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1.
Nat Protoc ; 15(11): 3579-3594, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33028982

RESUMO

Efficient methods to functionalize proteins are essential for the development of many diagnostic and therapeutic compounds, such as fluorescent probes for immunohistochemistry, zirconium-89 radiolabeled mAbs (89Zr-mAbs) for positron emission tomography and antibody-drug conjugates (ADCs). This protocol describes a step-by-step procedure for the light-induced functionalization of proteins with compounds bearing the photochemically active aryl azide group. As an illustration of the potential utility of our approach, this protocol focuses on the synthesis of 89Zr-mAbs using photoactivatable derivatives of the metal ion binding chelate desferrioxamine B (DFO). The light-induced synthesis of 89Zr-mAbs is a unique, one-pot process involving simultaneous radiolabeling and protein conjugation. The photoradiochemical synthesis of purified 89Zr-mAbs, starting from unmodified proteins, [89Zr][Zr(C2O4)4]4- (89Zr-oxalate), and a photoactivatable DFO derivative, can be performed in <90 min. The method can be easily adapted to prepare other radiolabeled proteins, ADCs or fluorescently tagged proteins by using drug molecules or fluorophores functionalized with photoactive moieties.


Assuntos
Anticorpos Monoclonais/química , Imunoconjugados/química , Radioisótopos/química , Zircônio/química , Técnicas de Química Sintética/instrumentação , Técnicas de Química Sintética/métodos , Desenho de Equipamento , Luz , Modelos Moleculares
2.
Int J Nanomedicine ; 15: 6137-6152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884268

RESUMO

Background: Beyond clinical atherosclerosis imaging of vessel stenosis and plaque morphology, early detection of inflamed atherosclerotic lesions by molecular imaging could improve risk assessment and clinical management in high-risk patients. To identify inflamed atherosclerotic lesions by molecular imaging in vivo, we studied the specificity of our radiotracer based on maleylated (Mal) human serum albumin (HSA), which targets key features of unstable atherosclerotic lesions. Materials and Methods: Mal-HSA was radiolabeled with a positron-emitting metal ion, zirconium-89 (89Zr4+). The targeting potential of this probe was compared with unspecific 89Zr-HSA and 18F-FDG in an experimental model of atherosclerosis (Apoe-/- mice, n=22), and compared with wild-type (WT) mice (C57BL/6J, n=21) as controls. Results: PET/MRI, gamma counter measurements, and autoradiography showed the accumulation of 89Zr-Mal-HSA in the atherosclerotic lesions of Apoe-/- mice. The maximum standardized uptake values (SUVmax) for 89Zr-Mal-HSA at 16 and 20 weeks were 26% and 20% higher (P<0.05) in Apoe-/- mice than in control WT mice, whereas no difference in SUVmax was observed for 18F-FDG in the same animals. 89Zr-Mal-HSA uptake in the aorta, as evaluated by a gamma counter 48 h postinjection, was 32% higher (P<0.01) for Apoe-/- mice than in WT mice, and the aorta-to-blood ratio was 8-fold higher (P<0.001) for 89Zr-Mal-HSA compared with unspecific 89Zr-HSA. HSA-based probes were mainly distributed to the liver, spleen, kidneys, bone, and lymph nodes. The phosphor imaging autoradiography (PI-ARG) results corroborated the PET and gamma counter measurements, showing higher accumulation of 89Zr-Mal-HSA in the aortas of Apoe-/- mice than in WT mice (9.4±1.4 vs 0.8±0.3%; P<0.001). Conclusion: 89Zr radiolabeling of Mal-HSA probes resulted in detectable activity in atherosclerotic lesions in aortas of Apoe-/- mice, as demonstrated by quantitative in vivo PET/MRI. 89Zr-Mal-HSA appears to be a promising diagnostic tool for the early identification of macrophage-rich areas of inflammation in atherosclerosis.


Assuntos
Aterosclerose/diagnóstico por imagem , Maleatos/química , Imagem Molecular/métodos , Radioisótopos , Albumina Sérica Humana/química , Zircônio , Animais , Aorta/diagnóstico por imagem , Aorta/patologia , Aterosclerose/patologia , Autorradiografia , Modelos Animais de Doenças , Feminino , Fluordesoxiglucose F18 , Humanos , Marcação por Isótopo , Macrófagos/patologia , Imagem por Ressonância Magnética , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Sondas Moleculares/química , Sondas Moleculares/farmacocinética , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/patologia , Tomografia por Emissão de Pósitrons , Radioisótopos/química , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/química , Distribuição Tecidual , Zircônio/química , Zircônio/farmacocinética
3.
PLoS One ; 15(8): e0236466, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764764

