RESUMO
Mesenchymal stem/stromal cells (MSCs) are an extensively studied cell type in clinical trials due to their easy availability, substantial ex vivo proliferative capacity, and therapeutic efficacy in numerous pre-clinical animal models of disease. The prevailing understanding suggests that their therapeutic impact is mediated by the secretion of exosomes. Notably, MSC exosomes present several advantages over MSCs as therapeutic agents, due to their non-living nature and smaller size. However, despite their promising therapeutic potential, the clinical translation of MSC exosomes is hindered by an incomplete understanding of their biodistribution after administration. A primary obstacle to this lies in the lack of robust labels that are highly sensitive, capable of directly and easily tagging exosomes with minimal non-specific labeling artifacts, and sensitive traceability with minimal background noise. One potential candidate to address this issue is radioactive iodine. Protocols for iodinating exosomes and tracking radioactive iodine in live imaging are well-established, and their application in determining the biodistribution of exosomes has been reported. Nevertheless, the effects of iodination on the structural or functional activities of exosomes have never been thoroughly examined. In this study, we investigate these effects and report that these iodination methods abrogate CD73 enzymatic activity on MSC exosomes. Consequently, the biodistribution of iodinated exosomes may reflect the biodistribution of denatured exosomes rather than functionally intact ones.
Assuntos
Exossomos , Células-Tronco Mesenquimais , Neoplasias da Glândula Tireoide , Animais , Radioisótopos do Iodo , Distribuição TecidualRESUMO
Quantitative nuclear imaging techniques are in high demand for various disease diagnostics and cancer theranostics. The non-invasive imaging modality requires radiotracing through the radioactive decay emission of the radionuclide. Current preclinical and clinical radiotracers, so-called nuclear imaging probes, are radioisotope-labeled small molecules. Liposomal radiotracers have been rapidly developing as novel nuclear imaging probes. The physicochemical properties and structural characteristics of liposomes have been elucidated to address their long circulation and stability as radiopharmaceuticals. Various radiolabeling methods for synthesizing radionuclides onto liposomes and synthesis strategies have been summarized to render them biocompatible and enable specific targeting. Through a variety of radionuclide labeling methods, radiolabeled liposomes for use as nuclear imaging probes can be obtained for in vivo biodistribution and specific targeting studies. The advantages of radiolabeled liposomes including their use as potential clinical nuclear imaging probes have been highlighted. This review is a comprehensive overview of all recently published liposomal SPECT and PET imaging probes.
Assuntos
Lipossomos , Radioisótopos , Lipossomos/química , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/químicaRESUMO
Yttrium-90 (90Y) microspheres are widely used for the treatment of liver-dominant malignant tumors. They are infused via catheter into the hepatic artery branches supplying the tumor under fluoroscopic guidance based on pre-therapy angiography and Technetium-99m macroaggregated albumin (99mTc-MAA) planning. However, at present, these microspheres are suspended in radiolucent media such as dextrose 5% (D5) solution. In order to monitor the real-time implantation of the microspheres into the tumor, the 90Y microspheres could be suspended in omnipaque contrast for allowing visualization of the correct distribution of the microspheres into the tumor. The radiochemical purity of mixing 90Y-microspheres in various concentrations of omnipaque was investigated. The radiochemical purity and feasibility of mixing 99mTc-MAA with various concentrations of a standard contrast agent were also investigated. Results showed the radiochemical feasibility of mixing 90Y-microspheres with omnipaque is radiochemically acceptable for allowing real-time visualization of radioembolization under fluoroscopy.
