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Targeted liposomal drug formulations may enter cells by receptor-mediated endocytosis and then traffick by membrane flow into acidic intracellular compartments. In order to understand the impact of these intracellular pH changes on liposomal drug unloading, the effect of pH on the release from folate-targeted liposomes of three model compounds with distinct pH dependencies was examined. 5(6)-carboxyfluorescein, which titrates from its anionic to uncharged form following internalization by KB cells, displays strong endocytosis-dependent release, since only its uncharged (endosomal) form is membrane permeable. Endocytosis-triggered unloading of drugs of this sort is enhanced by encapsulating the drug in a weak buffer at neutral pH, so that acidification of the intraliposomal compartment following cellular uptake can occur rapidly. Sulforhodamine B, in contrast, retains both anionic and cationic charges at endosomal pH (~pH 5), and consequently, escapes the endosomes only very slowly. Doxorubicin, which is commonly loaded into liposomes in its membrane-impermeable (cationic) form using an acidic buffer, still displays endocytosis-triggered unloading, since sufficient uncharged doxorubicin remains at endosomal pHs to allow rapid re-equilibration of the drug according to the new proton gradient across the membrane. In this case, when the extraliposomal [H+] increases 250-fold from 4 × 10–8 M (pH 7.4, outside the cell) to 10–5 M (pH 5, inside the endosome), the ratio of doxorubicin inside to outside the liposome must decrease by a factor of 250. Therefore, the collapse of the transliposomal pH gradient indirectly drives an efflux of the drug molecule from the liposome. Since a change in intraliposomal pH is not required to unload drugs of this type, the intraliposomal compartment can be buffered strongly at acidic pH to prevent premature release of the drug outside the cell. In summary, pH triggered release of liposome-encapsulated drugs can be achieved both with drugs that increase as well as decrease their membrane permeabilities upon acidification, as long as the intraliposomal buffer strength and pH is rationally selected. 相似文献
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Armağan Koçer 《Journal of liposome research》2013,23(3-4):219-225
In order to reduce the toxicity and increase the efficacy of drugs, there is a need for smart drug delivery systems. Liposomes are one of the promising tools for this purpose. An ideal liposomal delivery system should be stable, long-circulating, accumulate at the target site and release its drug in a controlled manner. Even though there have been many developments to this end, the dilemma of having a stable liposome during circulation but converting it into a leaky structure at the target site is still a major challenge. So far, most attempts have focused on destabilizing the liposome in response to a specific stimulus at a target site, but with limited success. Our approach is to keep the stable liposome but build in a remote-controlled valve as a new release mechanism, instead. The valve is a pore-forming bacterial membrane protein. It has been engineered such that, after being reconstituted into the liposomes, its opening and closing can be controlled on command by the ambient pH, light or a combination of both. In addition, a much higher degree of flexibility for fine-tuning of the liposome's response to its environment is achieved. 相似文献
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目的:评价盐酸多柔比星脂质体单药(PLD)与盐酸多柔比星脂质体联合洛铂治疗复发性卵巢癌的安全性和临床疗效。方法:收集2012年4月至2015年10月我科收治的31例复发晚期上皮性卵巢癌患者,根据患者是否存在铂类耐药分为多柔比星组(单药组)15例及多柔比星+洛铂组(对照组)16例。单药组给盐酸多柔比星脂质体50 mg/m~2,静滴;对照组给盐酸多柔比星脂质体20-30 mg/m~2,洛铂30-50 mg/m~2,静脉滴注,两组每21-28天重复一次,观察和比较两组的临床疗效和毒性反应的发生情况。结果:所有患者完成3-8周期,客观有效率(ORR)为38.7%。单药组为33.3%,对照组为占43.8%,两组ORR比较差异无统计学意义(P=0.411)。单药组骨髓抑制的毒副作用较对照组发生率显著升高高(P=0.019),两组其他毒副反应的发生情况比较差异无统计学意义(P0.05)。单药组和对照组中位生存时间(MST)分别为10个月(95%CI:1.242-18.758)、18个月(95%CI:8.261-27.739),中位无进展生存期(PFS)分别为7个月(95%CI:2.210-13.797)、13个月(95%CI:4.368-21.632),两组MST、PFS比较差异均无统计学意义(P0.277)。结论:聚乙二醇脂质体阿霉素单体或聚乙二醇脂质体阿霉素联合洛铂治疗复发性卵巢癌的疗效相当,而聚乙二醇脂质体阿霉素单体的安全性更高。 相似文献