RESUMO

AIM: The present work concerns the comparison of the performances of three systems for dosimetry in RPT that use different techniques for absorbed dose calculation (organ-level dosimetry, voxel-level dose kernel convolution and Monte Carlo simulations). The aim was to assess the importance of the choice of the most adequate calculation modality, providing recommendations about the choice of the computation tool. METHODS: The performances were evaluated both on phantoms and patients in a multi-level approach. Different phantoms filled with a 177Lu-radioactive solution were used: a homogeneous cylindrical phantom, a phantom with organ-shaped inserts and two cylindrical phantoms with inserts different for shape and volume. A total of 70 patients with NETs treated by PRRT with 177Lu-DOTATOC were retrospectively analysed. RESULTS: The comparisons were performed mainly between the mean values of the absorbed dose in the regions of interest. A general better agreement was obtained between Dose kernel convolution and Monte Carlo simulations results rather than between either of these two and organ-level dosimetry, both for phantoms and patients. Phantoms measurements also showed the discrepancies mainly depend on the geometry of the inserts (e.g. shape and volume). For patients, differences were more pronounced than phantoms and higher inter/intra patient variability was observed. CONCLUSION: This study suggests that voxel-level techniques for dosimetry calculation are potentially more accurate and personalized than organ-level methods. In particular, a voxel-convolution method provides good results in a short time of calculation, while Monte Carlo based computation should be conducted with very fast calculation systems for a possible use in clinics, despite its intrinsic higher accuracy. Attention to the calculation modality is recommended in case of clinical regions of interest with irregular shape and far from spherical geometry, in which Monte Carlo seems to be more accurate than voxel-convolution methods.


Assuntos
Lutécio/química , Imagens de Fantasmas/estatística & dados numéricos , Radioisótopos/química , Radiometria/estatística & dados numéricos , Receptores de Peptídeos/isolamento & purificação , Algoritmos , Humanos , Método de Monte Carlo , Doses de Radiação , Receptores de Peptídeos/química , Estudos Retrospectivos
4.
PLoS One ; 15(7): e0235711, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645091

RESUMO

The current knowledge of the half-lives (T1/2) of several radiolanthanides is either affected by a high uncertainty or is still awaiting confirmation. The scientific information deriving from this imprecise T1/2 data has a significant impact on a variety of research fields, e.g., astrophysics, fundamental nuclear sciences, and nuclear energy and safety. The main reason for these shortcomings in the nuclear databases is the limited availability of suitable sample material together with the difficulties in performing accurate activity measurements with low uncertainties. In reaction to the urgent need to improve the current nuclear databases, the long-term project "ERAWAST" (Exotic Radionuclides from Accelerator Waste for Science and Technology) was launched at Paul Scherrer Institute (PSI). In this context, we present a wet radiochemical separation procedure for the extraction and purification of dysprosium (Dy), terbium (Tb), gadolinium (Gd), and samarium (Sm) fractions from highly radioactive tantalum specimens, in order to obtain 154Dy, 157-158Tb, 148,150Gd, and 146Sm samples, needed for T1/2 determination studies. Ion-exchange chromatography was successfully applied for the separation of individual lanthanides. All separations were conducted in aqueous phase. The separation process was monitored via γ-spectrometry using suitable radioactive tracers. Both the purity and the quantification of the desired radiolanthanides were assessed by inductively coupled plasma mass spectrometry. Test experiments revealed that, prior to the Dy, Tb, Gd, and Sm separation, the removal of hafnium, lutetium, and barium from the irradiated tantalum material was necessary to minimize the overall dose rate exposure (in the mSv/h range), as well to obtain pure lanthanide fractions. With the herein proposed separation method, exotic 154Dy, 157-158Tb, 148,150Gd, and 146Sm radionuclides were obtained in sufficient amounts and purity for the preparation of samples for envisaged half-life measurements. During the separation process, fractions containing holmium, europium, and promethium radionuclides were collected and stored for further use.


Assuntos
Elementos da Série dos Lantanídeos/isolamento & purificação , Radioquímica/métodos , Radioisótopos/química , Cromatografia por Troca Iônica , Európio/isolamento & purificação , Meia-Vida , Hólmio/isolamento & purificação , Elementos da Série dos Lantanídeos/química , Extração Líquido-Líquido/métodos , Espectrometria de Massas , Promécio/isolamento & purificação , Espectrometria gama , Tantálio/química
5.
PLoS One ; 15(5): e0229452, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32357150

RESUMO

Most of South Africa's energy is derived from the combustion of coal in pulverized coal-fired power plants (CFPP). However, when compared with the rest of the world, limited information regarding the main radioactive elements (U and Th) and specific radionuclides of interest (K40, Ra226 and Th232) from South African CFPP is available in the public domain. This paper aims to quantify the U, Th and specific radionuclides found in the coal used in selected South African CFPP in comparison to world averages found in literature. The U and Th concentrations were obtained by ICP-MS. The main radionuclides, K40, Ra226 and Th238, were quantified using gamma spectrometry. The U concentration and Th concentrations for the coal used in all the power plants was above the world average of 1.9 mg/kg and 3.2 mg/kg respectively. The coals with the highest Th content originated from the Mpumalanga power plant, while the U content in the Freestate power plant samples was the highest of the three. The concentrations of the K40 were between 88.43±10.75-110.76±8.92 Bq/kg, which are in-line with world averages of 4-785 Bq/kg. Similarly, the Ra226 and Th232 values were between 21.69±2.83-52.63±4.04 Bq/kg and 19.91±1.24-22.97±1.75 Bq/kg respectively, which are also in line with the world averages of 1-206 Bq/kg and 1-170 Bq/kg respectively. Radiological hazard indices such as radium equivalent (Raeq); external hazard index (Hex) and internal hazard index (Hin), that were estimated from these average radionuclide concentrations were less than the prescribed values found in literature. This indicated that no significant health risk was posed by the coal being used from these coal fields.