Assuntos
Embolização Terapêutica , Neoplasias Hepáticas , Humanos , Microesferas , Agregado de Albumina Marcado com Tecnécio Tc 99m , Iohexol , Estudos de Viabilidade , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Embolização Terapêutica/métodos , Compostos Radiofarmacêuticos , Neoplasias Hepáticas/diagnóstico por imagemRESUMO
Traumatic brain injury (TBI) modelled by lateral fluid percussion-induction (LFPI) in rats is a widely used experimental rodent model to explore and understand the underlying cellular and molecular alterations in the brain caused by TBI in humans. Current improvements in imaging with positron emission tomography (PET) have made it possible to map certain features of TBI-induced cellular and molecular changes equally in humans and animals. The PET imaging technique is an apt supplement to nanotheranostic-based treatment alternatives that are emerging to tackle TBI. The present study aims to investigate whether the two radioligands, [11C]PBR28 and [18F]flumazenil, are able to accurately quantify in vivo molecular-cellular changes in a rodent TBI-model for two different biochemical targets of the processes. In addition, it serves to observe any palpable variations associated with primary and secondary injury sites, and in the affected versus the contralateral hemispheres. As [11C]PBR28 is a radioligand of the 18 kD translocator protein, the up-regulation of which is coupled to the level of neuroinflammation in the brain, and [18F]flumazenil is a radioligand for GABAA-benzodiazepine receptors, whose level mirrors interneuronal activity and eventually cell death, the use of the two radioligands may reveal two critical features of TBI. An up-regulation in the [11C]PBR28 uptake triggered by the LFP in the injured (right) hemisphere was noted on day 14, while the uptake of [18F]flumazenil was down-regulated on day 14. When comparing the left (contralateral) and right (LFPI) hemispheres, the differences between the two in neuroinflammation were obvious. Our results demonstrate a potential way to measure the molecular alterations in a rodent-based TBI model using PET imaging with [11C]PBR28 and [18F]flumazenil. These radioligands are promising options that can be eventually used in exploring the complex in vivo pharmacokinetics and delivery mechanisms of nanoparticles in TBI treatment.
Assuntos
Lesões Encefálicas Traumáticas/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Acetamidas , Animais , Lesões Encefálicas Traumáticas/etiologia , Lesões Encefálicas Traumáticas/patologia , Radioisótopos de Carbono , Modelos Animais de Doenças , Flumazenil , Radioisótopos de Flúor , Masculino , Percussão , Piridinas , Ratos , Ratos Sprague-DawleyRESUMO
In this study, MnFe(2)O(4) nanoparticle (MFNP)-decorated graphene oxide nanocomposites (MGONCs) are prepared through a simple mini-emulsion and solvent evaporation process. It is demonstrated that the loading of magnetic nanocrystals can be tuned by varying the ratio of graphene oxide/magnetic nanoparticles. On top of that, the hydrodynamic size range of the obtained nanocomposites can be optimized by varying the sonication time during the emulsion process. By fine-tuning the sonication time, MGONCs as small as 56.8 ± 1.1 nm, 55.0 ± 0.6 nm and 56.2 ± 0.4 nm loaded with 6 nm, 11 nm, and 14 nm MFNPs, respectively, are successfully fabricated. In order to improve the colloidal stability of MGONCs in physiological solutions (e.g., phosphate buffered saline or PBS solution), MGONCs are further conjugated with polyethylene glycol (PEG). Heating by exposing MGONCs samples to an alternating magnetic field (AMF) show that the obtained nanocomposites are efficient hyperthermia agents. At concentrations as low as 0.1 mg Fe mL(-1) and under an 59.99 kA m(-1) field, the highest specific absorption rate (SAR) recorded is 1588.83 W g(-1) for MGONCs loaded with 14 nm MFNPs. It is also demonstrated that MGONCs are promising as magnetic resonance imaging (MRI) T(2) contrast agents. A T(2) relaxivity value (r(2) ) as high as 256.2 (mM Fe)(-1) s(-1) could be achieved with MGONCs loaded with 14 nm MFNPs. The cytotoxicity results show that PEGylated MGONCs exhibit an excellent biocompatibility that is suitable for biomedical applications.
Assuntos
Compostos Férricos/química , Grafite/química , Compostos de Manganês/química , Nanocompostos/química , Materiais Biocompatíveis/química , Compostos Férricos/toxicidade , Grafite/toxicidade , Humanos , Células MCF-7 , Microscopia Eletrônica de Transmissão , Nanocompostos/toxicidade , Nanotecnologia , Polietilenoglicóis/química , Células Tumorais CultivadasRESUMO
Positron emission tomography (PET) is an extensively used nuclear functional imaging technique, especially for central nervous system (CNS) and oncological disorders. Currently, drug development is a lengthy and costly pursuit. Imaging with PET radiotracers could be an effective way to hasten drug discovery and advancement, because it facilitates the monitoring of key facets, such as receptor occupancy quantification, drug biodistribution, pharmacokinetic (PK) analyses, validation of target engagement, treatment monitoring, and measurement of neurotransmitter concentrations. These parameters demand careful analyses for the robust appraisal of newly formulated drugs during preclinical and clinical trials. In this review, we discuss the usage of PET imaging in radiopharmaceutical development; drug development approaches with PET imaging; and PET developments in oncological and cardiac drug discovery.
