RESUMEN
A new micellar electrokinetic capillary chromatographic (MEKC) method has been developed and optimized for simultaneous quantitation of doxorubicin (Dox) and fullerenol (Frl) in rat serum. The separation was carried out in a capillary (48.5-40 cm to the detector - 50 µm id fused-silica capillary with bubble cell, 150 µm) at an applied voltage of 25 kV and temperature of 25 °C. For the background electrolyte 10 mmol L- 1 borate buffer pH 9.3 plus 15 mmol L-1 phosphate buffer pH 7.0 (with the final pH of the mixture adjusted to 7.0 with HCl), with added 10 % (V/V) methanol, and 15 mmol L-1 sodium dodecyl sulfate as a surfactant, were used. The hydrodynamic injection was carried out at 5.0 kPa during the period of 100 s. Linear calibration curves were established over the concentration range 0.5-500.0 mg L- 1 for Dox and 10.0-500.0 mg L- 1 for Frl (at 234 nm). The proposed MEKC procedure was fully validated and applied for the deter mination of Dox and Frl in Wistar rats after intra pe ritoneal administration of both molecules.
Asunto(s)
Cromatografía Capilar Electrocinética Micelar , Doxorrubicina , Fulerenos , Ratas Wistar , Animales , Doxorrubicina/sangre , Cromatografía Capilar Electrocinética Micelar/métodos , Fulerenos/química , Fulerenos/sangre , Ratas , Masculino , Antibióticos Antineoplásicos/sangre , Calibración , Reproducibilidad de los ResultadosRESUMEN
Pirarubicin (THP), doxorubicin (DOX), cyclophosphamide (CTX), and vincristine (VCR) are widely used in the treatment of patients with non-Hodgkin's Lymphoma. Herein, a precise and sensitive method was developed for the determination of THP, DOX, CTX and VCR in human plasma by high-performance liquid-chromatography-tandem mass spectrometry (LC-MS/MS). Liquid-liquid extraction was applied to extract THP, DOX, CTX, VCR, and the internal standard (IS, Pioglitazone) in plasma. Agilent Eclipse XDB-C18 (3.0 mm × 100 mm) was utilized and chromatographic separation was obtained in eight minutes. Mobile phases were composed of methanol and buffer (10 mM ammonium formate containing 0.1% formic acid). The method was linear within the concentration range of 1-500 ng/mL for THP, 2-1000 ng/mL for DOX, 2.5-1250 ng/mL for CTX, and 3-1500 ng/mL for VCR. The intra- and inter-day precisions of QC samples were found to be below 9.31 and 13.66%, and accuracy ranged from -0.2 to 9.07%, respectively. THP, DOX, CTX, VCR and the internal standard were stable in several conditions. Finally, this method was successfully utilized to simultaneously determine THP, DOX, CTX and VCR in human plasma of 15 patients with non-Hodgkin's Lymphoma after intravenous administration. Finally, the method was successfully employed in the clinical determination of THP, DOX, CTX, and VCR in patients with non-Hodgkin lymphoma after administration of RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) regimens.
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Linfoma no Hodgkin , Humanos , Espectrometría de Masas en Tándem/métodos , Linfoma no Hodgkin/química , Linfoma no Hodgkin/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Doxorrubicina/sangre , Doxorrubicina/uso terapéutico , Ciclofosfamida/sangre , Ciclofosfamida/uso terapéutico , Vincristina/sangre , Vincristina/uso terapéutico , Técnicas de Dilución del Indicador , Cromatografía Líquida de Alta Presión/métodosRESUMEN
A rapid, efficient, and sensitive liquid chromatographic assay hyphenated to fluorometric detector (HPLC-FLD) was developed and validated for the determination of doxorubicin (DXR) and prodigiosin (PDG) in rat plasma. The sample pre-treatment involves a protein precipitation with acetonitrile with satisfying extraction efficiency (98% and 85% for DXR and PDG, respectively). The chromatographic separation was accomplished using stationary phase: Agilent Zorbax Eclipse plus-C18 analytical column (250 × 4.6 mm, 5 µm) and gradient eluting mobile phase of ammonium acetate (pH = 3), acetonitrile and methanol with programmed fluorescence detection. As the proposed method has been validated, it was subsequently implemented to evaluate DXR and PDG loaded on novel eco-friendly Casein nano drug delivery system after intravenous injection in healthy rats. A comparative pharmacokinetics' study was carried out in rats for DXR in free form, DXR alone entrapped in the nanomicelle and DXR with PDG entrapped in the nano micelle. After testing the differences in pharmacokinetic parameters of the different formulations using ANOVA, the results showed insignificant differences among the tested parameters. This indicates that the presented nanomicelle delivery system has succeeded to incorporate PDG and DXR in a hydrophilic, safe, and potent formulation. This novel nanomicelle has negligible effect on the distribution and elimination of DXR.