Assuntos
Carvão Mineral/análise , Centrais Elétricas , Poluentes Radioativos do Solo/isolamento & purificação , Cinza de Carvão/análise , Humanos , Doses de Radiação , Monitoramento de Radiação , Radioisótopos/química , Radioisótopos/isolamento & purificação , Rádio (Elemento)/química , Rádio (Elemento)/isolamento & purificação , Poluentes Radioativos do Solo/química , África do Sul , Espectrometria gama , Tório/química , Tório/isolamento & purificação , Urânio/química , Urânio/isolamento & purificação
6.
Nihon Yakurigaku Zasshi ; 155(3): 159-163, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32378635

RESUMO

Positron emission tomography (PET) is a molecular imaging technique that visualizes pathophysiology in the body using radiotracers at tracer doses (~µg). PET would provide the information regarding not only pharmacokinetics of radiolabeled compounds, but also target engagements, patient selection, and biomarkers. Previously small molecules are widely used as radiotracers, but recently biopharmaceuticals are launched, providing a novel type radiotracer. In general, antibodies are radiolabeled by long physiological half-lives radionuclides such as Cu-64 and Zr-89 because of their slow pharmacokinetics. However, shorter half-lives radiolabeled tracers (C-11 and F-18) might be suitable on the point view of radiation. Now small protein ligands such as affibodies (~7 kDa) are developed as a radiotracer. We are trying to develop a novel approach to label proteins for PET imaging, which are based on radiolabeled amino acids and cell-free protein synthesis system. In this review, we introduced the topics of protein-based PET tracers.


Assuntos
Produtos Biológicos , Tomografia por Emissão de Pósitrons , Proteínas/química , Radioisótopos/química , Radioisótopos de Cobre , Humanos , Zircônio
7.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 37(2): 219-224, 2020 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-32329272

RESUMO

Prostate cancer is the most common tumor of the urinary system, and its mortality rate is second only to lung cancer. With the specific and high expression on the surface of prostate cancer cells, prostate-specific membrane antigen (PSMA) has been an ideal theranostic target of prostate cancer with great clinical significance and research value. Positron emission tomography/computed tomography (PET/CT), a new modality of molecular imaging combining functional metabolic information and anatomical structure, provides high diagnostic performance for cancer detection. This paper mainly reviewed recent progress of PSMA inhibitors labeled by positron-emitting radionuclides for early diagnosis, preoperative staging, response assessment, restaging and metastasis detection of prostate cancer.


Assuntos
Calicreínas/antagonistas & inibidores , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Antígeno Prostático Específico/antagonistas & inibidores , Neoplasias da Próstata/diagnóstico por imagem , Radioisótopos/química , Elétrons , Humanos , Masculino
8.
Inorg Chem ; 59(8): 5728-5741, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32242663

RESUMO

[44/47Sc]Sc3+, [68Ga]Ga3+, and [111In]In3+ are the three most attractive trivalent smaller radiometalnuclides, offering a wide range of distinct properties (emission energies and types) in the toolbox of nuclear medicine. In this study, all three of the metal ions are successfully chelated using a new oxine-based hexadentate ligand, H3glyox, which forms thermodynamically stable neutral complexes with exceptionally high pM values [pIn (34) > pSc (26) > pGa (24.9)]. X-ray diffraction single crystal structures with stable isotopes revealed that the ligand is highly preorganized and has a perfect fit to size cavity to form [Sc(glyox)(H2O)] and [In(glyox)(H2O)] complexes. Quantitative radiolabeling with gallium-68 (RCY > 95%, [L] = 10-5 M) and indium-111 (RCY > 99%, [L] = 10-8 M) was achieved under ambient conditions (RT, pH 7, and 15 min) with very high apparent molar activities of 750 MBq/µmol and 650 MBq/nmol, respectively. Preliminary quantitative radiolabeling of [44Sc]ScCl3 (RCY > 99%, [L] = 10-6 M) was fast at room temperature (pH 7 and 10 min). In vitro experiments revealed exceptional stability of both [68Ga]Ga(glyox) and [111In]In(glyox) complexes against human serum (transchelation <2%) and its suitability for biological applications. Additionally, on chelation with metal ions, H3glyox exhibits enhanced fluorescence, which was employed to determine the stability constants for Sc(glyox) in addition to the in-batch UV-vis spectrophotometric titrations; as a proof-of-concept these complexes were used to obtain fluorescence images of live HeLa cells using Sc(glyox) and Ga(glyox), confirming the viability of the cells. These initial investigations suggest H3glyox to be a valuable chelator for radiometal-based diagnosis (nuclear and optical imaging) and therapy.


