential were used as target cells, while non-invasive and non-metastatic 67NR cells were used as subtractive cells. Ten potential aptamers were generated after multi-pool selection. Studies on the selected aptamers revealed that SRZ1 had the highest and specific binding affinity to 4T1 cells. Then we developed SRZ1 aptamer-carried DOTAP:DOPE-DOX NPs. In vitro uptake results which were conducted by FACS indicated that the aptamer significantly promoted the uptake efficiency of DOTAP:DOPE-DOX NPs by 4T1 cells. ATPlite assay was performed to test 4T1, 67NR and NMuMG cell viability after treatment with free doxorubicin, DOTAP:DOPE-DOX particles and aptamer‑loaded DOTAP:DOPE-DOX particles. As expected, the aptamers effectively enhanced accumulation of doxorubicin in the 4T1 tumor tissues as determined by in vivo mouse body images and biodistribution analysis. Consistent with the in vitro findings, aptamer-conjugated doxorubicin-loaded DOTAP:DOPE particles markedly suppressed tumor growth and significantly increased the survival rate of 4T1 tumor-bearing mice. These studies demonstrated that aptamer SRZ1 could be a promising molecule for chemotherapeutic drug targeting deliver.

  3. Optical properties and inclusion of an organic fluorophore in organized media of micellar solutions and beta-cyclodextrin

    NASA Astrophysics Data System (ADS)

    El-Sayed, Yusif S.

    2013-02-01

    In this study, we prepared a new chalcone compound (3-(4'-diethylaminophenyl)-1-(2-pyridinyl) prop-2-en-1-one abbreviated as DEAPPP) and examined its characterization and photophysical properties such as singlet absorption, molar absorptivity, fluorescence spectra, and fluorescence quantum yield (ϕf). DEAPPP dye exhibited a large red shift in both absorption and emission spectra as solvent polarity increases, indicating a large change in dipole moment of molecule upon excitation. Also, the fluorescence quantum yield was solvent dependent. The absorption and fluorescence emission spectral properties of DEAPPP have been investigated in organized media of aqueous micellar and β-cyclodextrin (CD) solutions. While the absorption spectra were less sensitive to the nature of the added surfactant or CD, the characteristics of the intramolecular charge transfer (ICT) fluorescence were highly sensitive to the properties of the medium. The ICT maximum was strongly blue-shifted with a great enhancement in the fluorescence quantum yield on adding micellar or CD. This indicated that the solubilization of DEAPPP increased in the micellar core and an inclusion complex with β-CD was formed. The critical micelle concentration (CMC) as well as the polarity of the micellar core of sodium dodecyl sulfate (SDS), Cetyltrimethylammonium bromide (CTAB) and Triton X-100 (TX-100) have been determined. The CMC values were in good agreement with the reported values while the polarity was lower indicating that DEAPPP molecules were incorporated in the micellar core not at the micellar interface. The binding constants of DEAPPP: micelles or DEAPPP: CD complexes have been also determined.

  4. Complete Regression of Xenograft Tumors upon Targeted Delivery of Paclitaxel via Π-Π Stacking Stabilized Polymeric Micelles

    PubMed Central

    Shi, Yang; van der Meel, Roy; Theek, Benjamin; Blenke, Erik Oude; Pieters, Ebel H.E.; Fens, Marcel H.A.M.; Ehling, Josef; Schiffelers, Raymond M.; Storm, Gert; van Nostrum, Cornelus F.; Lammers, Twan; Hennink, Wim E.

    2015-01-01

    Treatment of cancer patients with taxane-based chemotherapeutics, such as paclitaxel (PTX), is complicated by their narrow therapeutic index. Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of PTX, as they can be tailored to encapsulate large amounts of hydrophobic drugs and achieve prolonged circulation kinetics. As a result, PTX deposition in tumors is increased while drug exposure to healthy tissues is reduced. However, many PTX-loaded micelle formulations suffer from low stability and fast drug release in the circulation, limiting their suitability for systemic drug targeting. To overcome these limitations, we have developed paclitaxel (PTX)-loaded micelles which are stable without chemical crosslinking and covalent drug attachment. These micelles are characterized by excellent loading capacity and strong drug retention, attributed to π-π stacking interaction between PTX and the aromatic groups of the polymer chains in the micellar core. The micelles are based on methoxy poly(ethylene glycol)-b-(N-(2-benzoyloxypropyl) methacrylamide) (mPEG-b-p(HPMAm-Bz)) block copolymers, which improved the pharmacokinetics and the biodistribution of PTX, and substantially increased PTX tumor accumulation (by more than 2000%; as compared to Taxol® or control micellar formulations). Improved biodistribution and tumor accumulation were confirmed by hybrid μCT-FMT imaging using near-infrared labeled micelles and payload. The PTX-loaded micelles were well tolerated at different doses while they induced complete tumor regression in two different xenograft models (i.e. A431 and MDA-MB-468). Our findings consequently indicate that π-π stacking-stabilized polymeric micelles are promising carriers to improve the delivery of highly hydrophobic drugs to tumors and to increase their therapeutic index. PMID:25831471