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Caseínas/química , Doxorrubicina/sangre , Micelas , Sistema de Administración de Fármacos con Nanopartículas/química , Prodigiosina/sangre , Animales , Caseínas/sangre , Caseínas/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Doxorrubicina/química , Doxorrubicina/farmacocinética , Masculino , Sistema de Administración de Fármacos con Nanopartículas/análisis , Sistema de Administración de Fármacos con Nanopartículas/farmacocinética , Prodigiosina/química , Prodigiosina/farmacocinética , Ratas , Ratas Wistar , Espectrometría de FluorescenciaRESUMEN
BACKGROUND: Aidi Injection (ADI), a Chinese herbal preparation with anti-cancer activity, is used for the treatment of hepatocellular carcinoma (HCC). Several clinical studies have shown that co-administration of ADI with doxorubicin (DOX) is associated with reduced toxicity of chemotherapy, enhanced clinical efficacy and improved quality of life for patients. However, limited information is available about the herb-drug interactions between ADI and DOX. The study aimed to investigate the pharmacokinetic mechanism of herb-drug interactions between ADI and DOX in a rat model of HCC. METHODS: Experimental HCC was induced in rats by oral administration of diethylnitrosamine. The HCC rats were pretreated with ADI (10 mL/kg, intraperitoneal injection) for 14 consecutive days prior to administration of DOX (7 mg/kg, intravenous injection) to investigate pharmacokinetic interactions. Plasma concentrations of DOX and its major metabolite, doxorubicinol (DOXol), were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: Preadministration of ADI significantly altered the pharmacokinetics of DOX in HCC rats, leading to increased plasma concentrations of both DOX and DOXol. The area under the plasma drug concentration-time curve (AUCs) of DOX and DOXol in rats pretreated with ADI were 3.79-fold and 2.92-fold higher, respectively, than those in control rats that did not receive ADI. CONCLUSIONS: Increased levels of DOX and DOXol were found in the plasma of HCC rats pretreated with ADI.
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Antibióticos Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/metabolismo , Doxorrubicina/farmacocinética , Medicamentos Herbarios Chinos/farmacología , Interacciones de Hierba-Droga , Neoplasias Hepáticas/metabolismo , Animales , Antibióticos Antineoplásicos/sangre , Área Bajo la Curva , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/inducido químicamente , Dietilnitrosamina , Doxorrubicina/sangre , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/inducido químicamente , Masculino , Ratas Sprague-DawleyRESUMEN
Detection of anticancer drug (doxorubicin) using an electrochemical sensor is developed based on a transition metal vanadate's related carbon composite material. With an environmentally friendly process, we have synthesized a metal oxide composite of iron vanadate nanoparticle assembled with sulfur-doped carbon nanofiber (FeV/SCNF). The FeV/SCNF composite was characterized using XRD, TEM, FESEM with elemental mapping, XPS and EDS. In contrast to other electrodes reported in the literature, a much-improved electrochemical efficiency is shown by FeV/SCNF composite modified electrodes. Amperometric technique has been employed at 0.25 V (vs. Ag/AgCl) for the sensitive detection of DOX within a wide range of 20 nM-542.5 µM and it possesses enhanced selectivity in presence of common interferents. The modified electrochemical sensors show high sensitivity of 46.041 µA µM-1 cm-2. The newly developed sensor could be used for the determination of doxorubicin in both blood serum and drug formulations with acceptable results, suggesting its feasibility for real-time applications.