Assuntos
Quelantes/farmacologia , Complexos de Coordenação/farmacologia , Corantes Fluorescentes/farmacologia , Oximas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Quelantes/síntese química , Complexos de Coordenação/sangue , Complexos de Coordenação/química , Estabilidade de Medicamentos , Corantes Fluorescentes/química , Radioisótopos de Gálio/química , Células HeLa , Humanos , Radioisótopos de Índio/química , Marcação por Isótopo , Ligantes , Microscopia de Fluorescência/métodos , Oximas/síntese química , Estudo de Prova de Conceito , Radioisótopos/química , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/química , Escândio/química , Termodinâmica
9.
J Med Chem ; 63(9): 4496-4505, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302130

RESUMO

The insertion of single 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres of trans-amide bonds (triazole scan) was recently applied to the 177Lu-labeled tumor-targeting analog of minigastrin, [Nle15]MG11. The reported novel mono-triazolo-peptidomimetics of [Nle15]MG11 showed either improved resistance against enzymatic degradation or a significantly increased affinity toward the target receptor but never both. To enhance further the tumor-targeting properties of the minigastrin analogs, we studied conjugates with multiple amide-to-triazole substitutions for additive or synergistic effects. Promising candidates were identified by modification of two or three amide bonds, which yielded both improved stability and increased receptor affinity of the peptidomimetics in vitro. Biodistribution studies of radiolabeled multi-triazolo-peptidomimetics in mice bearing receptor-positive tumor xenografts revealed up to 4-fold increased tumor uptake in comparison to the all-amide reference compound [Nle15]MG11. In addition, we report here for the first time a linear peptidomimetic with three triazole insertions in its backbone and maintained biological activity.


Assuntos
Antineoplásicos/farmacologia , Gastrinas/farmacologia , Peptidomiméticos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Desenho de Fármacos , Gastrinas/síntese química , Gastrinas/metabolismo , Gastrinas/farmacocinética , Humanos , Lutécio/química , Camundongos , Neoplasias/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacocinética , Ligação Proteica , Radioisótopos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Receptor de Colecistocinina B/metabolismo , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética
10.
J Med Chem ; 63(9): 4484-4495, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32302139

RESUMO

MG11 is a truncated analog of minigastrin, a peptide with high affinity and specificity toward the cholecystokinin-2 receptor (CCK2R), which is overexpressed by different tumors. Thus, radiolabeled MG11 derivatives have great potential for use in cancer diagnosis and therapy. A drawback of MG11 is its fast degradation by proteases, leading to moderate tumor uptake in vivo. We introduced 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres to replace labile amide bonds of the peptide. The "triazole scan" yielded peptidomimetics with improved resistance to enzymatic degradation and/or enhanced affinity toward the CCK2R. Remarkably, our lead compound achieved a 10-fold increase in receptor affinity, resulting in a 2.6-fold improved tumor uptake in vivo. Modeling of the ligand-CCK2R complex suggests that an additional cation-π interaction of the aromatic triazole moiety with the Arg356 residue of the receptor is accountable for these observations. We show for the first time that the amide-to-triazole substitution strategy offers new opportunities in drug development that go beyond the metabolic stabilization of bioactive peptides.


Assuntos
Antineoplásicos/farmacologia , Gastrinas/farmacologia , Peptidomiméticos/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Feminino , Gastrinas/síntese química , Gastrinas/metabolismo , Gastrinas/farmacocinética , Humanos , Lutécio/química , Camundongos , Neoplasias/metabolismo , Peptidomiméticos/síntese química , Peptidomiméticos/metabolismo , Peptidomiméticos/farmacocinética , Ligação Proteica , Conformação Proteica , Radioisótopos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Receptor de Colecistocinina B/metabolismo , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética
11.
Int J Nanomedicine ; 15: 1253-1266, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161456

RESUMO

Purpose: This study aimed to develop a chelate-free radiolabeled nanoparticle platform for simultaneous positron emission tomography (PET) and magnetic resonance (MR) imaging that provides contrast-enhanced diagnostic imaging and significant image quality gain by integrating the high spatial resolution of MR with the high sensitivity of PET. Methods: A commercially available super-paramagnetic iron oxide nanoparticle (SPION) (Feraheme®, FH) was labeled with the [89Zr]Zr using a novel chelate-free radiolabeling technique, heat-induced radiolabeling (HIR). Radiochemical yield (RCY) and purity (RCP) were measured using size exclusion chromatography (SEC) and radio-thin layer chromatography (radio-TLC). Characterization of the non-radioactive isotope 90Zr-labeled FH was performed by transmission electron microscopy (TEM). Simultaneous PET-MR phantom imaging was performed with different 89Zr-FH concentrations. The MR quantitative image analysis determined the contrast-enhancing properties of FH. The signal-to-noise ratio (SNR) and full-width half-maximum (FWHM) of the line spread function (LSF) were calculated before and after co-registering the PET and MR image data. Results: High RCY (92%) and RCP (98%) of the [89Zr]Zr-FH product was achieved. TEM analysis confirmed the 90Zr atoms adsorption onto the SPION surface (≈ 10% average radial increase). Simultaneous PET-MR scans confirmed the capability of the [89Zr]Zr-FH nano-platform for this multi-modal imaging technique. Relative contrast image analysis showed that [89Zr]Zr-FH can act as a dual-mode T1/T2 contrast agent. For co-registered PET-MR images, higher spatial resolution (FWHM enhancement ≈ 3) and SNR (enhancement ≈ 8) was achieved at a clinical dose of radio-isotope and Fe. Conclusion: Our results demonstrate FH is a highly suitable SPION-based platform for chelate-free labeling of PET tracers for hybrid PET-MR. The high RCY and RCP confirmed the robustness of the chelate-free HIR technique. An overall image quality gain was achieved compared to PET- or MR-alone imaging with a relatively low dosage of [89Zr]Zr-FH. Additionally, FH is suitable as a dual-mode T1/T2 MR image contrast agent.


