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1.
Int J Pharm X ; 2: 100055, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32984812

RESUMO

Highly porous 3D-scaffolds, made from cut, electrospun PLA fibers, are relatively new and promising systems for controlled drug-delivery applications. Because knowledge concerning fundamental processes of drug delivery from those scaffolds is limited, we noninvasively characterized drug-loading and drug-release mechanisms of these polymer-fiber sponges (PFS). We screened simplified PFS-implantation scenarios with EPR and µCT to quantify and 3D-visualize the absorption of model-biofluids and an oil, a possible drug-loading liquid. Saturation of PFS (6 × 8 mm, h x d) is governed by the high hydrophobicity of the material and air-entrapment. It required up to 45 weeks for phosphate-buffered saline and 11 weeks for a more physiological, surface-active protein-solution, indicating the slow fluid-uptake of PFS as an effective mechanism to substantially prolong the release of a drug incorporated within the scaffold. Medium-chain triglycerides, as a good wetting liquid, saturated PFS within seconds, suggesting PFS potential to serve as carrier-vessels for immobilizing hydrophobic drug-solutions to define a liquid's 3D-interface. Oil-retention under mechanical stress was therefore investigated. 1H NMR permitted insights into PFS-oil interaction, confirming surface-relaxation and restricted diffusion; both did not influence drug release from oil-loaded PFS. Results facilitate better understanding of PFS and their potential use in drug delivery.

2.
Mol Imaging Biol ; 21(6): 1182-1191, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30945122

RESUMO

PURPOSE: The enzyme O6-methylguanine-DNA methyltransferase (MGMT) is an important component of the DNA repair machinery. MGMT removes O6-methylguanine from the DNA by transferring the methyl group to a cysteine residue in its active site. Recently, we detected the single nucleotide polymorphism (SNP) rs12917 (C/T) in the MGMT sequence adjacent to the active site in Hodgkin lymphoma (HL) cell line KM-H2. We now investigated whether this SNP is also present in other HL cell lines and patient samples. Furthermore, we asked whether this SNP might have an impact on metabolic response in 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET), and on overall treatment outcome based on follow-up intervals of at least 34 months. PROCEDURES: We determined the frequency of this MGMT polymorphism in 5 HL cell lines and in 29 pediatric HL (PHL) patients. The patient cohort included 17 female and 12 male patients aged between 4 and 18 years. After characterization of the sequence, we tested a possible association between rs12917 and age, gender, Ann Arbor stage, treatment group, metabolic response following two courses of OEPA (vincristine, etoposide, prednisone, and doxorubicin) chemotherapy, radiotherapy indication, and relapse status. RESULTS: We detected the minor T allele in four of five HL cell lines. 11/29 patients carried the minor T allele whereas 18/29 patients showed homozygosity for the major C allele. Interestingly, we observed significantly better metabolic response in PHL patients carrying the rs12917 C allele resulting in a lower frequency of radiotherapy indication. CONCLUSION: MGMT polymorphism rs12917 seems to affect chemotherapy response in PHL. The prognostic value of this polymorphism should be investigated in a larger patient cohort.


Assuntos
Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Fluordesoxiglucose F18/química , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/genética , Polimorfismo de Nucleotídeo Único/genética , Tomografia por Emissão de Pósitrons , Proteínas Supressoras de Tumor/genética , Adolescente , Sequência de Bases , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Humanos , Masculino
3.
BMC Cancer ; 18(1): 941, 2018 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-30285657

RESUMO

BACKGROUND: Chronic active Epstein-Barr virus (EBV) infection (CAEBV) of the T-/NK-cell type, systemic form is a rare and potentially life-threatening illness caused by persistent EBV infection. The highest incidence is found in children and adolescents with increased frequency among Asians and Native Americans, while the disease is uncommon in Western countries. Typically patients present with unspecific symptoms, like fever, lymphadenopathy, hepatosplenomegaly and liver dysfunction. Due to fatal complications including hemophagocytic syndrome, coagulopathy, multiple organ failure and development of EBV-positive lymphoproliferative disease (LPD) or lymphoma early diagnosis is critical for successful treatment. However, in consequence of the lack of experience due to the low incidence in Europe, a broad spectrum of clinical manifestations and a particularly unexpected group of patients, diagnosis can be challenging. Inhere we describe the clinicopathological findings of an African adult with CAEBV associated LPD with a brief review of the literature. CASE PRESENTATION: A 42-year-old African man with fever, enlargement of the spleen and a suspected epileptic seizure was referred to our hospital. Diagnostic testing repeatedly revealed a massive EBV-DNA load in peripheral blood. Whole-body PET-CT-scan presented a strong uptake at multiple bone marrow sites, the thyroid and the adrenal glands. Histopathological analysis of bone marrow and thyroid gland revealed a highly proliferating, atypical and predominantly intravascular cytotoxic T-cell population with intracellular EBV-encoded RNA. Clonality analysis revealed the presence of polyclonal T-cell-receptor. Based on these findings a CAEBV of the T-/NK-cell type, systemic form was diagnosed. Subsequent therapy including three cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisolone resulted in decreased EBV load, clinical improvement and ongoing complete remission. CONCLUSION: Adult-onset CAEBV of T/NK-cell type usually comprises a poor prognosis and is extremely rare in Western countries. Therefore, our case highlights the need for a clinical awareness of this disease in patients with systemic illness and for a comprehensive multidisciplinary diagnostic approach to facilitate diagnosis. Treatment options include antiviral drugs, immunosuppressive agents and systemic chemotherapy with or without allogeneic stem cell transplantation. Given the limited data these options need to be decided upon in each patient individually considering severity of the disease, comorbidities and response.