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Antineoplásicos/análisis , Doxorrubicina/análisis , Nanocompuestos/química , Nanofibras/química , Antineoplásicos/sangre , Antineoplásicos/química , Antineoplásicos/orina , Carbono/química , Disolventes Eutécticos Profundos/química , Doxorrubicina/sangre , Doxorrubicina/química , Doxorrubicina/orina , Técnicas Electroquímicas/instrumentación , Técnicas Electroquímicas/métodos , Electrodos , Humanos , Hierro/química , Límite de Detección , Oxidación-Reducción , Azufre/química , Vanadatos/síntesis química , Vanadatos/químicaRESUMEN
The toxic side effects of chemotherapy have long limited its efficacy, prompting expensive and long-drawn efforts to develop more targeted cancer therapeutics. An alternative approach to mitigate off-target toxicity is to develop a device that can sequester chemotherapeutic agents from the veins that drain the target organ before they enter systemic circulation. This effectively localizes the chemotherapy to the target organ, minimizing any hazardous side effects. 3D printing is ideal for fabricating these devices, as the geometric control afforded allows us to precisely dictate its hemodynamic performance in vivo. However, the existing materials compatible with 3D printing do not have drug-binding capabilities. Here, we report the stable coating of genomic DNA on a 3D-printed structure for the capture of doxorubicin. Genomic DNA is an effective chemotherapeutic-agent capture material due to the intrinsic DNA-targeting mechanism of action of these drugs. Stable DNA coatings were achieved through a combination of electrostatic interactions and ultraviolet C (UVC, 254 nm) cross-linking. These UVC cross-linked DNA coatings were extremely stable-leaching on average 100 pg of genomic DNA per mm2 of 3D-printed structure over a period of 30 min. In vitro studies of these materials in phosphate buffered saline and human serum demonstrated that they were able to capture, on average, 72 and 60 ng of doxorubicin per mm2 of structure, respectively. The stability and efficacy of these genomic DNA-coated 3D-printed materials represent a significant step forward towards the translation of these devices to clinical applications for the potential improvement of chemotherapy treatment.
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Antineoplásicos/aislamiento & purificación , ADN/química , Doxorrubicina/aislamiento & purificación , Ácidos Nucleicos Inmovilizados/química , Resinas Acrílicas/química , Antineoplásicos/sangre , Antineoplásicos/química , Doxorrubicina/sangre , Doxorrubicina/química , Humanos , Impresión TridimensionalRESUMEN
Using the chemical doxorubicin (DOX), the objective of the present study was to evaluate the impact of dose metrics selection in the new approach method of integrating physiologically-based kinetic (PBK) modelling and relevant human cell-based assays to inform a priori the point of departure for human health risk. We reviewed the literature on the clinical consequences of DOX treatment to identify dosing scenarios with no or mild cardiotoxicity observed. Key concentrations of DOX that induced cardiomyocyte toxicity in vitro were derived from studies of our own and others. A human population-based PBK model of DOX was developed and verified against pharmacokinetic data. The model was then used to predict plasma and extracellular and intracellular heart concentrations of DOX under selected clinical settings and compared with in vitro outcomes, based on several dose metrics: Cmax (maximum concentration) or AUC (area under concentration-time curve) in free or total form of DOX. We found when using in vitro assays to predict cardiotoxicity for DOX, AUC is a better indicator. Our study illustrates that when appropriate dose metrics are used, it is possible to combine PBK modelling with in vitro-derived toxicity information to define margins of safety and predict low-risk human exposure levels.
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Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Modelos Biológicos , Medición de Riesgo/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/sangre , Línea Celular , Doxorrubicina/administración & dosificación , Doxorrubicina/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miocardio/metabolismo , Adulto JovenRESUMEN
Two-dimensional (2D) MoS2core-shell nanoparticles were synthesized using an eco-friendly surface functionalization-agent with L-glutathione and cystamine (L-GSH-MoS2-CYS) using ultrasonic frequency of 20-25 kHz. The novel modified electrode was evaluated for the electrochemical detection of doxorubicin (DOX), through cyclic and differential pulse voltammetric techniques. The electro-catalytic oxidation currents of DOX exhibited a linear relationship in the concentration ranges 0.1-78.3 and 98.3-1218 µM, with a detection limit of 31 nM. A sensitivity of 0.017µA µM-1 cm-2 was acquired at 0.48 V. The fabricated L-GSH-MoS2-CYS modified electrode showed excellent precision, selectivity, repeatability, and reproducibility during the determination of DOX levels in blood serum samples. Thus, the fabricated L-GSH-MoS2-CYS/GCE modified electrode has potential for clinical applications for optimization of chemotherapeutic drugs owing to its selectivity, ease of preparation, and long-term stability. Graphical abstract.