Assuntos
Imagem por Ressonância Magnética/métodos , Nanopartículas de Magnetita/química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/química , Cromatografia em Gel , Cromatografia em Camada Delgada , Meios de Contraste/química , Óxido Ferroso-Férrico/química , Humanos , Nanopartículas de Magnetita/uso terapêutico , Imagens de Fantasmas , Radioisótopos/química , Razão Sinal-Ruído , Zircônio/química
12.
Int J Nanomedicine ; 15: 31-47, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021163

RESUMO

Purpose: Using our chelate-free, heat-induced radiolabeling (HIR) method, we show that a wide range of metals, including those with radioactive isotopologues used for diagnostic imaging and radionuclide therapy, bind to the Feraheme (FH) nanoparticle (NP), a drug approved for the treatment of iron anemia. Material and methods: FH NPs were heated (120°C) with nonradioactive metals, the resulting metal-FH NPs were characterized by inductively coupled plasma mass spectrometry (ICP-MS), dynamic light scattering (DLS), and r1 and r2 relaxivities obtained by nuclear magnetic relaxation spectrometry (NMRS). In addition, the HIR method was performed with [90Y]Y3+, [177Lu]Lu3+, and [64Cu]Cu2+, the latter with an HIR technique optimized for this isotope. Optimization included modifying reaction time, temperature, and vortex technique. Radiochemical yield (RCY) and purity (RCP) were measured using size exclusion chromatography (SEC) and thin-layer chromatography (TLC). Results: With ICP-MS, metals incorporated into FH at high efficiency were bismuth, indium, yttrium, lutetium, samarium, terbium and europium (>75% @ 120 oC). Incorporation occurred with a small (less than 20%) but statistically significant increases in size and the r2 relaxivity. An improved HIR technique (faster heating rate and improved vortexing) was developed specifically for copper and used with the HIR technique and [64Cu]Cu2+. Using SEC and TLC analyses with [90Y]Y3+, [177Lu]Lu3+ and [64Cu]Cu2+, RCYs were greater than 85% and RCPs were greater than 95% in all cases. Conclusion: The chelate-free HIR technique for binding metals to FH NPs has been extended to a range of metals with radioisotopes used in therapeutic and diagnostic applications. Cations with f-orbital electrons, more empty d-orbitals, larger radii, and higher positive charges achieved higher values of RCY and RCP in the HIR reaction. The ability to use a simple heating step to bind a wide range of metals to the FH NP, a widely available approved drug, may allow this NP to become a platform for obtaining radiolabeled nanoparticles in many settings.


Assuntos
Óxido Ferroso-Férrico/química , Marcação por Isótopo/métodos , Nanopartículas/química , Radioisótopos/química , Quelantes/química , Cromatografia em Gel , Radioisótopos de Cobre/química , Difusão Dinâmica da Luz , Lutécio/química , Espectroscopia de Ressonância Magnética , Compostos Radiofarmacêuticos/química
13.
J Med Chem ; 63(5): 1964-1977, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32048838

RESUMO

Bacterial infections remain a major threat to humanity and are a leading cause of death and disability. Antimicrobial resistance has been declared as one of the top ten threats to human health by the World Health Organization, and new technologies are urgently needed for the early diagnosis and monitoring of deep-seated and complicated infections in hospitalized patients. This review summarizes the radiotracers as applied to imaging of bacterial infections. We summarize the recent progress in the development of pathogen-specific imaging and the application of radiotracers in understanding drug pharmacokinetics as well as the local biology at the infection sites. We also highlight the opportunities for medicinal chemists in radiotracer development for bacterial infections, with an emphasis on target selection and radiosynthetic approaches. Imaging of infections is an emerging field. Beyond clinical applications, these technologies could provide unique insights into disease pathogenesis and expedite bench-to-bedside translation of new therapeutics.


