Doxorubicin In Blood Research Articles

Application of Optical Methods for Determination of Concentration of Doxorubicin in Blood and Plasma.

The aim of presented research is to develop a simple and quick method of spectrophotometric detection for the determination of doxorubicin hydrochloride in blood and plasma. Anthracycline antibiotics are among the most effective antineoplastic agents. However, despite their high efficacy in the treatment of various types of cancer, their administration is limited primarily because they exhibit myocardial toxicity. This may be a limiting factor in the dosage of medications; nevertheless, drugs exhibiting this mechanism of action constitute a very important group of chemotherapeutics. One of the more widely studied antibiotics from the anthracycline group is doxorubicin. It exhibits the highest antineoplastic activity from among a number of derivative compounds. Because of the adverse effects of doxorubicin, especially cardiotoxicity, it is important to maintain control of its concentration in body fluids. The method in the study consists of extraction doxorubicin from the plasma or blood and measurements of the absorbance of light in the visible light range in a DOX solution with respect to a reference sample. The research used blood and plasma samples spiked with doxorubicin to give concentrations in the range of 0.2–10 µg/mL. Obtained LODs were 1.6 µg/mL and 1.2 µg/mL, respectively.

PH-sensitive loading/releasing of doxorubicin using single-walled carbon nanotube and multi-walled carbon nanotube: A molecular dynamics study

Background and objectiveDoxorubicin is one of the drugs used to treat cancer, and many studies have been conducted to control its release. In this study, carbon nanotubes have been proposed as a doxorubicin carrier, and the effect of carboxyl functional group on the controlled release of doxorubicin has been studied. MethodsThis study has been done by molecular dynamics simulation and was based on changing the pH as a mechanism controller. ResultsThis work is intended to test the efficacy of this drug carrier for the release of doxorubicin. A comparison was also made between single-walled and double-walled carbon nanotubes to answer the question of which one can be a better carrier for doxorubicin. The study of DOXORUBICIN adsorption and release showed that the DOXORUBICIN adsorption on single-walled carbon nanotube and multi-walled carbon nanotube in neutral pH was stronger than it was in acidic pH, which could be due to the electrostatic interactions between the carboxyl group of nanotubes and DOXORUBICIN. Based on this and according to the investigation of hydrogen bonds, diffusion coefficients, and other results it was clear that the drug release in acidic pH was appropriate for body conditions. Since cancer tissues pH is acidic, this shows the suitability of carbon nanotube in drug delivery and DOXORUBICIN release in cancer tissues. In addition, it was shown that the blood pH (pH = 7) is suitable for DOXORUBICIN loading on the carbon nanotube and carbon nanotube-DOXORUBICIN linkage remained stable at this pH; accordingly, the carbon nanotube could deliver DOXORUBICIN in blood quite well and release it in cancerous tissues. This suggests the carbon nanotubes as a promising drug carrier in the cancer therapy which can be also investigated in experiments. ConclusionIt was revealed that the bonds between multi-walled carbon nanotube and DOXORUBICIN was stronger and this complex had a slower release in the cancer tissues compared to the single-walled carbon nanotube; this can be regarded as an advantage over the single-walled carbon nanotube in the DOXORUBICIN delivery and release.

Co-delivery of glycyrrhizin and doxorubicin by alginate nanogel particles attenuates the activation of macrophage and enhances the therapeutic efficacy for hepatocellular carcinoma.