Asunto(s)
Cistamina/química , Disulfuros/química , Doxorrubicina/sangre , Glutatión/química , Nanopartículas del Metal/química , Molibdeno/química , Carbono/química , Doxorrubicina/química , Técnicas Electroquímicas/instrumentación , Técnicas Electroquímicas/métodos , Electrodos , Humanos , Límite de Detección , Oxidación-Reducción , Reproducibilidad de los ResultadosRESUMEN
PURPOSE: Current treatment options for muscle-invasive bladder cancer (MIBC) are associated with substantial morbidity. Local release of doxorubicin (DOX) from phosphatidyldiglycerol-based thermosensitive liposomes (DPPG2-TSL-DOX) potentiated by hyperthermia (HT) in the bladder wall may result in bladder sparing without toxicity of systemic chemotherapy. We investigated whether this approach, compared to conventional DOX application, increases DOX concentrations in the bladder wall while limiting DOX in essential organs. MATERIALS AND METHODS: Twenty-one pigs were anaesthetized, and a urinary catheter equipped with a radiofrequency-emitting antenna for HT (60 minutes) was placed. Experimental groups consisted of iv low or full dose (20 or 60 mg/m2) DPPG2-TSL-DOX with/without HT, iv low dose (20 mg/m2) free DOX with HT, and full dose (50 mg/50 mL) intravesical DOX with/without HT. After the procedure, animals were immediately sacrificed. HPLC was used to measure DOX levels in the bladder, essential organs and serum, and fluorescence microscopy to evaluate DOX distribution in the bladder wall. RESULTS: Iv DPPG2-TSL-DOX with HT resulted in a significantly higher bladder wall DOX concentration which was more homogeneous distributed, than iv and intravesical free DOX administration with HT. Specifically in the detrusor, DPPG2-TSL-DOX with HT led to a >7- and 44-fold higher DOX concentration, compared to iv free DOX with HT and intravesical DOX, respectively. Organ DOX concentrations were significantly lower in heart and kidneys, and similar in liver, spleen and lungs, following iv DPPG2-TSL-DOX with HT, compared to iv free DOX. Intravesical DOX led to the lowest organ DOX concentrations. CONCLUSION: Iv DPPG2-TSL-DOX combined with HT achieved higher DOX concentrations in the bladder wall including the detrusor, compared to conventional iv and intravesical DOX application. In combination with lower DOX accumulation in heart and kidneys, compared to iv free chemotherapy, DPPG2-TSL-DOX with HT has great potential to attain a role as a bladder-sparing treatment for MIBC.
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Doxorrubicina/uso terapéutico , Hipertermia Inducida , Músculos/patología , Fosfatidilgliceroles/química , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Animales , Antibióticos Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Doxorrubicina/sangre , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Femenino , Fluorescencia , Humanos , Hipertermia Inducida/efectos adversos , Liposomas , Invasividad Neoplásica , Porcinos , Temperatura , Neoplasias de la Vejiga Urinaria/sangreRESUMEN
In order to prolong the release and reduce the toxicity of anticancer drug - doxorubicin (DOX), delivery systems (DS) using different polyanions have been developed. Structural (size, morphological stability) and functional (encapsulation efficiency, DOX release) characteristics of three types of DS are compared: CaCO3 porous vaterites doped with polyanions by co-precipitation and coating techniques, and DOX-polyanion conjugates. Using scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS), it was shown that the doping enhances the morphological stability of CaCO3-based DS during the DOC loading. Doping of CaCO3 cores by co-precipitation reduces its sizes (up to 1 µm) and DOX encapsulation efficiency. Polyanion-coated CaCO3 cores and polyanion drug conjugates show about 98 w/w% DOX encapsulation. For the first time, it was shown that the release of DOX from developed DS into human blood plasma is more intense (from 1.3 to 3.0 times for different DS) than into model tumour environment.