Assuntos
Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacologia , Antineoplásicos/farmacologia , Fármacos Cardiovasculares/farmacologia , Monitoramento de Medicamentos/métodos , Humanos , Traçadores RadioativosRESUMO
Nuclear imaging is a powerful non-invasive imaging technique that is rapidly developing in medical theranostics. Nuclear imaging requires radiolabeling isotopes for non-invasive imaging through the radioactive decay emission of the radionuclide. Nuclear imaging probes, commonly known as radiotracers, are radioisotope-labeled small molecules. Nanomaterials have shown potential as nuclear imaging probes for theranostic applications. By modifying the surface of nanomaterials, multifunctional radio-labeled nanomaterials can be obtained for in vivo biodistribution and targeting in initial animal imaging studies. Various surface modification strategies have been developed, and targeting moieties have been attached to the nanomaterials to render biocompatibility and enable specific targeting. Through integration of complementary imaging probes to a single nanoparticulate, multimodal molecular imaging can be performed as images with high sensitivity, resolution, and specificity. In this review, nanomaterial nuclear imaging probes including inorganic nanomaterials such as quantum dots (QDs), organic nanomaterials such as liposomes, and exosomes are summarized. These new developments in nanomaterials are expected to introduce a paradigm shift in nuclear imaging, thereby creating new opportunities for theranostic medical imaging tools.
RESUMO
We describe here a facile and benign synthetic strategy to integrate the fluorescent behavior of conjugated polymers and superparamagnetic properties of iron oxide nanocrystals into silica nanocapsules, forming a new type of bifunctional magnetic fluorescent silica nanocapsule (BMFSN). The resultant BMFSNs are uniform, colloidally stable in aqueous medium, and exhibit the desired dual functionality of fluorescence and superparamagnetism in a single entity. Four conjugated polymers with different emissions were used to demonstrate the versatility of employing this class of fluorescent materials for the preparation of BMFSNs. The applicability of BMFSNs in cellular imaging was studied by incubating them with human liver cancer cells, the result of which demonstrated that the cells could be visualized by dual-mode fluorescence and magnetic resonance imaging. Furthermore, the superparamagnetic behavior of the BMFSNs was exploited for in vitro magnetic-guided delivery of the nanocapsules into the cancer cells, thereby highlighting their potential for targeting biomedical applications.
Assuntos
Compostos Férricos/química , Corantes Fluorescentes/química , Neoplasias Hepáticas/química , Neoplasias Hepáticas/patologia , Nanocápsulas/química , Polímeros/química , Dióxido de Silício/química , Linhagem Celular Tumoral , Fluorescência , Humanos , Imageamento por Ressonância Magnética/métodos , Nanocápsulas/ultraestrutura , NanopartículasRESUMO
Positron emission tomography (PET) offers the study of biochemical, physiological, and pharmacological functions at a cellular and molecular level. The performance of a PET study mostly depends on the used radiotracer of interest. However, the development of a novel PET tracer is very difficult, as it is required to fulfill a lot of important criteria. PET radiotracers usually encounter different chemical modifications including redox reaction, hydrolysis, decarboxylation, and various conjugation processes within living organisms. Due to this biotransformation, different chemical entities are produced, and the amount of the parent radiotracer is declined. Consequently, the signal measured by the PET scanner indicates the entire amount of radioactivity deposited in the tissue; however, it does not offer any indication about the chemical disposition of the parent radiotracer itself. From a radiopharmaceutical perspective, it is necessary to quantify the parent radiotracer's fraction present in the tissue. Hence, the identification of radiometabolites of the radiotracers is vital for PET imaging. There are mainly two reasons for the chemical identification of PET radiometabolites: firstly, to determine the amount of parent radiotracers in plasma, and secondly, to rule out (if a radiometabolite enters the brain) or correct any radiometabolite accumulation in peripheral tissue. Besides, radiometabolite formations of the tracer might be of concern for the PET study, as the radiometabolic products may display considerably contrasting distribution patterns inside the body when compared with the radiotracer itself. Therefore, necessary information is needed about these biochemical transformations to understand the distribution of radioactivity throughout the body. Various published review articles on PET radiometabolites mainly focus on the sample preparation techniques and recently available technology to improve the radiometabolite analysis process. This article essentially summarizes the chemical and structural identity of the radiometabolites of various radiotracers including [11C]PBB3, [11C]flumazenil, [18F]FEPE2I, [11C]PBR28, [11C]MADAM, and (+)[18F]flubatine. Besides, the importance of radiometabolite analysis in PET imaging is also briefly summarized. Moreover, this review also highlights how a slight chemical modification could reduce the formation of radiometabolites, which could interfere with the results of PET imaging.