Assuntos
Bactérias/metabolismo , Infecções Bacterianas/metabolismo , Desenvolvimento de Medicamentos/tendências , Imagem Molecular/tendências , Traçadores Radioativos , Animais , Bactérias/química , Infecções Bacterianas/diagnóstico , Desenvolvimento de Medicamentos/métodos , Humanos , Imagem Molecular/métodos , Radioisótopos/química , Radioisótopos/metabolismo
14.
Inorg Chem ; 59(3): 1985-1995, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31976659

RESUMO

44Sc is an attractive positron-emitting radionuclide for PET imaging; herein, a new complex of the Sc3+ ion with nonmacrocyclic chelator H4pypa was synthesized and characterized with high-resolution electrospray-ionization mass spectrometry (HR-ESI-MS), as well as different nuclear magnetic resonance (NMR) spectroscopic techniques (1H, 13C, 1H-13C HSQC, 1H-13C HMBC, COSY, and NOESY). In aqueous solution (pH = 7), [Sc(pypa)]- presented two isomeric forms, the structures of which were predicted using density functional theory (DFT) calculation with a small energy difference of 22.4 kJ/mol, explaining their coexistence. [Sc(pypa)]- was found to have superior thermodynamic stability (pM = 27.1) compared to [Sc(AAZTA)]- (24.7) and [Sc(DOTA)]- (23.9). In radiolabeling, [44Sc][Sc(pypa)]- formed efficiently at RT in 15 min over a range of pH (2-5.5), resulting in a complex that is highly stable (>99%) in mouse serum over at least six half-lives of scandium-44. Similar labeling efficiency was observed with the PSMA (prostate-specific membrane antigen)-targeting H4pypa-C7-PSMA617 at pH = 5.5 (RT, 15 min), confirming negligible disturbance from the bifunctionalization on scandium-44 scavenging. Moreover, the kinetic inertness of the radiocomplex was proved in vivo. Surprisingly, the molar activity was found to have profound influence on the pharmacokinetics of the radiotracers where lower molar activity drastically reduced the background accumulations, particularly, kidney, and thus, yielded a much higher tumor-to-background contrast.


Assuntos
Quelantes/química , Complexos de Coordenação/química , Neoplasias Experimentais/diagnóstico por imagem , Antígeno Prostático Específico/análise , Radioisótopos/química , Compostos Radiofarmacêuticos/química , Escândio/química , Termodinâmica , Animais , Quelantes/síntese química , Quelantes/farmacocinética , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacocinética , Teoria da Densidade Funcional , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Tomografia por Emissão de Pósitrons , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Escândio/farmacocinética , Distribuição Tecidual
15.
PLoS One ; 15(1): e0223814, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31910217

RESUMO

INTRODUCTION: Chimeric antigen receptor (CAR) T-cells have been recently developed and are producing impressive outcomes in patients with hematologic malignancies. However, there is no standardized method for cell trafficking and in vivo CAR T-cell monitoring. We assessed the feasibility of real-time in vivo 89Zr-p-Isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS, DFO) labeled CAR T-cell trafficking using positron emission tomography (PET). RESULTS: The 89Zr-DFO radiolabeling efficiency of Jurkat/CAR and human peripheral blood mononuclear cells (hPBMC)/CAR T-cells was 70%-79%, and cell radiolabeling activity was 98.1-103.6 kBq/106 cells. Cell viability after radiolabeling was >95%. Cell proliferation was not significantly different during the early period after radiolabeling, compared with unlabeled cells; however, the proliferative capacity decreased over time (day 7 after labeling). IL-2 or IFN-γ secretion was not significantly different between unlabeled and labeled CAR T-cells. PET/magnetic resonance imaging in the xenograft model showed that most of the 89Zr-DFO-labeled Jurkat/CAR T-cells were distributed in the lung (24.4% ± 3.4%ID) and liver (22.9% ± 5.6%ID) by one hour after injection. The cells gradually migrated from the lung to the liver and spleen by day 1, and remained stable in these sites until day 7 (on day 7: lung 3.9% ± 0.3%ID, liver 36.4% ± 2.7%ID, spleen 1.4% ± 0.3%ID). No significant accumulation of labeled cells was identified in tumors. A similar pattern was observed in ex vivo biodistributions on day 7 (lung 3.0% ± 1.0%ID, liver 19.8% ± 2.2%ID, spleen 2.3% ± 1.7%ID). 89Zr-DFO-labeled hPBMC/CAR T-cells showed a similar distribution, compared with Jurkat/CAR T-cells, on serial PET images. CAR T cell distribution was cross-confirmed by flow cytometry, Alu polymerase chain reaction, and immunohistochemistry. CONCLUSION: Real-time in vivo cell trafficking is feasible using PET imaging of 89Zr-DFO-labeled CAR T-cells. This can be used to investigate cellular kinetics, initial in vivo biodistribution, and safety profiles in future CAR T-cell development.


Assuntos
Desferroxamina/análogos & derivados , Isotiocianatos/farmacologia , Radioisótopos/farmacologia , Receptores de Antígenos de Linfócitos T/isolamento & purificação , Receptores de Antígenos Quiméricos/isolamento & purificação , Zircônio/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desferroxamina/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Humanos , Imunoconjugados/farmacologia , Marcação por Isótopo , Células Jurkat , Leucócitos Mononucleares/química , Leucócitos Mononucleares/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Radioisótopos/química , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/química , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/química , Linfócitos T/imunologia , Distribuição Tecidual
16.
Carbohydr Polym ; 231: 115652, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31888820

RESUMO

Hyaluronan (HA) have been widely used as the ideal biomaterials. It is important to understand their degradation and distribution for better optimization. From a new aspect of using radiotracers, we designed the HA-tyramine-bisphosphonate derivative for dual-labelling with two radionuclides (99mTc and 131I) simultaneously for in vitro and in vivo tracking. This dual-radiolabelled HA derivative can still be non-covalently crosslinked by hydroxyapatites to form injectable gel. The excellent properties of the gel, such as robust, biodegradable, and self-healing capacity were maintained. We firstly proved the possibility to distinguish different radionuclides in the degraded gel using the high-resolution gamma-ray spectrometry. The radiolabelled gel showed lower toxicity than pure hydroxyapatites against various cell lines, while the in vivo results proved that the 99mTc/131I-labelling of the gel was safe and stable enough for imaging and quantitatively tracking. The present method can also be applied for the development of dual-radiolabelled gels from other polysaccharides.