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Antibióticos Antineoplásicos/administración & dosificación , Carbonato de Calcio/química , Doxorrubicina/administración & dosificación , Antibióticos Antineoplásicos/sangre , Doxorrubicina/sangre , Portadores de Fármacos , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Estabilidad de Medicamentos , Humanos , PolielectrolitosRESUMEN
The widespread clinical use of the cytostatic doxorubicin together with the induction of chronic cardiomyopathy necessitates the conduct of further pharmacokinetic trials. Novel analytical technologies suitable for point-of-care applications can facilitate drug level analyses but might be prone to interferences from structurally similar compounds. Besides the alcohol metabolite doxorubicinol, aglycone metabolites of doxorubicin might affect its determination in plasma. To evaluate their analytical relevance, a validated HPLC method for the quantification of doxorubicin, doxorubicinol and four aglycones was used. The degradation pattern of doxorubicin in plasma under long-term storage was analysed with respect to the formation of aglycone products. In addition, overall 50 clinical samples obtained within the EPOC-MS-001-Doxo trial were analysed. Substantial degradation of doxorubicin in plasma occurred within a storage period of one year, but this did not lead to the formation of aglycones. In clinical samples, 7-deoxydoxorubicinolone was the major aglycone detectable in 35/50 samples and a concentration range of 1.0-12.7 µg L-1. If at all, the other aglycones were only determined in very low concentrations. Therefore, analytical interferences from aglycones seem to be unlikely with the exception of 7-deoxydoxorubicinolone whose concentration accounted for up to 65% of the doxorubicin concentration in the clinical samples analysed.
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Doxorrubicina/sangre , Doxorrubicina/metabolismo , Plasma/química , Cromatografía Líquida de Alta Presión/métodos , Doxorrubicina/análogos & derivados , Monitoreo de Drogas/métodos , HumanosRESUMEN
INTRODUCTION: Doxorubicin is an anthracycline antibiotic used as an anticancer agent. Long-term use of this anticancer agent could accumulate its metabolite, doxorubicinol, and cause cardiomyopathy, due to its cardiotoxicity. This cardiotoxic effect depends on the amount of doxorubicin and doxorubicinol accumulated in the body. This study aimed to analyze doxorubicin and doxorubicinol levels in the blood plasma of breast cancer patients. METHODS: Participants of this study were 30 breast cancer patients who had received doxorubicin in their therapy regimen. The samples were analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), with the Acquity UPLC BEH C18 Waters chromatography column (2.1 x 100 mm : 1.7 µm). Plasma (250 µL) samples were prepared by protein precipitation, using methanol. The mobile phase consisted of 0.1% acetic acid (eluent A) and acetonitrile (eluent B), with gradient elution; the flow rate was 0.15 mL/min and runtime, 7 min. RESULTS AND DISCUSSION: This method was linear in the range of 1-1000 ng/mL for doxorubicin and 0.5-500 ng/mL for doxorubicinol. This method was successfully used to analyze doxorubicin and doxorubicinol, simultaneously, using hexamethylphosphoramide as the internal standard, in the plasma of breast cancer patients. Results showed that the measured concentrations of doxorubicin and doxorubicinol ranged between 12.54-620.01 ng/mL and 1.10-27.00 ng/mL, respectively. The measured cumulative doses of doxorubicin ranged between 48.76 and 319.01 mg/m2; thus, the risk of cardiomyopathy in the surveyed patients was under 4%, according to literature.
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Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/sangre , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/efectos adversos , Doxorrubicina/sangre , Adulto , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Neoplasias de la Mama/sangre , Neoplasias de la Mama/diagnóstico , Doxorrubicina/administración & dosificación , Femenino , Humanos , Persona de Mediana EdadRESUMEN
BACKGROUND: Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDA-approved PEG-liposomes of DOX for the treatment of over 600,000 cancer patients, and it can overcome doxorubicin-induced cardiomyopathy and other side effects and prolong life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment. OBJECTIVE: We intended to prepare a novel DOX liposome that was prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical application. METHODS: DOX liposomes were prepared using the combination of thin-film dispersion ultrasonic method and ammonium sulfate gradient method and the factors that influenced formulation quality were optimized. After formulation, particle size, entrapment efficiency, drug loading, stability, and pharmacokinetics were determined. RESULTS: DOX liposomes were near-spherical morphology with the average size of 90 nm and polydispersity index (PDI) of less than 0.30. The drug loading was up to 7.5%, and the entrapment efficiency was over 80%. The pharmacokinetic studies showed that free DOX could be easily removed and the blood concentration of free DOX group was significantly lower than that of DOX liposomes, which indicated that the novel DOX liposome had a certain sustainedrelease effect. CONCLUSION: In summary, DOX liposome is economical and easy-prepared with prolonged circulation time. Lay Summary: Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDAapproved PEG-liposomes of DOX to treat over 600.000 cancer patients, overcoming doxorubicin- induced cardiomyopathy and other side effects and prolonging life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment. We intend to prepare a novel DOX liposome prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical use. The novel DOX liposome is economical and easy-prepared with prolonged circulation time.