RESUMO
Activatable cell-penetrating peptide (ACPP) conjugated polymeric nanoparticles containing gadolinium (Gd)-chelates and aggregation-induced emission fluorogens (AIEgens) have been synthesized and applied as a magnetic resonance imaging (MRI) and fluorescence imaging (FI) bimodal imaging probe with active tumor targeting. The polymeric nanoparticles have been generated by dissolving presynthesized linear block copolymers into water directly. With AIEgens, N-BP5-Gd-ACPPs showed tumor cell penetration, which can be characterized by in vitro FI. Preliminary in vivo experiments of Gd-chelated nanoparticles have demonstrated promising characteristics as a tumor-targeting MRI contrast agent with good biocompatibility. This study impacts the synthesis of functional copolymers and polymeric nanoparticles for their applications in bioimaging.
RESUMO
Gd3+-based contrast agents have been extensively used for signal enhancement of T1-weighted magnetic resonance imaging (MRI) due to the large magnetic moment and long electron spin relaxation time of the paramagnetic Gd3+ ion. The key requisites for the development of Gd3+-based contrast agents are their relaxivities and stabilities which can be achieved by chemical modifications. These modifications include coordinating Gd3+ with a chelator such as diethylenetriamine pentaacetic acid (DTPA) or 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), encapsulating Gd3+ in nanoparticles, conjugation to biomacromolecules such as polymer micelles and liposomes, or non-covalent binding to plasma proteins. In order to have a coherent diagnostic and therapeutic approach and to understand diseases better, the combination of MRI and optical imaging (OI) techniques into one technique entity has been developed to overcome the conventional boundaries of either imaging modality used alone through bringing the excellent spatial resolution of MRI and high sensitivity of OI into full play. Novel MRI and OI bimodal probes have been extensively studied in this regard. This review is an attempt to shed some light on the bimodal imaging probes by summarizing all recent noteworthy publications involving Gd3+ containing MR-optical imaging probes. The several key elements such as novel synthetic strategy, high sensitivity, biocompatibility, and targeting of the probes are highlighted in the review. STATEMENT OF SIGNIFICANCE: The present article aims at giving an overview of the existing bimodal MRI and OI imaging probes. The review structured as a series of examples of paramagnetic Gd3+ ions, either as ions in the crystalline structure of inorganic materials or chelates for contrast enhancement in MRI, while they are used as optical imaging probes in different modes. The comprehensive review focusing on the synthetic strategies, characterizations and properties of these bimodal imaging probes will be helpful in a way to prepare related work.
Assuntos
Meios de Contraste , Gadolínio , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Imagem ÓpticaRESUMO
In this report, we present the synthesis and evaluation of six new 64Cu-labeled triphenylphosphonium (TPP) cations. Biodistribution studies were performed using the athymic nude mice bearing U87MG human glioma xenografts to explore the impact of TPP moieties, linkers, bifunctional chelators (BFCs), and molecular charge on biological properties of 64Cu radiotracers. On the basis of the results from this study, it is concluded that (1) mTPP (tris(4-methoxyphenyl)phosphonium) is a better mitochondrion-targeting molecule than TPP and 3mTPP (tris(2,4,6-trimethoxyphenyl)phosphonium); (2) DO3A (1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acid) and DO2A (1,4,7,10-tetraazacyclododecane-4,7-diacetic acid) are suitable BFCs for the 64Cu-labeling of TPP cations; (3) NOTA-Bn ( S-2-(4-thioureidobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid) has a significant adverse effect on the radiotracer tumor uptake and tumor-to-background ratios; and (4) monoanionic BFCs should be avoided to ensure that 64Cu chelate has a neutral or negative charge. Considering the tumor uptake and tumor/liver ratios, 64Cu(DO2A-xy-TPP)+ is the best candidate for more extensive evaluations in different tumor-bearing animal models.