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The article presents magnetoliposomes as potential carriers of doxorubicin. The magnetic properties of nanoparticles embedded in liposomes enable the targeting of drug-loaded carriers to cancer cells and subsequent release of their payload using an external alternating magnetic field as a trigger. The cytotoxicity of empty and doxorubicin-loaded magnetoliposomes in the absence and after exposure to magnetic field was evaluated in cancerous and normal breast cells. The characteristic shows the carrier with size distribution <130 nm, slightly negative zeta potential and polydispersity index <0.2. Doxorubicin was encapsulated in magnetoliposomes with an efficiency of 31 % and released in the presence of an alternating magnetic field at 50 %. Magnetoliposomes with drug provided high cytotoxic effect on tumor cells and low cytotoxic effect on normal cells. The research conducted in this article may indicate the potential application of the studied magnetoliposomes in release of drugs under the influence of magnetic field in cancer cells. 相似文献
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《Journal of liposome research》2013,23(1):427-437
AbstractSeveral drugs have limited potency due to their rapid elimination or inactivation. The anticancer drug 5-fluoro-deoxyuridine (FUdR), which is frequently used in therapeutic treatment of liver metastases from colon tumors, is an example of such drugs. It is rapidly eliminated from circulation and metabolized, mainly by the hepatocytes in the liver. Over the past few years we have investigated the possibility to keep the drug away from the hepatocytes and to save it from rapid inactivation by encapsulating it in liposomes. In this way the liposomal drug is expected to accumulate in the macrophages of the liver (Kupffer cells), which form a major target site for intravenously administered liposomes. There, as the liposomal structure is gradually degraded by lysosomal enzymes, the drug will be released, initially within the lysosomal compartment, while subsequently it will leak out of the lysosomes and eventually out of the cells so as to become available for uptake by intrahepatically situated tumor cells. In this contribution we describe this system for the prodrug dipalmitoyl-FUdR, incorporated in the liposomal bilayer, requiring an additional step for the drug to become available, i.e. the enzymatic deacylation of the prodrug. It is demonstrated that the rate of intralysosomal degradation of liposomes in Kupffer cells varies substantially with liposomal lipid composition and that the rate of release of active drug from the Kupffer cells parallels the rate of liposome degradation. In addition, it is demonstrated that in this way the antitumor activity of the FUdR can be enhanced by more than two orders of magnitude and that the degree of antitumor activity reflects, to a limited extent, the rate at which the liposomes are degraded. 相似文献
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《Journal of liposome research》2013,23(2):199-228
AbstractWe have previously demonstrated that liposomal doxorubicin (DXR), targeted against the CD 19 receptor of human B lymphoma (Namalwa) cells resulted in selective affinity of SIL[anti-CD19] for CD19+ Namalwa cells in vitro and significantly increased therapeutic efficacy in mice compared to non-targeted liposomal DXR or to free drug (1). In this study we have examined the cellular trafficking of DXR in Namalwa cells for free drug compared to non-targeted liposomal drug (DXR-SL) or immunoliposomal drug targeted via the monoclonal antibody anti-CD19 (DXR-SIL[anti-CD19]). Liposomes were sterically stabilized with lipid derivatives of polyethylene glycol (PEG) and anti-CD 19 was attached to the PEG terminus. Time-dependent studies using flow cytometry revealed that free DXR accumulated rapidly in cells. Drug from DXR-SIL[anti-CD19] accumulated less rapidly in Namalwa cells than free drug but the cellular levels of DXR were several-fold higher than for drug presented in non-targeted DXR-SL. Internalization of SIL[anti-CD 19] into a low pH compartment could be demonstrated