  5. Oxidative Stress Promotes Doxorubicin-Induced Pgp and BCRP Expression in Colon Cancer Cells Under Hypoxic Conditions.

    PubMed

    Pinzón-Daza, Martha L; Cuellar-Saenz, Yenith; Nualart, Francisco; Ondo-Mendez, Alejandro; Del Riesgo, Lilia; Castillo-Rivera, Fabio; Garzón, Ruth

    2017-01-20

    P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are ATP binding cassette (ABC) transporters that are overexpressed in different drug-resistant cancer cell lines. In this study, we investigated whether doxorubicin promotes Pgp and/or BCRP expression to induce drug resistance in colon cancer cells under hypoxic conditions. We analyzed HIF-1α activity via ELISA, Pgp, and BCRP expression by qRT-PCR and the relationship between doxorubicin uptake and ABC transporter expression via confocal microscopy in HT-29WT and HT-29 doxorubicin-resistant colon cancer cells (HT-29DxR). These cells were treated with doxorubicin and/or CoCl2 (chemical hypoxia), and reactive oxygen species inductors. We found that the combination of chemically induced hypoxia and doxorubicin promoted Pgp mRNA expression within 24 h in HT-29WT and HT-29DxR cells. Both doxorubicin and CoCl2 alone or in combination induced Pgp and BCRP expression, as demonstrated via confocal microscopy in each of the above two cell lines. Thus, we surmised that Pgp and BCRP expression may result from synergistic effects exerted by the combination of doxorubicin-induced ROS production and HIF-1α activity under hypoxic conditions. However, HIF-1α activity disruption via the administration of E3330, an APE-1 inhibitor, downregulated Pgp expression and increased doxorubicin delivery to HT-29 cells, where it served as a substrate for Pgp, indicating the existence of an indirect relationship between Pgp expression and doxorubicin accumulation. Thus, we concluded that Pgp and BCRP expression can be regulated via cross-talk between doxorubicin and hypoxia, promoting drug resistance in HT-29 WT, and HT-29DxR cells and that this process may be ROS dependent. J. Cell. Biochem. 9999: 1-11, 2017. © 2017 Wiley Periodicals, Inc.

  6. Carnitine partially protects the rat testis against the late damage produced by doxorubicin administered during pre-puberty.

    PubMed

    Cabral, R E L; Okada, F K; Stumpp, T; Vendramini, V; Miraglia, S M

    2014-11-01

    Doxorubicin, an anticancer drug, is widely included in chemotherapy protocols to combat childhood cancer. Carnitine, an important quaternary amine, is present in testis and epididymis and is involved in sperm maturation; it has been used in infertility treatment. In a previous study, our group observed that L-carnitine given before etoposide, another chemotherapeutic drug, reduces the spermatogenic damage and protects germ cells against apoptosis. This study aimed to evaluate the antiapoptotic and cytoprotective actions of L-carnitine in long- and mid-term basis, on the seminiferous epithelium of doxorubicin-treated pre-pubertal rats. Forty-eight 30-day-old male Wistar rats were distributed into four groups: sham-control; doxorubicin; carnitine; carnitine/doxorubicin (L-carnitine injected 1 h before doxorubicin). The rats were submitted to euthanasia at 64 and 100 days of age and their testes were collected for biometric, morphometric, and histopathological analyses. The numerical density of apoptotic germ cells was obtained (TUNEL method). In adult phase (100 days), the following spermatic parameters were analyzed: mature spermatid (19 step) count and sperm daily production per testis; sperm number and transit time through the epididymal caput/corpus and cauda; frequency of morphologically abnormal spermatozoa (from epididymal fluid), as well as sperm DNA integrity (Comet assay). The testicular and spermatic parameters at both ages were improved in rats treated with carnitine before doxorubicin. At 64 days, the TUNEL-positive germ cell frequency was lower in the carnitine/doxorubicin-treated rats comparatively to the doxorubicin-treated rats. At 100 days of age, the sperm DNA fragmentation was also lower in the previously carnitine-treated rats, as evidenced by the analysis of three parameters. Carnitine reduced the late testicular and spermatic damages caused by doxorubicin, probably providing a partial cytoprotection against the deleterious action of doxorubicin