Assuntos
Meios de Contraste/farmacologia , Difosfonatos/química , Géis/química , Radioisótopos/química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Plásticos Biodegradáveis/química , Plásticos Biodegradáveis/farmacologia , Meios de Contraste/química , Difosfonatos/farmacologia , Raios gama , Géis/farmacologia , Humanos , Ácido Hialurônico/química , Radioisótopos do Iodo/química , Radioisótopos do Iodo/farmacologia , Radioisótopos/farmacologia , Análise Espectral , Tecnécio/química , Tecnécio/farmacologia , Engenharia Tecidual/métodos , Tiramina/química , Tiramina/farmacologia
17.
J Nucl Med ; 61(1): 152-161, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31896726

RESUMO

The quantitative accuracy and image quality of multi-isotope SPECT is affected by various hardware-related perturbations. The present study evaluates the simultaneous acquisition of multiple isotopes using a multiplexed multi-pinhole SPECT system, assesses the extent of different error sources, and proposes experimental procedures for its objective characterization. Methods: Phantom measurements with single-, dual- and triple-isotope combinations of 99mTc, 111In, 123I, 177Lu, and 201Tl were performed with the NanoSPECT/CTPLUS to evaluate system energy resolution, count rate performance, sensitivity, collimator penetration, hardware versus object scatter, spectral crosstalk, spatial resolution, spatial registration accuracy, image uniformity, image noise, and image quality. Results: The intrinsic detector properties were suitable for the simultaneous acquisition of up to 3 isotopes with limitations for count rates exceeding 104 kcps and γ-energies lower than 75 keV. Spectral crosstalk between isotopes was more likely mediated by hardware than by source scatter and was strongly dependent on the isotope combination. Simultaneous multi-isotope acquisitions slightly degraded spatial resolution and image uniformity for spatially superimposed but not for spatially separated activity distributions while the background noise level was increased for all multi-isotope studies. For particular isotopes, collimator penetration and x-ray fluorescence contributed a significant portion of error. Conclusion: The NanoSPECT/CTPLUS enables the simultaneous acquisition of 3 radioisotopes with high quantitative accuracy and only little loss of image quality when the activity ratio is adapted to isotope-specific count rate sensitivities and when the system calibration is performed with phantoms of appropriate size.


Assuntos
Tomografia Computadorizada de Emissão de Fóton Único/instrumentação , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tomografia Computadorizada por Raios X/métodos , Algoritmos , Animais , Calibragem , Radioisótopos de Índio/química , Radioisótopos do Iodo/química , Lutécio/química , Camundongos , Imagem Multimodal , Imagens de Fantasmas , Radioisótopos/química , Ratos , Reprodutibilidade dos Testes , Software , Tecnécio/química , Radioisótopos de Tálio/química
18.
Appl Biochem Biotechnol ; 190(2): 540-550, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31396886

RESUMO

Use of nanoparticles as carriers of anticancer drugs is a suitable way for targeted drug delivery and reduction of the side effects. This research focuses on a novel drug carrier for therapeutic goals by the bacterial magnetic nanoparticles (magnetosomes). The unique characteristics of magnetosomes make them ideal nanobiotechnological materials. In this study, magnetic nanoparticles of Alphaproteobacterium MTB-KTN90 were labeled with the radioisotope rhenium-188 and optimized the factors affecting the labeling efficiency. The results showed that the labeling efficiency of magnetosomes with rhenium-188 was more than 96%. The optimum concentration of bacterial nanoparticles was 133 mg/ml and the best time for maximum efficiency labeling was 60 min. The labeling stability showed that the 188Re-nanoparticle complexes have good stability in 29 h. The results of magnetic nanoparticles bacterial cytotoxicity on cancer cells AsPC1 did not show significant toxicity to concentration of 100 µg/µl. Finally, the biogenic magnetic nanoparticles labeled with rhenium-188 can be introduced as a valuable candidate for the targeted therapy of tumor with reducing radiation to surrounding healthy tissues.