using a pH-sensitive probe, HPTS, encapsulated in liposomes. The endocytosis and intracellular fate of DXR-loaded liposomes were also studied by confocal microscopy, subcellular fractionation, and HPLC. At early times (1 h), DXR from targeted preparations appeared mainly at the cell surface with some DXR sequestered within vesicular structures, likely endosomes, in cells. DXR from non-targeted preparations (I)XR-SL) was only found on the cell surface after a one hour incubation. After two hours, drug from the targeted DXR formulation was mostly found within vesicular structures, whereas drug from the non-targeted formulation was still present only at the surface of the cells. The intracellular levels of DXR from DXR-S1L[anti-CD 19) continued to increase with longer incubation periods, and this endocytotic event could be abolished by metabolic inhibitors. Namalwa cells incubated with DXR-SIL[anti-CD 19] for 48 hours appear to demonstrate nuclear accumulation of DXR. This suggests that lysosomal processing of targeted liposomes allows trafficking of DXR from the lysosomal apparatus to its nuclear site of action. The cytotoxicity of DXR-SIL[anti-CD19] was 5-fold higher than that observed for non-targeted controls. The use of the cationic exchange resin, Dowex, to absorb DXR released from liposomes outside the cells demonstrated that a substantial portion of the cytotoxicity of DXR-SL, but not DXR-SIL, was due to uptake of released drug into cells. The targeted formulations were shown to be selectively apoptotic to CD 19 ' cells compared to CD 19 cells. 相似文献
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Previously, we showed that the encapsulation and release properties of a liposomal ciprofloxacin formulation could be modified post manufacture, by addition of surfactant in concert with osmotic swelling of the liposomes. This strategy may provide more flexibility and convenience than the alternative of manufacturing multiple batches of liposomes differing in composition to cover a wide range of release profiles. The goal of this study was to develop a surfactant-associated liposomal ciprofloxacin (CFI) formulation possessing good long-term stability which could be delivered as an inhaled aerosol. Preparations of 12.5 mg/ml CFI containing 0.4% polysorbate 20 were formulated between pH 4.7 and 5.5. These formulations, before and after mesh nebulization, and after refrigerated storage for up to 2 years, were characterized in terms of liposome structure by cryogenic transmission electron microscopy (cryo-TEM) imaging, vesicle size by dynamic light scattering, pH, drug encapsulation by centrifugation-filtration, and in vitro release (IVR) performance. Within the narrower pH range of 4.9 to 5.2, these formulations retained their physicochemical stability after 2-year refrigerated storage, were robust to mesh nebulization, and formed respirable aerosols with a volume mean diameter (VMD) of 3.7 μm and a geometric standard deviation (GSD) of 1.7. This study demonstrates that it may be possible to provide a range of release profiles by simple addition of surfactant to a liposomal formulation post manufacture, and that these formulations may retain their physicochemical properties after long-term refrigerated storage and following aerosolization by mesh nebulizer.KEY WORDS: ciprofloxacin, drug delivery, liposome, nebulized aerosol, surfactant 相似文献
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《Journal of liposome research》2013,23(1):53-79
AbstractThe characterization of two liposomal formulations of boronated DNA-interacting agents has been performed. It is shown that the two boronated drugs, WSA-Water Soluble Acridine and WSP-Water Soluble Phenantridine, can be encapsulated within unilamellar sterically stabilized liposomes with high drug-to-lipid ratios (up to 0.50:1 (mol:mol)), using transmembrane pH gradients. The steric stabilization of the liposomes was accomplished by the addition of DSPE-PEG(2000) (PEG-lipid) to DSPC/Cho lipid mixtures and the composition used was DSPC: Cho: DSPE-PEG 55:40:5 (moI%). The loading of the drugs resulted in drug precipitation in the liposomal aqueous core