  7. Phase II trial of 4'-epi-doxorubicin in locally advanced or metastatic gastric cancer.

    PubMed

    Cazap, E; Estevez, R; Bruno, M; Levy, D; Algamiz, C; Chacon, R; Badano, C; Romero, A; Desimone, G; Roca, E

    1988-06-30

    Patients with locally advanced or metastatic gastric adenocarcinoma received an i.v. bolus of 4'-epi-doxorubicin, 75/mg/m2/cycle, every 21 days. Partial responses were observed in 5 of 23 evaluable patients (21.7%). Treatment was generally well tolerated and toxicity was mild. The response rate to epirubicin appears to be very similar to that reported for doxorubicin. Larger doses of epirubicin could be safely used in future studies, and further evaluation of epirubicin in phase III trials is indicated.

  8. Hydrogen-containing saline attenuates doxorubicin-induced heart failure in rats.

    PubMed

    Wu, Shujing; Zhu, Liqun; Yang, Jing; Fan, Zhixin; Dong, Yanli; Luan, Rui; Cai, Jingjing; Fu, Lu

    2014-08-01

    Interactions between doxorubicin (DOX) and iron generate reactive oxygen species and contribute to DOX-induced heart failure. Hydrogen, as a selective antioxidant, is a promising potential therapeutic option for the treatment of a variety of diseases. Therefore, we investigated the preventive effects of hydrogen treatment on DOX-induced heart failure in rats. We found that cardiac function was significantly improved and that the plasma levels of oxidative-stress markers and myocardial autophagic activity were decreased in animals treated with hydrogen-containing saline. Therefore, we conclude that hydrogen-containing saline may have beneficial effects for doxorubicin-induced heart failure.

  9. A glucose-targeted mixed micellar formulation outperforms Genexol in breast cancer cells.

    PubMed

    Moretton, Marcela A; Bernabeu, Ezequiel; Grotz, Estefanía; Gonzalez, Lorena; Zubillaga, Marcela; Chiappetta, Diego A

    2017-05-01

    Breast cancer represents the top cancer among women, accounting 521.000 deaths per year. Development of targeted nanomedicines to breast cancer tissues represents a milestone to reduce chemotherapy side effects. Taking advantage of the over-expression of glucose (Glu) membrane transporters in breast cancer cells, we aim to expand the potential of a paclitaxel (PTX)-loaded mixed micellar formulation based on polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) by its surface decoration with Glu moieties. The glycopolymer (Soluplus(Glu)) was obtained by microwave-assisted ring opening reaction of δ-gluconolactone initiated by Soluplus®. The glycosylation was confirmed by (1)H NMR and by agglutination assays employing Concanavalin A. The hydrodynamic diameter of Soluplus(Glu) micelles was characterized by dynamic light scattering (100.3±3.8nm) as well as the critical micellar concentration value (0.0151% w/v). Then, a mixed micelle formulation employing Soluplus®, Soluplus(Glu) and TPGS (3:1:1wt ratio) loaded with PTX (4mg/mL) was developed as a multifunctional nanocarrier. Its in vitro anticancer performance in MCF-7 (1.6-fold) and MDA-MB-231 (14.1-fold) was significantly enhanced (p<0.05) versus the unique commercially available micellar-based PTX-nanoformulation (Genexol®). Furthermore, the in vitro PTX cellular uptake assays revealed that the drug intracellular/cell content was significantly (p<0.05) higher for the Glu-containing mixed micelles versus Genexol® after 6h of incubation with MCF-7 (30.5-fold) and MDA-MB-231 (5-fold). Overall, results confirmed the potential of our Glu-decorated mixed colloidal formulation as an intelligent nanocarrier for PTX-targeted breast cancer chemotherapy.