Nanocarrier drug delivery systems (NDDS) have been paid more attention over conventional drug delivery system for cancer therapy. However, the efficacy is hampered by the fast clearance of activated macrophage from the blood circulation system. In this study, glycyrrhizin (GL) was introduced into alginate (ALG) nanogel particles (NGPs) to construct multifunctional delivery vehicle to decrease the fast clearance of activated macrophage and enhance the anticancer efficacy with the combination therapy of GL and doxorubicin (DOX).Methods: We firstly synthesized the GL-ALG NGPs with intermolecular hydrogen bond and ionic bond as the multifunctional delivery vehicle. The immune response and phagocytosis of macrophage on GL-ALG NGPs were investigated on RAW 264.7 macrophages. The pharmacokinetic study of DOX loaded in GL-ALG NGPs was performed in rats. The active targeting effects of GL-ALG NGPs were further studied on hepatocellular carcinoma cell (HepG2) and H22 tumor-bearing mice. Moreover, the anticancer molecular mechanism of DOX/GL-ALG NGPs was investigated on HepG2 cells in vitro and tumor-bearing mice in vivo.Results: GL-ALG NGPs could not only avoid triggering the immuno-inflammatory responses of macrophages but also decreasing the phagocytosis of macrophage. The bioavailability of DOX was increased about 13.2 times by DOX/GL-ALG NGPs than free DOX in blood. The mice with normal immune functions used in constructing the tumor-bearing mice instead of the nude mouse also indicated the good biocompatibility of NGPs. GL-mediated ALG NGPs exhibited excellent hepatocellular carcinoma targeting effect in vitro and in vivo. The results suggested that the anticancer molecular mechanism of the combination therapy of glycyrrhizin and doxorubicin in ALG NGPs was performed via regulating apoptosis pathway of Bax/Bcl-2 ratio and caspase-3 activity, which was also verified in H22 tumor-bearing mice.Conclusion: DOX/GL-ALG NGPs could attenuate the activation of macrophage and enhance the therapeutic efficacy for hepatocellular carcinoma. Our results suggest that the combination therapy would provide a new strategy for liver cancer treatment.

Abstract 2155: Achieving complete response to locoregional disease without toxicity using temperature-sensitive liposomes and ultrasound-mediated hyperthermia.

Abstract By stabilizing doxorubicin within temperature-sensitive liposomes and repeating delivery twice per week for four weeks, extended survival and complete response were obtained in syngeneic murine breast tumors. Further, with the stabilized formulation, cardiac toxicity and leukopenia were not detected. Liposomes composed of DPPC:MPPC:DSPE-PEG2k, 86:10:4 were prepared in the presence of copper(II) gluconate and triethanolamine and extruded with 100 nm membrane filters. Cu-liposomes were loaded with Dox at 0.2 mg-drug/mg-lipid with 100% loading. We studied the efficacy of CuDox liposomes (CuDox-LTSLs) using the highly invasive neu deletion (NDL) tumor. Treatment began when the tumor diameter reached 4 mm. The fluorescence of circulating doxorubicin in blood was quenched after the digestion of liposomes with Triton X-100, indicating that the circulating drug remained associated with copper. Dox fluorescence was restored upon reducing the pH using a citrate-saline buffer. Over the 28 days of the study, CuDox-LTSLs were administrated intravenously two times per week at a therapeutic level of 6 mg-drug/kg-body weight. The entire tumor was insonified with a peak ultrasound pressure of 1.1 MPa at a frequency of 1.5 MHz at 42°C for 5 min prior to and 20 min post drug injection. A total of 30 mice were studied, including groups spanning drug treatment with ultrasound, ultrasound, drug treatment and no treatment. Although a single dose administration of CuDox-LTSLs combined with insonation of the entire tumor suppressed the tumor growth, complete response was achieved only upon repeated treatment over a period of 28 days. At 30 days after the last administered dose, none of the mice from the other groups survive; however, 100% of mice treated with ultrasound combined with CuDox-LTSLs survive and the remaining tumor is undetectable. In conclusion, repeated treatment of stabilized temperature sensitive doxorubicin liposomes is highly effective in the treatment of aggressive murine tumors. Acknowledgement: NIHR01CA134659 and NIHR01CA103828 Citation Format: Azadeh Kheirolomoom, Chun-Yen Lai, Sarah M. TAM, Lisa M. Even, Elizabeth S. Ingham, Brett Z. Fite, Katherine D. Watson, Katherine W. Ferrara. Achieving complete response to locoregional disease without toxicity using temperature-sensitive liposomes and ultrasound-mediated hyperthermia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2155. doi:10.1158/1538-7445.AM2013-2155