Assuntos
Quelantes/síntese química , Radioisótopos de Cobre , Oniocompostos/síntese química , Compostos Organofosforados/síntese química , Compostos Radiofarmacêuticos/síntese química , Animais , Cátions , Linhagem Celular Tumoral , Quelantes/química , Quelantes/farmacocinética , Eletricidade , Humanos , Fígado/metabolismo , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Nus , Mitocôndrias/fisiologia , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/metabolismo , Oniocompostos/química , Oniocompostos/farmacocinética , Compostos Organofosforados/química , Compostos Organofosforados/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Relação Estrutura-Atividade , Tecnécio Tc 99m Sestamibi/farmacocinética , Distribuição Tecidual , Transplante HeterólogoRESUMO
Radiolabeled organic cations, such as triphenylphosphonium (TPP), represents a new class of radiotracers for imaging cancers and the transport function of multidrug resistance P-glycoproteins (particularly MDR1 Pgp) by single photon emission computed tomography (SPECT) or positron emission tomography (PET). This report presents the synthesis and biological evaluation of (64)Cu-labeled 2-(diphenylphosphoryl)ethyldiphenylphosphonium (TPEP) cations as novel PET radiotracers for tumor imaging. Biodistribution studies were performed using the athymic nude mice bearing subcutaneous U87MG human glioma xenografts to explore the impact of linkers, bifunctional chelators (BFCs), and chelates on biodistribution characteristics of the (64)Cu-labeled TPEP cations. Metabolism studies were carried out using normal athymic nude mice to determine the metabolic stability of four (64)Cu radiotracers. It was found that most (64)Cu radiotracers described in this study have significant advantages over (99m)Tc-Sestamibi for their high tumor/heart and tumor/muscle ratios. Both BFCs and linkers have significant impact on biological properties of (64)Cu-labeled TPEP cations. For example, (64)Cu(DO3A-xy-TPEP) has much lower liver uptake and better tumor/liver ratios than (64)Cu(DO3A-xy-TPP), suggesting that TPEP is a better mitochondrion-targeting molecule than TPP. Replacing DO3A with DO2A results in (64)Cu(DO2A-xy-TPEP) (+), which has a lower tumor uptake than (64)Cu(DO3A-xy-TPEP). Substitution of DO3A with NOTA-Bn leads to a significant decrease in tumor uptake for (64)Cu(NOTA-Bn-xy-TPEP). The use of DOTA-Bn to replace DO3A has little impact on the tumor uptake, but the tumor/liver ratio of (64)Cu(DOTA-Bn-xy-TPEP) (-) is not as good as that of (64)Cu(DO3A-xy-TPEP), probably due to the aromatic benzene ring in DOTA-Bn. Addition of an extra acetamido group in (64)Cu(DOTA-xy-TPEP) results in a lower liver uptake, but tumor/liver ratios of (64)Cu(DOTA-xy-TPEP) and (64)Cu(DO3A-xy-TPEP) are comparable due to a faster tumor washout of (64)Cu(DOTA-xy-TPEP). Substitution of xylene with the PEG 2 linker also leads to a significant reduction in both tumor and liver uptake. MicroPET imaging studies on (64)Cu(DO3A-xy-TPEP) in athymic nude mice bearing U87MG glioma xenografts showed that the tumor was clearly visualized as early as 1 h postinjection with very high T/B contrast. There was very little metabolite (<2%) detectable in the urine and feces samples for (64)Cu(DO3A-xy-TPEP), (64)Cu(DOTA-Bn-xy-TPEP)(-), and (64)Cu(NOTA-Bn-xy-TPEP). Considering both tumor uptake and T/B ratios (particularly tumor/heart, tumor/liver, and tumor/muscle), it was concluded that (64)Cu(DO3A-xy-TPEP) is a promising PET radiotracer for imaging the MDR-negative tumors.