as observed by cryo-transmission electron microscopy (c-TEM). Moreover, it is shown that when pH gradients across the bilayer were used for remote loading of WSP or when ammonium sulfate gradients were used for remote loading of WSA, the formation of small bilayer fragments (discs) was induced. We present compelling evidence that the formation of discs is a consequence of precipitate growth in the liposomal interior. The precipitate growth causes some of the liposomes to rupture resulting in the above mentioned disc-formation and a substantial decrease in trapping efficiency. The in vitro stability of the drug loaded liposomes was excellent, both in buffer and in 25% human serum. For most of the formulations, the release of the drugs was below or around 10% after 24 hours at 37oC. Furthermore, the influence of initial internal pH and internal buffering capacity on release properties of WSA and WSP were investigated. It is shown that the release profiles of the drugs can be controlled, to a large extent, by varying the composition of the internal liposomal aqueous phase. 相似文献
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Lidija Habjanec Ruža Frkanec Beata Halassy Jelka Tomašić 《Journal of liposome research》2013,23(1):1-16
The adjuvant activity of liposomes and immunostimulating peptidoglycan monomer (PGM) in different formulations has been studied in mice model using ovalbumin (OVA) as an antigen. PGM is a natural compound of bacterial origin with well-defined chemical structure: GlcNAc-MurNAc-l-Ala-d-isoGln-mesoDpm(εNH2)-d-Ala-d-Ala. It is a non-toxic, non-pyrogenic, and water-soluble immunostimulator. The aim of this study was to investigate the influence of different liposomal formulations of OVA, with or without PGM, on the production of total IgG, as well as of IgG1 and IgG2a subclasses of OVA-specific antibodies (as indicators of Th2 and Th1 type of immune response, respectively). CBA mice were immunized s.c. with OVA mixed with liposomes, OVA with PGM mixed with liposomes, OVA encapsulated into liposomes and OVA with PGM encapsulated into liposomes. Control groups were OVA in saline, OVA with PGM in saline, and OVA in CFA/IFA adjuvant formulation. The entrapment efficacy of OVA was monitored by HPLC method. The adjuvant activity of the mixture of OVA and empty liposomes, the mixture of OVA, PGM, and liposomes and PGM encapsulated with OVA into liposomes on production of total anti-OVA IgG was demonstrated. The mixture of PGM and liposomes exhibited additive immunostimulating effect on the production of antigen-specific IgGs. The analysis of IgG subclasses revealed that encapsulation of OVA into liposomes favors the stimulation of IgG2a antibodies, indicating the switch toward the Th1 type of immune response. When encapsulated into liposomes or mixed with liposomes, PGM induced a switch from Th1 to Th2 type of immune response. It could be concluded that appropriate formulations of antigen, PGM, and liposomes differently affect the humoral immune response and direct the switch in the type of immune response (Th1/Th2). 相似文献
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Coating of liposomes with polyethylene-glycol (PEG) by incorporation in the liposome bilayer of PEG-derivatized lipids results in inhibition of liposome uptake by the reticulo-endothelial system and significant prolongation of liposome residence time in the blood stream. Parallel developments in drug loading technology have improved the efficiency and stability of drug entrapment in liposomes, particularly with regard to cationic amphiphiles such as anthracyclines. An example of this new generation of liposomes is a formulation of pegylated liposomal doxorubicin known as Doxil® or Caelyx®, whose clinical pharmacokinetic profile is characterized by slow plasma clearance and small volume of distribution. A hallmark of these long-circulating liposomal drug carriers is their enhanced accumulation in tumors. The mechanism underlying this passive targeting effect is the phenomenon known as enhanced permeability and retention (EPR) which has been described in a broad variety of experimental tumor types. Further to the passive targeting effect, the liposome drug delivery platform offers the possibility of grafting tumor-specific ligands on the liposome membrane for active targeting to tumor cells, and potentially intracellular drug delivery. The pros and cons of the liposome platform in cancer targeting are discussed vis-à-vis nontargeted drugs, using as an example a liposome drug delivery system targeted to the folate receptor. 相似文献