Assuntos
Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/fisiologia , Subpopulações de Linfócitos T/virologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Biópsia , População Negra , Doença Crônica , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/imunologia , Humanos , Imunofenotipagem , Linfonodos/metabolismo , Linfonodos/patologia , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prednisona/uso terapêutico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Migrantes , Resultado do Tratamento , Vincristina/uso terapêutico , Carga Viral
4.
Mol Imaging Biol ; 20(3): 457-464, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29063303

RESUMO

PURPOSE: Determining the glomerular filtration rate (GFR) is essential for clinical medicine but also for pre-clinical animal studies. Functional imaging using positron emission tomography (PET) allows repetitive almost non-invasive measurements. The aim of the study was the development and evaluation of easily synthesizable PET tracers for GFR measurements in small animals. PROCEDURES: Diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) were labeled with Ga-68. The binding to blood cells and plasma proteins was tested in vitro. The distribution of the tracers in rats was analyzed by PET imaging and ex vivo measurements. From the time-activity-curve of the blood compartment (heart) and the total tracer mass excreted by the kidney, the GFR was calculated. These values were compared directly with the inulin clearance in the same animals. RESULTS: Both tracers did not bind to blood cells. [68Ga]DPTA but not [68Ga]EDTA showed strong binding to plasma proteins. For this reason, [68Ga]DPTA stayed much longer in the blood and only 30 % of the injected dose was eliminated by the kidney within 60 min whereas the excretion of [68Ga]EDTA was 89 ± 1 %. The calculated GFR using [68Ga]EDTA was comparable to the measured inulin clearance in the same animal. Using [68Ga]-DPTA, the measurements led to values which were 80 % below the normal GFR. The results also revealed that definition of the volume of interest for the blood compartment affects the calculation and may lead to a slight overestimation of the GFR. CONCLUSIONS: [68Ga]EDTA is a suitable tracer for GFR calculation from PET imaging in small animals. It is easy to be labeled, and the results are in good accordance with the inulin clearance. [68Ga]DTPA led to a marked underestimation of GFR due to its strong binding to plasma proteins and is therefore not an appropriate tracer for GFR measurements.


Assuntos
Ácido Edético/química , Radioisótopos de Gálio/química , Taxa de Filtração Glomerular , Ácido Pentético/química , Tomografia por Emissão de Pósitrons , Animais , Proteínas Sanguíneas/metabolismo , Eritrócitos/metabolismo , Humanos , Inulina/metabolismo , Masculino , Ratos , Distribuição Tecidual
5.
Appl Radiat Isot ; 122: 72-77, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28113072

RESUMO

99mTc-labeled MAA is commonly used for single photon emission computed tomography SPECT. In contrast, positron emission tomography/CT (PET/CT) delivers images with significantly higher resolution. The generator produced radionuclide 68Ga is widely used for PET/CT imaging agents and 68Ga-labeled MAA represents an attractive alternative to 99mTc-labeled MAA. We report a simple and rapid NaCl based labeling procedure for the labeling of MAA with 68Ga using a commercially available MAA labeling kit for 99mTc. The procedure delivers 68Ga-labeled MAA with a high specific activity and a high labeling efficiency (>99%). The synthesis does not require a final step of separation or the use of organic solvents.

6.
Nat Protoc ; 11(6): 1057-66, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27172166

RESUMO

Gallium-68 ((68)Ga) is a generator-produced radionuclide with a short half-life (t½ = 68 min) that is particularly well suited for molecular imaging by positron emission tomography (PET). Methods have been developed to synthesize (68)Ga-labeled imaging agents possessing certain drawbacks, such as longer synthesis time because of a required final purification step, the use of organic solvents or concentrated hydrochloric acid (HCl). In our manuscript, we provide a detailed protocol for the use of an advantageous sodium chloride (NaCl)-based method for radiolabeling of chelator-modified peptides for molecular imaging. By working in a lead-shielded hot-cell system,(68)Ga(3+) of the generator eluate is trapped on a cation exchanger cartridge (100 mg, ∼8 mm long and 5 mm diameter) and then eluted with acidified 5 M NaCl solution directly into a sodium acetate-buffered solution containing a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or DOTA-like chelator-modified peptide. The main advantages of this procedure are the high efficiency and the absence of organic solvents. It can be applied to a variety of peptides, which are stable in 1 M NaCl solution at a pH value of 3-4 during reaction. After labeling, neutralization, sterile filtration and quality control (instant thin-layer chromatography (iTLC), HPLC and pH), the radiopharmaceutical can be directly administered to patients, without determination of organic solvents, which reduces the overall synthesis-to-release time. This procedure has been adapted easily to automated synthesis modules, which leads to a rapid preparation of (68)Ga radiopharmaceuticals (12-16 min).


Assuntos
Radioisótopos de Gálio/química , Compostos Heterocíclicos com 1 Anel/química , Marcação por Isótopo/métodos , Peptídeos/química , Peptídeos/isolamento & purificação , Cloreto de Sódio/química
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