RESUMO
PEGylation is currently used for the synthesis of stealth liposomes and to enhance the pharmacokinetic and biopharmaceutical properties of payloads. PEGylated dendron phospholipids can decrease the detachment of polyethylene glycol (PEG) from the liposomal surface owing to an increased hydrophobic anchoring effect on the phospholipid bilayer of liposomes and thus generating super stealth liposomes that are suitable for the systemic delivery of anticancer drugs. Herein, doxorubicin hydrochloride-loaded super stealth liposomes were studied for the treatment of breast cancer lung metastasis in an animal model. The results demonstrated that the super stealth liposomes had suitable physicochemical properties for in vivo administration and could significantly increase the efficacy of doxorubicin in breast cancer lung metastasis tumor-bearing mice compared to the free drug. The super stealth liposomes also increased doxorubicin accumulation inside the tumor tissue. The permanence of PEG on the surface of the super stealth liposomes favored the formation of a depot of therapeutic nanocarriers inside the tumor tissue by improving their permanence after stopping treatment. The doxorubicin-loaded super stealth liposomes increased the survival of the mouse tumor model. These promising results demonstrate that the doxorubicin-loaded super stealth liposomes could be an effective nanomedicine to treat metastatic breast cancer.
Assuntos
Neoplasias da Mama , Doxorrubicina , Lipossomos , Polietilenoglicóis , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Animais , Lipossomos/química , Polietilenoglicóis/química , Polietilenoglicóis/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Camundongos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Humanos , Linhagem Celular Tumoral , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Camundongos Endogâmicos BALB C , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinéticaRESUMO
Cerebrovascular impairment represents one of the main causes of death worldwide with a mortality rate of 5.5 million per year. The disability of 50% of surviving patients has high social impacts and costs in long period treatment for national healthcare systems. For these reasons, the efficacious clinical treatment of patients, with brain ischemic stroke, remains a medical need. To this aim, a liposome nanomedicine, with monosialic ganglioside type 1 (GM1), OX26 (an anti-transferrin receptor antibody), and CDP-choline (a neurotrophic drug) (CDP-choline/OX26Lip) was prepared. CDP-choline/OX26Lip were prepared by a freeze and thaw method and then extruded through polycarbonate filters, to have narrow size distributed liposomes of ~80 nm. CDP-choline/OX26Lip were stable in human serum, they had suitable pharmacokinetic properties, and 30.0 ± 4.2% of the injected drug was still present in the blood stream 12 h after its systemic injection. The post-ischemic therapeutic effect of CDP-choline/OX26Lip is higher than CDP-choline/Lip, thus showing a significantly high survival rate of the re-perfused post-ischemic rats, i.e. 96% and 78% after 8 days. The treatment with CDP-choline/OX26Lip significantly decreased the peroxidation rate of ~5-times compared to CDP-choline/Lip; and the resulting conjugated dienes, that was 13.9 ± 1.1 mmol/mg proteins for CDP-choline/Lip and 3.1 ± 0.8 for CDP-choline/OX26Lip. OX26 increased the accumulation of GM1-liposomes in the brain tissues and thus the efficacious of CDP-choline. Therefore, this nanomedicine may represent a strategy for the reassessment of CDP-choline to treat post-ischemic events caused by brain stroke, and respond to a significant clinical need.
RESUMO
Separation and identification of chiral molecules is a topic widely discussed in the literature and of fundamental importance, especially in the pharmaceutical and food fields, both from industrial and laboratory points of view. Several techniques are used to carry out these analyses, but high-performance liquid chromatography is often the "gold standard." The high costs of chiral columns, necessary for this technique, led researchers to look for an alternative, and capillary electrophoresis (CE) is a technique capable of overcoming some of the disadvantages of liquid chromatography, often providing comparable results in terms of sensitivity and robustness. We addressed this topic, already widely discussed in the literature, providing an overview of the last 6 years of the most frequent and recent applications of CE. To make the manuscript more effective, we decided to divide it into paragraphs that represent the main field of application, from enantioseparation in complex matrices (pharmacokinetic studies or toxicological dosage of drugs, analysis of environmental pollutants, and analyses of foods) to quality control analyses on pharmaceutical formulas. About these, which are the fields of most meaningful use, we mentioned some of the most innovative and performing methods, with a look to the future on the application of new materials used, such as chiral selectors, that can make these types of analyses accessible to all, reducing cost, time, and excessive use of toxic solvents.