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Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/análogos & derivados , Lecitinas/química , Polietilenglicoles/química , Estearatos/química , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/sangre , Antibióticos Antineoplásicos/química , Preparaciones de Acción Retardada , Doxorrubicina/administración & dosificación , Doxorrubicina/sangre , Doxorrubicina/química , Doxorrubicina/farmacocinética , Composición de Medicamentos , Liberación de Fármacos , Estabilidad de Medicamentos , Inyecciones Intravenosas , Liposomas , Masculino , Tamaño de la Partícula , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacocinética , Ratas Sprague-Dawley , Tecnología FarmacéuticaRESUMEN
Chemically modified peptide apelin-12 ([MeArg1, NLe10]-apelin12, peptide M) is able to reduce reactive oxygen species (ROS) formation, cell death, and metabolic and ionic homeostasis disorders in experimental myocardial ischemia-reperfusion injury. These beneficial effects indicate the therapeutic potential of this compound in cardiovascular diseases. The goals of this work were to optimize the synthesis of peptide M, and to study its proteolytic stability and effect on the heart function of rabbits with doxorubicin (Dox) cardiomyopathy. We have developed a rational method of solid-phase synthesis of peptide M using the Fmoc methodology in combination with the temporary protection of the guanidine function of arginine residues by protonation (salt formation) during the formation of the amide bond. It avoids the formation of by-products, and simplifies the post-synthetic procedures, providing an increase in the yield of the final product of higher purity. Comparative evaluation of the proteolytic stability of peptide M and apelin-12 in human blood plasma was carried out using 1H NMR spectroscopy. It was shown that the half-life of peptide M in plasma is approximately three times longer than that of apelin-12. Intravenous infusion of increasing doses of peptide M caused a gradual increase in left ventricular (LV) fractional shortening and ejection fraction in rabbits after 8 weeks of Dox administration (2 mg/kg weekly). The effect of the modified peptide on LV systolic dysfunction was significantly more pronounced than the effect of apelin-12, which suggests the promise of using this pharmacological agonist of the APJ receptor in patients with heart failure.
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Péptidos y Proteínas de Señalización Intercelular/síntesis química , Técnicas de Síntesis en Fase Sólida/métodos , Animales , Doxorrubicina/sangre , Proteínas del Ojo/sangre , Proteínas del Ojo/síntesis química , Proteínas del Ojo/química , Péptidos y Proteínas de Señalización Intercelular/sangre , Péptidos y Proteínas de Señalización Intercelular/química , Espectroscopía de Resonancia Magnética , Masculino , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/química , ConejosRESUMEN
BACKGROUND: Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships. The aim is to provide a rational dosing concept allowing for a reduction of variability in systemic therapy intensity and subsequently unforeseen side effects. METHODS: Doxorubicin plasma concentrations in paediatric cancer patients were simulated for different treatment schedules using a population pharmacokinetic model which considers age-dependent differences in doxorubicin clearance. Overall drug exposure and peak concentrations were assessed. Simulation results were used to support a three round Delphi consensus procedure with the aim to clarify the pharmacological goals of doxorubicin dosing in young children. A group of 28 experts representing paediatric trial groups and clinical centres were invited to participate in this process. RESULTS: Pharmacokinetic simulations illustrated the substantial differences in therapy intensity associated with current dosing strategies. Consensus among the panel members was obtained on a standardised a priori dose adaptation that individualises doxorubicin doses based on age and body surface area targeting uniform drug exposure across children treated with the same protocol. Further, a reduction of peak concentrations in very young children by prolonged infusion was recommended. CONCLUSIONS: An approach to standardise current dose modification schemes in young children is proposed. The consented concept takes individual pharmacokinetic characteristics into account and involves adaptation of both the dose and the infusion duration potentially improving the safety of doxorubicin administration.