  10. DNA packaging induced by micellar aggregates: a novel in vitro DNA condensation system.

    PubMed

    Ghirlando, R; Wachtel, E J; Arad, T; Minsky, A

    1992-08-11

    Evidence for a conceptually novel DNA packaging process is presented. X-ray scattering, electron microscopy, and circular dichroism measurements indicate that in the presence of positively charged micellar aggregates and flexible anionic polymers, such as negatively charged polypeptides or single-stranded RNA species, a complex is formed in which DNA molecules are partially embedded within a micellar scaffold and partially condensed into highly packed chiral structures. Based on studies of micelle-DNA and micelle-flexible anionic polymer systems, as well as on the known effects of a high charge density upon the micellar organization, a DNA packaging model is proposed. According to this model, the DNA induces the elongation of the micelles into rodlike aggregates, forming a closely packed matrix in which the DNA molecules are immobilized. In contrast, the flexible anionic polymers stabilize clusters of spherical micelles which are proposed to effect a capping of the rodlike micelles, thus arresting their elongation and creating surfactant-free segments of the DNA that are able to converge and collapse. Thus, unlike other in vitro DNA packaging systems, in which condensation follows encounters between charge-neutralized DNA molecules, a prepackaging phase where the DNA is immobilized within a matrix is proposed in this case. Cellular and nuclear membranes have been implicated in DNA packaging processes in vivo, and negatively charged polyelectrolytes were shown to be involved in the processes. These observations, combined with the basic tenets of the DNA condensation system described here, allow for the progression to the study of more elaborate model systems and thus might lead to insights into the nature and roles of the intricate in vivo DNA-membrane complexes.

  11. Polyene photoisomerization rates: Are they distinct in aqueous block copolymer micellar solutions and gels?

    SciTech Connect

    Mali, K.S.; Dutt, G.B.; Mukherjee, T.

    2006-02-07

    Photoisomerization of 3,3{sup '}-diethyloxadicarbocyanine iodide (DODCI) has been investigated in water, 5% and 30% aqueous triblock copolymer, poly(ethylene oxide){sub 20}-poly(propylene oxide){sub 70}-poly(ethylene oxide){sub 20} (P123) by measuring the fluorescence quantum yields and lifetimes in the temperature range 293-318 K. Reports available in literature indicate that 5% aqueous P123 exists as micellar solution, whereas 30% aqueous P123 forms gel due to micelle-micelle entanglement. This study has been undertaken to find out how the polyene photoisomerization rates are influenced in the sol and gel phases. It has been observed that 60%-70% of DODCI is located in the palisade layer of the micelles in the sol as well as gel phases and the photoisomerization rate of this component is identical in both the phases at a particular temperature. The remainder of the probe is located in the interfacial region and isomerization rates of this fraction are slower by a factor of 1.4-1.1 in the gel phase compared with the micellar solution. The retardation of the isomerization rate in the gel phase has been explained on the basis of enhancement in the friction experienced by the probe due to micelle-micelle entanglement at the interface. Compared to the isomerization rates in water, the rates of photoisomerization of DODCI located in the palisade layer, interfacial region of micellar solution, and interfacial region of the micelles in the gel phase are slower by factors of 3.5, 1.5-1.9, and 2, respectively. The outcome of this study validates the point that in organized media photoisomerization rates are sensitive to the localized friction, which is not uniform unlike in a homogeneous solution.

  12. Analysis of catechins in Theobroma cacao beans by cyclodextrin-modified micellar electrokinetic chromatography.

    PubMed

    Gotti, Roberto; Furlanetto, Sandra; Pinzauti, Sergio; Cavrini, Vanni

    2006-04-21

    A micellar electrokinetic chromatography (MEKC) method was developed for the quantitation of polyphenols (+)-catechin and (-)-epicatechin (catechin monomers) and the methylxanthine theobromine in Theobroma cacao beans. Owing to the poor stability of catechin monomers in alkaline conditions, a 50 mM Britton-Robinson buffer at a pH 2.50 was preferred as the background electrolyte. Under these conditions, the addition of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) at a concentration of 12 mM to the SDS micellar solution (90 mM), resulted in a cyclodextrin-modified micellar electrokinetic chromatography (CD-MEKC) endowed with two peculiar advantages compare to the conventional MEKC: (i) strong improvement of separation of the most important phytomarkers of T. cacao and (ii) enantioselectivity toward (+/-)-catechin. In particular, separation of methylxanthines (theobromine and caffeine), procyanidin dimers B1 and B2, and catechins (epicatechin and catechin) was obtained simultaneously to the enantioseparation of racemic catechin within 10min. The enantioselectivity of the method makes it suitable in evaluation of possible epimerisation at the C-2 position of epicatechin monomer potentially occurring during heat processing and storage of T. cacao beans. The extraction procedure of the phytomarkers from the beans was approached using ultrasonic bath under mild conditions optimized by a multivariate strategy. The method was validated for robustness, selectivity, sensitivity, linearity, range, accuracy and precision and it was applied to T. ca