Assuntos
Alphaproteobacteria/metabolismo , Magnetismo , Nanopartículas , Radioisótopos/química , Radioterapia/métodos , Rênio/química , Linhagem Celular Tumoral , Humanos
19.
J Nucl Med ; 61(3): 453-460, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31562219

RESUMO

The use of 89Zr-antibody PET imaging to measure antibody biodistribution and tissue pharmacokinetics is well established, but current PET systems lack the sensitivity needed to study 89Zr-labeled antibodies beyond 2-3 isotope half-lives (7-10 d), after which a poor signal-to-noise ratio is problematic. However, studies across many weeks are desirable to better match antibody circulation half-life in human and nonhuman primates. These studies investigated the technical feasibility of using the primate mini-EXPLORER PET scanner, making use of its high sensitivity and 45-cm axial field of view, for total-body imaging of 89Zr-labeled antibodies in rhesus monkeys up to 30 d after injection. Methods: A humanized monoclonal IgG antibody against the herpes simplex viral protein glycoprotein D (gD) was radiolabeled with 89Zr via 1 of 4 chelator-linker combinations (benzyl isothiocyanate-DFO [DFO-Bz-NCS], where DFO is desferrioxamine B; DFO-squaramide; DFO*-Bz-NCS, where DFO* is desferrioxamine*; and DFO*-squaramide). The pharmacokinetics associated with these 4 chelator-linker combinations were compared in 12 healthy young male rhesus monkeys (∼1-2 y old, ∼3 ± 1 kg). Each animal was initially injected intravenously with unlabeled antibody in a peripheral vessel in the right arm (10 mg/kg, providing therapeutic-level antibody concentrations), immediately followed by approximately 40 MBq of one of the 89Zr-labeled antibodies injected intravenously in a peripheral vessel in the left arm. All animals were imaged 6 times over a period of 30 d, with an initial 60-min dynamic scan on day 0 (day of injection) followed by static scans of 30-45 min on approximately days 3, 7, 14, 21, and 30, with all acquired using a single bed position and images reconstructed using time-of-flight list-mode ordered-subsets expectation maximization. Activity concentrations in various organs were extracted from the PET images using manually defined regions of interest. Results: Excellent image quality was obtained, capturing the initial distribution phase in the whole-body scan; later time points showed residual 89Zr mainly in the liver. Even at 30 d after injection, representing approximately 9 half-lives of 89Zr and with a total residual activity of only 20-40 kBq in the animal, the image quality was sufficient to readily identify activity in the liver, kidneys, and upper and lower limb joints. Significant differences were noted in late time point liver uptake, bone uptake, and whole-body clearance between chelator-linker types, whereas little variation (±10%) was observed within each type. Conclusion: These studies demonstrate the ability to image 89Zr-radiolabeled antibodies up to 30 d after injection while maintaining satisfactory image quality, as provided by the primate mini-EXPLORER with high sensitivity and long axial field of view. Quantification demonstrated potentially important differences in the behavior of the 4 chelators. This finding supports further investigation.


Assuntos
Quelantes/química , Imunoconjugados/química , Imunoconjugados/farmacocinética , Tomografia por Emissão de Pósitrons , Radioisótopos/química , Irradiação Corporal Total , Zircônio/química , Animais , Desferroxamina/química , Estabilidade de Medicamentos , Imunoconjugados/administração & dosagem , Injeções , Macaca mulatta , Distribuição Tecidual
20.
Clin Cancer Res ; 26(1): 147-158, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31515460

RESUMO

PURPOSE: Small-molecule inhibitors have revolutionized treatment of certain genomically defined solid cancers. Despite breakthroughs in treating systemic disease, central nervous system (CNS) metastatic progression is common, and advancements in treating CNS malignancies remain sparse. By improving drug penetration across a variably permeable blood-brain barrier and diffusion across intratumoral compartments, more uniform delivery and distribution can be achieved to enhance efficacy. EXPERIMENTAL DESIGN: Ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots), were functionalized with αv integrin-binding (cRGD), or nontargeting (cRAD) peptides, and PET labels (124I, 89Zr) to investigate the utility of dual-modality cRGD-C' dots for enhancing accumulation, distribution, and retention (ADR) in a genetically engineered mouse model of glioblastoma (mGBM). mGBMs were systemically treated with 124I-cRGD- or 124I-cRAD-C' dots and sacrificed at 3 and 96 hours, with concurrent intravital injections of FITC-dextran for mapping blood-brain barrier breakdown and the nuclear stain Hoechst. We further assessed target inhibition and ADR following attachment of dasatinib, creating nanoparticle-drug conjugates (Das-NDCs). Imaging findings were confirmed with ex vivo autoradiography, fluorescence microscopy, and p-S6RP IHC. RESULTS: Improvements in brain tumor delivery and penetration, as well as enhancement in the ADR, were observed following administration of integrin-targeted C' dots, as compared with a nontargeted control. Furthermore, attachment of the small-molecule inhibitor, dasatinib, led to its successful drug delivery throughout mGBM, demonstrated by downstream pathway inhibition. CONCLUSIONS: These results demonstrate that highly engineered C' dots are promising drug delivery vehicles capable of navigating the complex physiologic barriers observed in a clinically relevant brain tumor model.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Dasatinibe/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/tratamento farmacológico , Nanopartículas/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Dióxido de Silício/química , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Dasatinibe/química , Modelos Animais de Doenças , Glioblastoma/patologia , Radioisótopos do Iodo/química , Camundongos , Nanopartículas/química , Gradação de Tumores , Oligopeptídeos/química , Tomografia por Emissão de Pósitrons/métodos , Inibidores de Proteínas Quinases/química , Radioisótopos/química , Zircônio/química
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