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Antibióticos Antineoplásicos , Doxorrubicina , Neoplasias/tratamiento farmacológico , Adolescente , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/sangre , Antibióticos Antineoplásicos/farmacocinética , Niño , Preescolar , Simulación por Computador , Técnica Delphi , Doxorrubicina/administración & dosificación , Doxorrubicina/sangre , Doxorrubicina/farmacocinética , Humanos , Lactante , Recién Nacido , Modelos Biológicos , Neoplasias/sangre , Neoplasias/metabolismoRESUMEN
The aim of the study was to develop a physiologically-based pharmacokinetic (PBPK) model to describe and predict whole-body disposition of doxorubicin following intravenous administration. The PBPK model was established using previously published data in mice and included 10 tissue compartments: lungs, heart, brain, muscle, kidneys, pancreas, intestine, liver, spleen, adipose tissue, and plasma. Individual tissues were described by either perfusion-limited or permeability-limited models. All parameters were simultaneously estimated and the final model was able to describe murine data with good precision. The model was used for predicting doxorubicin disposition in rats, rabbits, dogs, and humans using interspecies scaling approaches and was qualified using plasma and tissue observed data. Reasonable prediction of the plasma pharmacokinetics and tissue distribution was achieved across all species. In conclusion, the PBPK model developed based on a rich dataset obtained from mice, was able to reasonably predict the disposition of doxorubicin in other preclinical species and humans. Applicability of the model for special populations, such as patients with hepatic impairment, was also demonstrated. The proposed model will be a valuable tool for optimization of exposure profiles of doxorubicin in human patients.
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Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Modelos Biológicos , Adulto , Animales , Antibióticos Antineoplásicos/sangre , Perros , Doxorrubicina/sangre , Femenino , Humanos , Masculino , Ratones , Conejos , Ratas , Especificidad de la Especie , Distribución TisularRESUMEN
For cancer treatment, intratumoral drug injection has many limitations and not commonly adopted. The poly[lactic-co-glycolic acid] (PLGA) has emerged as a promising vehicle to enhance the in vitro/in vivo characteristic of various drugs. We prepared doxorubicin-PLGA microspheres (DOX-PLGA MSs) using the electrospray method. An in vitro elution method was employed to evaluate the release of DOX from the MSs. We performed an in vivo study on rats, in which we directly injected DOX-PLGA MSs into the liver. We measured liver and plasma DOX concentrations to assess local retention and systemic exposure. The mean diameter of the MSs was 6.74⯱â¯1.01⯵m. The in vitro DOX release from the MSs exhibited a 12.3 % burst release on day 1, and 85.8 % of the drug had been released after 30 days. The in vivo tests revealed a higher local drug concentration at the target lobe of the liver than at the adjacent median lobe. In the first week, the DOX concentration in the peripheral blood of the MS group was lower than that of the direct DOX injection group. Based on the measured intrahepatic concentration and plasma pharmacokinetic profiles, DOX-PLGA MSs could be suitable vectors of chemotoxic agents for intratumoral injection.
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Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Sistemas de Liberación de Medicamentos , Microesferas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/sangre , Doxorrubicina/administración & dosificación , Doxorrubicina/sangre , Liberación de Fármacos , Inyecciones Intralesiones , Hígado/química , Hígado/metabolismo , Masculino , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/administración & dosificación , Ratas , Ratas Sprague-Dawley , Espectroscopía Infrarroja por Transformada de Fourier , Propiedades de Superficie , Distribución TisularRESUMEN
Doxorubicin, an anthracycline antitumor antibiotic, acts as a cancer treatment by interfering with the function of DNA. Herein, liquid chromatography-tandem mass spectrometry was for the first time developed and validated for the simultaneous determination of doxorubicin and its major metabolites doxorubicinol, doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinone in mouse plasma. The liquid-liquid extraction of a 10 µL mouse plasma sample with chloroform:methanol (4:1, v/v) and use of the selected reaction monitoring mode led to less matrix effect and better sensitivity. The lower limits of quantification levels were 0.5 ng/mL for doxorubicin, 0.1 ng/mL for doxorubicinol, and 0.01 ng/mL for doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinone. The standard curves were linear over the range of 0.5-200 ng/mL for doxorubicin; 0.1-200 ng/mL for doxorubicinol; and 0.01-50 ng/mL for doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinone in mouse plasma. The intra and inter-day relative standard deviation and relative errors for doxorubicin and its four metabolites at four quality control concentrations were 0.9-13.6% and -13.0% to 14.9%, respectively. This method was successfully applied to the pharmacokinetic study of doxorubicin and its metabolites after intravenous administration of doxorubicin at a dose of 1.3 mg/kg to female BALB/c nude mice.