Alterations in P-glycoprotein expression in mouse tissues by doxorubicin: implications for pharmacokinetics in multiple dosing regimens

The purpose of the studies presented here is to determine if alterations in doxorubicin (DOX) pharmacokinetics that seem to occur following multiple-dosing are due to changes in DOX elimination via P-glycoprotein (PGP) mediated transport in the liver, kidney and gut. A pharmacokinetic study in female Balb/c mice was carried out with blood and tissue DOX levels measured in animals following a single DOX treatment (6 mg/kg), and in animals following a second DOX treatment after receiving a DOX treatment a week earlier. The pharmacokinetics of DOX in blood and tissues was altered by earlier exposure to DOX, as the animals that were treated once a week for 2 weeks showed an increased rate of DOX elimination from blood and tissues following the second treatment. Immunoblot analysis of PGP expression in liver and kidney from naı̈ve and DOX-treated mice showed an approximately 1.2-fold elevation of PGP protein in these tissues in response to DOX exposure. Immunohistochemical staining of liver and small intestine sections for PGP showed 1.6-fold and 1.9-fold increases, respectively, in the DOX-treated tissues. These results have implications both in multiple-dosing regimens, as well as multiple-drug regimens, where DOX is used in combination with other drugs that are substrates for PGP-mediated efflux. Increases in PGP expression in both hepatic and extrahepatic tissues can lead to changes in the pharmacokinetics of DOX, as well as other drugs that are transported by PGP.

Antitumor activity of doxorubicin encapsulated in poly(ethylene glycol)-coated liposomes.

The antitumor activity of doxorubicin (DXR) which had been encapsulated in poly(ethylene glycol) (PEP)-coated long-circulating liposomes was examined in mice inoculated with colon 26 carcinoma cells. Six mol% of the distearoylphosphatidylethanolamine derivative of PEGs with different molecular weights was incorporated in liposomes (90-110 nm, mean diameter) composed of distearoylphosphatidylcholine/cholesterol (1/1, molar ratio), and the encapsulating efficiency of DXR in liposomes was more than 98% by the pH gradient method. Each concentration of DXR in blood and tumor tissue was significantly greater after administration of the drug encapsulated in PEG-coated liposomes (DXR-PEG-liposome) compared to the non-coated control liposomes or non-encapsulated free drug. DXR-PEG-liposome prepared with PEG1000 (DXR-PEG1000-liposome) more effectively increased the level of DXR in blood and tumor than did the preparations with PEG5000 or PEG 12000. A single treatment with DXR-PEG1000-liposome (10 mg DXR/kg) resulted in increased survival time. Further therapeutic improvement in terms of tumor growth retardation and prolongation of survival time were observed following multiple treatments with DXR-PEG1000-liposome (3 x 5 mg DXR/kg). Long-circulating liposome coating optimized PEGs should be useful for the delivery of chemotherapeutic agents for the treatment of solid tumors.

Pharmacokinetics of pirarubicin in pediatric patients.

The pharmacokinetics of pirarubicin and its active metabolite, doxorubicin, were studied after intravenous administration of pirarubicin (25-45 mg/m2) to ten pediatric patients. The concentration-time curves of pirarubicin in both blood and plasma showed representative biphasic patterns. Pirarubicin concentrations decreased rapidly from 0.5 to 2 h after administration and then decreased slowly until 24 h in all subjects. High concentrations of the metabolite, doxorubicin, were detected at 0.5 h after administration of pirarubicin which decreased gradually until 24 h. The area under the concentration-time curve from 0 to 24 h (AUC0-24) of pirarubicin and doxorubicin in blood were 3-4 times higher than those in plasma, suggesting that these drugs had a high affinity for blood cells. The AUC0-24 ratio of doxorubicin to pirarubicin in plasma was calculated to be 0.441. It might be indicated that not only pirarubicin but also doxorubicin are responsible for the therapeutic efficacy and the incidence of toxicity of pirarubicin. The pharmacokinetics of pirarubicin in pediatric patients was fundamentally similar to that of adults, but it was recognized that considerable interindividual variation in the disposition of pirarubicin and doxorubicin exists.