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AbstractConventional chemotherapy for leishmaniasis includes considerably toxic drugs and reports of drug-resistance are not uncommon. Liposomal encapsulated drugs appear as an option for the treatment of leishmaniasis, providing greater efficacy for the active and reducing its side effects by promoting superior tissue absorption, favouring drug penetration into the macrophages, and retarding its clearance from the site of action. In this paper, a review on the advances achieved with liposome-based anti-leishmaniasis drug delivery systems is presented. Formulations prepared with either conventional or modified (sugar-coated, cationic, niosomes, peptides- and antibodies-bounded) liposomes for the delivery of pentavalent antimonials, amphotericin B, pentamidine, paromomycyn, and miltefosine were covered. This literature review depicts a scenario of no effective therapeutic agents for the treatment of this neglected disease, where liposomal formulations appear to improve the effectiveness of the available antileishmania agents. 相似文献
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Tatiana C. Silva Sérgio De Paula Moura Henrique R. Ramos Pedro S. De Araujo 《Journal of liposome research》2013,23(4):353-368
Traditional venom immunotherapy uses injections of whole bee venom in buffer or adsorbed in Al (OH)3 in an expensive, time-consuming way. New strategies to improve the safety and efficacy of this treatment with a reduction of injections would, therefore, be of general interest. It would improve patient compliance and provide socio-economic benefits. Liposomes have a long tradition in drug delivery because they increase the therapeutic index and avoid drug degradation and secondary effects. However, bee venom melittin (Mel) and phospholipase (PLA2) destroy the phospholipid membranes. Our central idea was to inhibit the PLA2 and Mel activities through histidine alkylation and or tryptophan oxidation (with pbb, para-bromo-phenacyl bromide, and/or NBS- N-bromosuccinimide, respectively) to make their encapsulations possible within stabilized liposomes. We strongly believe that this formulation will be nontoxic but immunogenic. In this paper, we present the whole bee venom conformation characterization during and after chemical modification and after interaction with liposome by ultraviolet, circular dichroism, and fluorescence spectroscopies. The PLA2 and Mel activities were measured indirectly by changes in turbidity at 400n m, rhodamine leak-out, and hemolysis. The native whole bee venom (BV) presented 78.06%?of α-helical content. The alkylation (A-BV) and succynilation (S-BV) of BV increased 0.44 and 0.20%?of its α-helical content. The double-modified venom (S-A-BV) had a 0.74%?increase of α-helical content. The BV chemical modification induced another change on protein conformations observed by Trp that became buried with respect to the native whole BV. It was demonstrated that the liposomal membranes must contain pbb (SPC:Cho:pbb, 26:7:1) as a component to protect them from aggregation and/or fusion. The membranes containing pbb maintained the same turbidity (100%) after incubation with modified venom, in contrast with pbb-free membranes that showed a 15%?size decrease. This size decrease was interpreted as membrane degradation and was corroborated by a 50%?rhodamine leak-out. Another fact that confirmed our interpretation was the observed 100%?inhibition of the hemolytic activity after venom modification with pbb and NBS (S-A-BV). When S-A-BV interacted with liposomes, other protein conformational changes were observed and characterized by the increase of 1.93%?on S-A-BV α-helical content and the presence of tryptophan residues in a more hydrophobic environment. In other words, the S-A-BV interacted with liposomal membranes, but this interaction was not effective to cause aggregation, leak-out, or fusion. A stable formulation composed by S-A-BV encapsulated within liposomes composed by SPC:Cho:pbb, at a ratio of 26:7:1, was devised. Large unilamellar vesicles of 202.5 nm with a negative surface charge (–24.29 mV) encapsulated 95%?of S-A-BV. This formulation can, now, be assayed on VIT. 相似文献
