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1.
J Control Release ; 352: 199-210, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36084816

RESUMO

Liposomes are promising targeted drug delivery systems with the potential to improve the efficacy and safety profile of certain classes of drugs. Though attractive, there are unique analytical challenges associated with the development of liposomal drugs including human dose prediction given these are multi-component drug delivery systems. In this study, we developed a multimodal imaging approach to provide a comprehensive distribution assessment for an antibacterial drug, GSK2485680, delivered as a liposomal formulation (Lipo680) in a mouse thigh model of bacterial infection to support human dose prediction. Positron emission tomography (PET) imaging was used to track the in vivo biodistribution of Lipo680 over 48 h post-injection providing a clear assessment of the uptake in various tissues and, importantly, the selective accumulation at the site of infection. In addition, a pharmacokinetic model was created to evaluate the kinetics of Lipo680 in different tissues. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was then used to quantify the distribution of GSK2485680 and to qualitatively assess the distribution of a liposomal lipid throughout sections of infected and non-infected hindlimb tissues at high spatial resolution. Through the combination of both PET and MALDI IMS, we observed excellent correlation between the Lipo680-radionuclide signal detected by PET with the GSK2485680 and lipid component signals detected by MALDI IMS. This multimodal translational method can reduce drug attrition by generating comprehensive biodistribution profiles of drug delivery systems to provide mechanistic insight and elucidate safety concerns. Liposomal formulations have potential to deliver therapeutics across a broad array of different indications, and this work serves as a template to aid in delivering future liposomal drugs to the clinic.


Assuntos
Doenças Transmissíveis , Lipossomos , Animais , Camundongos , Humanos , Lipossomos/química , Distribuição Tecidual , Antibacterianos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Tomografia por Emissão de Pósitrons , Imagem Multimodal , Lipídeos
2.
Biomed Chromatogr ; 36(1): e5243, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34519076

RESUMO

Sensitive, high-throughput methods for pharmacokinetic (PK) profiling are essential for potential therapeutics during critical stages of clinical trials. The application of a microfluidic capillary zone electrophoresis mass spectrometry (CZE-MS) method for PK profiling allows for rapid, sensitive and in-depth analysis of multiple samples within a short timeframe. Here, a CZE-MS approach for PK analysis was compared with a traditional UHPLC-MS approach when analyzing serum extracts from rats treated with a potential Alzheimer's disease therapeutic, BNC-1. Resulting PK data generated from both methods displayed statistical similarities. Additionally, the separation efficiency attributed to the use of the CZE-MS method provided substantial metabolic regulation data that was not apparent in the UHPLC-MS method. Additionally, the coupling of the CZE-MS method to the data processing software, MZmine2, was used to monitor changes in metabolism and observe putative BNC-1-derived metabolites. The ability to perform fast analyses without sacrificing sensitivity or metabolic information suggests that this CZE-MS method is ideal for metabolomics-inclusive, high-throughput PK profiling.


Assuntos
Eletroforese Capilar/métodos , Espectrometria de Massas/métodos , Naftiridinas/sangue , Doença de Alzheimer , Animais , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Masculino , Naftiridinas/química , Naftiridinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
3.
J Biotechnol ; 342: 28-35, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34648893

RESUMO

The dopamine transporter (DAT) is targeted in substance use disorders (SUDs), and "non-classical"" DAT inhibitors with low abuse potential are therapeutic candidates. Lobinaline, from Lobelia cardinalis, is an atypical DAT inhibitor lead. Chemical synthesis of lobinaline is challenging; thus, "target-directed evolution" was used for lead optimization. A target protein is expressed in plant cells, and a mutant cell population is selected under conditions where target protein functional inhibition confers a survival advantage. Surviving mutants are "mined" for the targeted activity. Applied to a mutant L. cardinalis cell population expressing the human DAT, we identified 20 mutants overproducing DAT inhibitors. Microanalysis prioritized novel lobinaline derivatives, and we first investigated the more water-soluble lobinaline N-oxide. It inhibited rat synaptosomal [3H]DA uptake with an IC50 similar to lobinaline. Against repeated DA microinjections into the rat striatum, lobinaline produced transient DA clearance reductions. In contrast, lobinaline N-oxide prolongingly increased DA peak amplitudes, particularly in the ventral striatum. Lobinaline N-oxide also produced complex changes in post-peak DA clearance inconsistent with simple DAT inhibition. This unusual DAT interaction may prove therapeutically useful for treating SUDs. This study demonstrates the value of target-directed evolution of plant cells for optimizing lead compounds difficult to synthesize chemically.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Lobelia , Animais , Corpo Estriado , Dopamina , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Lobelia/genética , Ratos , Sinaptossomos
4.
Electrophoresis ; 40(22): 2921-2928, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31475363

RESUMO

Application of a microfluidic CE* device for CZE-MS allows for fast, rapid, and in-depth analysis of large sample sets. This microfluidic CZE-MS device, the 908 Devices ZipChip, involves minimal sample preparation and is ideal for small cation analytes, such as alkaloids. Here, we evaluated the microfluidic device for the analysis of alkaloids from Lobelia cardinalis hairy root cultures. Extracts from wild-type, transgenic, and selected mutant plant cultures were analyzed and data batch processed using the mass spectral processing software MZmine2 and the statistical software Prism 8. In total 139 features were detected as baseline resolved peaks via the MZmine2 software optimized for the electrophoretic separations. Statistically significant differences in the relative abundance of the primary alkaloid lobinaline (C27 H34 N2 ), along with several putative "lobinaline-like" molecules were observed utilizing this approach. Additionally, a method for performing both targeted and untargeted MS/MS experiments using the microfluidic device was developed and evaluated. Coupling data-processing software with CZE-MS data acquisition has enabled comprehensive metabolomic profiles from plant cell cultures to be constructed within a single working day.


Assuntos
Alcaloides/análise , Eletroforese Capilar/métodos , Lobelia , Plantas Geneticamente Modificadas , Espectrometria de Massas em Tandem/métodos , Biologia Computacional , Limite de Detecção , Modelos Lineares , Lobelia/química , Lobelia/citologia , Técnicas Analíticas Microfluídicas/métodos , Células Vegetais/química , Extratos Vegetais/química , Plantas Geneticamente Modificadas/química , Plantas Geneticamente Modificadas/citologia , Reprodutibilidade dos Testes
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