Assuntos
Quelantes/farmacologia , Radioisótopos de Cobre/química , Neoplasias/diagnóstico por imagem , Compostos Organofosforados/farmacocinética , Animais , Linhagem Celular Tumoral , Ciclamos , Compostos Heterocíclicos/química , Humanos , Cinética , Camundongos , Compostos Organofosforados/química , Compostos Organofosforados/metabolismo , Tomografia por Emissão de Pósitrons , Sensibilidade e Especificidade , Coloração e Rotulagem , Tecnécio Tc 99m Sestamibi/química , Distribuição Tecidual/efeitos dos fármacosRESUMO
Positron emission tomography (PET)-magnetic resonance (MR) or single photon emission computed tomography (SPECT)-MR hybrid imaging is being used in daily clinical practice. Due to its advantages over stand-alone PET, SPECT or MR imaging, in many areas such as oncology, the demand for hybrid imaging techniques is increasing dramatically. The use of multimodal imaging probes or biomarkers in a single molecule or particle to characterize the imaging subjects such as disease tissues certainly provides us with more accurate diagnosis and promotes therapeutic accuracy. A limited number of multimodal imaging probes are being used in preclinical and potential clinical investigations. The further development of multimodal PET-MR and SPECT-MR imaging probes includes several key elements: novel synthetic strategies, high sensitivity for accurate quantification and high anatomic resolution, favourable pharmacokinetic profile and target-specific binding of a new probe. This review thoroughly summarizes all recently available and noteworthy PET-MR and SPECT-MR multimodal imaging probes including small molecule bimodal probes, nano-sized bimodal probes, small molecular trimodal probes and nano-sized trimodal probes. To the best of our knowledge, this is the first comprehensive overview of all PET-MR and SPECT-MR multimodal probes. Since the development of multimodal PET-MR and SPECT-MR imaging probes is an emerging research field, a selection of 139 papers were recognized following the literature review. The challenges for designing multimodal probes have also been addressed in order to offer some future research directions for this novel interdisciplinary research field.
Assuntos
Imageamento por Ressonância Magnética/métodos , Sondas Moleculares/química , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Humanos , Imageamento por Ressonância Magnética/instrumentação , Imagem Multimodal/instrumentação , Tomografia por Emissão de Pósitrons/instrumentação , Tomografia Computadorizada de Emissão de Fóton Único/instrumentaçãoRESUMO
This report presents synthesis and evaluation of the 64Cu-labeled triphenylphosphonium (TPP) cations as new radiotracers for imaging tumors by positron emission tomography. Biodistribution properties of 64Cu-L1, 64Cu-L2, 64Cu-L3, and 99mTc-Sestamibi were evaluated in athymic nude mice bearing U87MG human glioma xenografts. The most striking difference is that 64Cu-L1, 64Cu-L2, and 64Cu-L3 have much lower heart uptake (<0.6% ID/g) than 99mTc-Sestamibi ( approximately 18% ID/g) at >30 min p.i. Their tumor/heart ratios increase steadily from approximately 1 at 5 min p.i. to approximately 5 at 120 min p.i. The tumor/heart ratio of 64Cu-L3 is approximately 40 times better than that of 99mTc-Sestamibi at 120 min postinjection. Results from in vitro assays show that 64Cu-L1 is able to localize in tumor mitochondria. The tumor is clearly visualized in the tumor-bearing mice administered with 64Cu-L1 as 30 min postinjection. The 64Cu-labeled TPP/TPA cations are very selective radiotracers that are able to provide the information of mitochondrial bioenergetic function in tumors by monitoring mitochondrial potential in a noninvasive fashion.