Assuntos
Eletroforese Capilar , Eletroforese Capilar/métodos , Cromatografia Líquida , Estereoisomerismo , Cromatografia Líquida de Alta Pressão , Preparações FarmacêuticasRESUMO
The present study focuses on the development and validation of an HPLC-DAD methodology for the detection of a potent chemotherapeutic agent, Maytansinoid Ravtansine (DM4), and its metabolite, S-methyl-DM4 (S-Me-DM4), in plasma samples. Methodologically, after a simple protein precipitation with acetonitrile and after drying 1 mL of supernatant, the sample (suspended with N,N-Dimethylacetamide, DMA) was directly analyzed by HPLC under isocratic elution using a mobile phase comprising milliQ water and methanol (25:75, v:v), both acidified with 0.1 % v:v formic acid. Employing a flow rate of 1.0 mL/min and a reversed-phase GraceSmart RP18 column thermostated at 40 °C, we achieved complete resolution and separation of DM4 and S-Me-DM4 within 13 min. The optimized injection volume of 20 µL and the wavelength set at 254 nm were utilized for quantitative analyses. Rigorous validation has not only ensured its reliability and reproducibility but has also addressed potential limitations associated with methodological inconsistency. The limit of detection and quantification of the method were 0.025 and 0.06 µg/mL for both the analytes, respectively. The calibration curve showed a good linearity in the range 0.06-20 µg/mL. For both analytes, the intraday precision and trueness were 2.3-8.2 % and -1.1 to 3.1 %, respectively, while the interday values were 0.7-10.1 % and -10.4 to 7.5 %, respectively. The developed methodology enables the concurrent determination and quantification of free DM4 and its metabolite, free S-Me-DM4, making it a valuable tool for assessing the pharmacokinetics and pharmacodynamics of DM4-based therapies. In addition, the procedure was successfully applied to analyse the presence of free DM4 or its metabolite, free S-Me-DM4, in human plasma samples spiked with the 1959-sss/DM4 antibody-drug conjugate (ADC). The utilization of the herein validated methodology allowed to confirm the presence of these analytes, thereby providing insights into their potential release from the ADC structure.
Assuntos
Maitansina , Humanos , Reprodutibilidade dos Testes , Cromatografia Líquida de Alta Pressão/métodos , Preparações FarmacêuticasRESUMO
Nowadays, it is vital to have new, complete, and rapid methods to screen and follow pharmacotoxicological and forensic cases. In this context, an important role is undoubtedly played by liquid chromatography-tandem mass spectrometry (LC-MS/MS) thanks to its advanced features. This instrument configuration can offer comprehensive and complete analysis and is a very potent analytical tool in the hands of analysts for the correct identification and quantification of analytes. The present review paper discusses the applications of LC-MS/MS in pharmacotoxicological cases because it is impossible to ignore the importance of this powerful instrument for the rapid development of pharmacological and forensic advanced research in recent years. On one hand, pharmacology is fundamental for drug monitoring and helping people to find the so-called "personal therapy" or "personalized therapy". On the other hand, toxicological and forensic LC-MS/MS represents the most critical instrument configuration applied to the screening and research of drugs and illicit drugs, giving critical support to law enforcement. Often the two areas are stackable, and for this reason, many methods include analytes attributable to both fields of application. In this manuscript, drugs and illicit drugs were divided in separate sections, with particular attention paid in the first section to therapeutic drug monitoring (TDM) and clinical approaches with a focus on central nervous system (CNS). The second section is focused on the methods developed in recent years for the determination of illicit drugs, often in combination with CNS drugs. All references considered herein cover the last 3 years, except for some specific and peculiar applications for which some more dated but still recent articles have been considered.