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Godefridus J. Peters Auke D. Adema Irene V. Bijnsdorp Marit L. Sandvold 《Nucleosides, nucleotides & nucleic acids》2013,32(12):1168-1180
Many drugs that are currently used for the treatment of cancer have limitations, such as induction of resistance and/or poor biological half-life, which reduce their clinical efficacy. To overcome these limitations, several strategies have been explored. Chemical modification by the attachment of lipophilic moieties to (deoxy)nucleoside analogs should enhance the plasma half-life, change the biodistribution, and improve cellular uptake of the drug. Attachment of a lipophilic moiety to a phosphorylated (deoxy)nucleoside analog will improve the activity of the drugs by circumventing the rate-limiting activation step of (deoxy)nucleoside analogs. Encapsulating drugs in nanoparticles or liposomes protects the drug against enzymatic breakdown in the plasma and makes it possible to get lipophilic compounds to the tumor site. In this review, we discuss the considerable progress that has been made in increasing the efficacy of classic (deoxy)nucleoside and fluoropyrimidine compounds by chemical modifications and alternative delivery systems. 相似文献
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环糊精是一类重要的药用高分子材料,通过与药物形成包合物结构而实现提高难溶性药物溶解性、增强药物稳定性、改善药物生
物利用度等目的。结合天然及改性环糊精的性质特点、体内代谢及生物安全性等信息,归纳了环糊精在已上市医药产品中的研究及应用,
为环糊精领域相关制剂的临床研究及产业化提供一定的参考。 相似文献
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嗜热菌玉米黄质(thermozeaxanthins,TZS)是从嗜热菌的磷脂提取物中分离得到的胡萝卜素单葡萄糖脂肪酸酯化合物,具有两亲性结构,通过检测包裹在脂质体内的荧光物质的漏出程度,来评价在不同pH缓冲液中TZS对脂质体膜的影响。脂质体由天然卵磷脂(eggPC)、大肠杆菌磷脂酰乙醇胺(E.coliPE)或不同碳链长度和饱和度的二棕榈酰磷脂酰胆碱(DPPC)、二油酰磷脂酰胆碱(DOPC)磷脂形成,结果表明:在pH5.0的缓冲液中,含0.01molTZS的脂质体比单纯由磷脂形成的脂质体要稳定,在pH8.2和9.0的环境中,其稳定作用不明显;由eggPC或E.coliPE与TZS形成的脂质体的稳定性在同样条件下要优于由DPPC或DOPC与TZS形成的脂质体。在pH6.5的缓冲液中,含有TZS的脂质体与对照脂质体的稳定性相近。TZS对脂质体的影响取决于TZS与磷脂双层膜的相互“匹配”,邓与磷脂的脂肪烃链的长度、饱和度有关。 相似文献
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目的:以角蛋白作为药物载体材料,制备智能响应性药物递送系统,研究其药物装载和释放性能。方法:利用去溶剂法制备角蛋白纳米颗粒(KNP),以罗丹明B(RB)和姜黄素(Cur)为亲水性和疏水性模式药物,制备载药KNP。利用钨灯丝扫描电镜(SEM)、动态光散射(DLS)、傅里叶变换红外光谱(FTIR)和药物体外释放实验等对KNP的尺寸、形貌、结构、载药和释药性能进行研究。结果:成功制备出粒径均一、约为300 nm 的KNP,能够装载亲水性和疏水性药物。载药颗粒在体外释放研究中表现出pH和氧化还原双重响应性。结论:利用去溶剂法,简便、安全地制备了分散性良好且具有pH和氧化还原双重响应性释放特性的角蛋白载药纳米颗粒,为角蛋白作为智能响应型药物递送载体的研究和应用提供了参考。 相似文献
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Abeer Alanazi Laila Fadda Ahlam Alhusaini Rehab Ahmad 《Journal of biochemical and molecular toxicology》2020,34(7)
The use of the cytotoxic antibiotic doxorubicin (DOXR) is limited by its dose‐dependent cardiotoxicity. The aim of this study was to evaluate the cardioprotective effect of the combination of carvedilol (CARD) and liposomal resveratrol (LIPO RESV) against DOXR‐induced cardiomyopathy in rats. The results of the present study showed that DOXR administration significantly increased heart weight/body weight ratio by 35.6%, creatine kinase‐MB (CK‐MB) by 40.6%, troponin‐I levels by 85%, and decreased reduced glutathione level and superoxide dismutase activity by 47% and 52%, respectively compared to the control group. Moreover, cardiac caspase‐3 protein expression was upregulated by 51.6% vs the control group. In contrast, treatment of DOXR‐administered rats with CARD, RESV, or LIPO RESV and their combination for 6 weeks improved all the above‐mentioned measured parameters. In conclusion, concomitant administration of CARD and LIPO RESV exerted additive pharmacological effects in some measured parameters against DOXR‐induced cardiomyopathy and this may be a useful cardioprotective strategy. 相似文献
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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. 相似文献