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Doxorrubicina/análogos & derivados , Doxorrubicina/sangre , Doxorrubicina/metabolismo , Naftacenos/sangre , Plasma/metabolismo , Animales , Antibióticos Antineoplásicos/sangre , Antibióticos Antineoplásicos/metabolismo , Cromatografía Liquida/métodos , Femenino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Espectrometría de Masas en Tándem/métodosRESUMEN
BACKGROUND AND OBJECTIVE: Targeted drug delivery of nanoparticles decorated with site-specific recognition ligands is of considerable interest to minimize cytotoxicity of chemotherapeutics in the normal cells. The study was designed to develop CD-340 antibody-conjugated polylactic-co-glycolic acid (PLGA) nanoparticles loaded with a highly water-soluble potent anticancer drug, doxorubicin (DOX), to specifically deliver entrapped DOX to breast cancer cells. METHODS: The study showed how to incorporate water-soluble drug in a hydrophobic PLGA (85:15) based matrix which otherwise shows poor drug loading due to leaching effect. The optimized formulation was covalently conjugated to anti-human epidermal growth factor receptor-2 (HER2) antibody (CD-340). Surface conjugation of the ligand was assessed by flow cytometry, confocal microscopy, and gel electrophoresis. Selectivity and cytotoxicity of the experimental nanoparticles were tested on human breast cancer cells SKBR-3, MCF-7, and MDA-MB-231. Both CD-340-conjugated and unconjugated nanoparticles were undergone in vitro and in vivo characterization. RESULT: Higher level of incorporation of DOX (8.5% W/W), which otherwise shows poor drug loading due to leaching effect of the highly water-soluble drug, was seen in this method. In HER2-overexpressing tumor xenograft model, radiolabeled antibody-conjugated nanoparticles showed preferentially more of the formulation accumulation in the tumor area when compared to the treatments with the unconjugated one or with the other control groups of mice. The ligand conjugated nanoparticles showed considerable potential in reduction of tumor growth and cardiac toxicity of DOX in mice, a prominent side-effect of the drug. CONCLUSION: In conclusion, CD-340-conjugated PLGA nanoparticles containing DOX preferentially delivered encapsulated drug to the breast cancer cells and in breast tumor and reduced the breast tumor cells by apoptosis. Site-specific delivery of the formulation to neoplastic cells did not affect normal cells and showed a drastic reduction of DOX-related cardiotoxicity.
Asunto(s)
Apoptosis/efectos de los fármacos , Cardiotoxicidad/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Nanopartículas/química , Receptor ErbB-2/metabolismo , Carga Tumoral/efectos de los fármacos , Animales , Anticuerpos/metabolismo , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Doxorrubicina/sangre , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Femenino , Humanos , Cinética , Ratones Endogámicos BALB C , Nanopartículas/ultraestructura , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Distribución Tisular/efectos de los fármacosRESUMEN
INTRODUCTION: Hepatocellular carcinoma is the most common liver malignancy and the third leading cause of cancer death worldwide. One crucial limitation in the pharmacotherapy for this tumour is its chemotherapy-resistant nature produced by the overexpression of several members of the ATP-binding cassette protein family that efflux drugs out of cells, as observed with the breast cancer resistant protein (BCRP). OBJECTIVES: This study aimed to assess the ability of Pluronic® F127 to reverse the multidrug resistance phenotype in two human hepatocellular cell lines. METHODS: PLC/PRF/5 and SKHep1 cells were exposed to Pluronic® F127 at several concentrations. The effect of F127 on BCRP expression (mRNA and protein), mitochondrial transmembrane potential and cell hypodiploidy was assessed. Finally, the effect of this copolymer on cytotoxicity of doxorubicin in both hepatoma cell lines was investigated, as expressed by its reverse resistance index. KEY FINDINGS: It was demonstrated that F127 in both cell lines contributes to chemosensitization, as shown by BCRP down-regulation, an altered mitochondrial transmembrane potential and hypodiploidy and reverse resistance index values. A remarkable dependence of these effects significantly correlated with the copolymer concentration. CONCLUSIONS: These findings further uncover the potential usefulness of this copolymer as multidrug resistance reversal agent, increasing the efficacy of cancer therapies.