Assuntos
Arsenicais/síntese química , Radioisótopos de Cobre , Neoplasias/metabolismo , Compostos Organofosforados/síntese química , Compostos Radiofarmacêuticos/síntese química , Animais , Arsenicais/química , Arsenicais/farmacologia , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacocinética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Cátions , Linhagem Celular Tumoral , Cicloexanos/síntese química , Cicloexanos/química , Cicloexanos/farmacocinética , Glioma/metabolismo , Glioma/patologia , Humanos , Camundongos , Camundongos Nus , Mitocôndrias/metabolismo , Transplante de Neoplasias , Compostos Organofosforados/química , Compostos Organofosforados/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Relação Estrutura-Atividade , Distribuição Tecidual , Transplante HeterólogoRESUMO
The aim of this study on dopamine transporter binding by [18F]FE-PE2I and PET was to describe an image-derived approach using reference tissue models: the Logan DVR approach and simplified reference tissue model (SRTM), the features of which were simple to operate and precise in the measurements. Using the approach, the authors sought to obtain binding images and parameters. [18F]FE-PE2I and dynamic PET as well as an MRI was performed on three rhesus monkeys, and metabolite corrected arterial plasma inputs were obtained. After co-registering of PET to MR images, both image sets were resliced. The time-activity curve of the cerebellum was used as indirect input, and binding parametric images were computed voxel-by-voxel. Voxel-wise linear calculations were used for the Logan DVR approach, and nonlinear least squares fittings for the SRTM. To determine the best linear regression in the Logan DVR approach, the distribution volume ratio was obtained using the optimal starting frame analysis. The obtained binding parameters were compared with those obtained by the other independent ROI-based numerical approaches: two-tissue compartment model (2TCM), Logan DVR approach and SRTM using PMOD software. Binding potentials (BP) obtained by the present approach agreed well with those obtained by ROI-based numerical approaches, although reference tissue models tended to underestimate the BP value than 2TCM. Image-derived Logan approach provided a low-noise image, the computation time was short, and the error in the optimal starting frame analysis was small. The present approach provides a high-quality binding parametric image and reliable parameter value easily.
RESUMO
Pharmacokinetics of Gd(DO3A-Lys), a macrocyclic gadolinium-based magnetic resonance imaging (MRI) contrast agent functionalized with a lysine derivative, was studied in Wistar rats. Kinetic data were fitted using a two-compartment model and revealed Gd(DO3A-Lys) to have a distribution half-life, t1/2 (α), of 1.3 min, an elimination half-life, t1/2 (ß), of 24.9 min and a large volume of distribution, VD , of 0.49 L/kg indicative of the agent being able to rapidly distribute into tissues and organs. Contrast-enhanced magnetic resonance angiography (CE-MRA) in an orthotopic U87MG glioma mouse model demonstrated considerable enhancement of both the tumor and surrounding vasculature after intravenous administration of Gd(DO3A-Lys). Applying dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the glioma of different sizes further showed distinct uptake characteristics and patterns of enhancement, which suggests the potential for differentiating changes at different stages of tumor growth. Our results indicate that Gd(DO3A-Lys) could be a promising candidate for glioma MR imaging.
Assuntos
Meios de Contraste/farmacocinética , Gadolínio/farmacocinética , Glioma/irrigação sanguínea , Compostos Heterocíclicos com 1 Anel/farmacocinética , Angiografia por Ressonância Magnética/métodos , Animais , Meios de Contraste/química , Modelos Animais de Doenças , Gadolínio/química , Glioma/diagnóstico , Compostos Heterocíclicos com 1 Anel/química , Lisina/química , Masculino , Compostos Organometálicos/química , Compostos Organometálicos/farmacocinética , Ratos , Ratos WistarRESUMO
Branched copolymer nanoparticles (D(h) =20-35 nm) possessing 1,4,7, 10-tetraazacyclododecane-N,N',Nâ³,Nâ´-tetraacetic acid macrocycles within their cores have been synthesized and applied as magnetic resonance imaging (MRI) nanosized contrast agents in vivo. These nanoparticles have been generated from novel functional monomers via reversible addition-fragmentation chain transfer polymerization. The process is very robust and synthetically straightforward. Chelation with gadolinium and preliminary in vivo experiments have demonstrated promising characteristics as MRI contrast agents with prolonged blood retention time, good biocompatibility, and an intravascular distribution. The ability of these nanoparticles to perfuse and passively target tumor cells through the enhanced permeability and retention effect is also demonstrated. These novel highly functional nanoparticle platforms have succinimidyl ester-activated benzoate functionalities within their corona, which make them suitable for future peptide conjugation and subsequent active cell-targeted MRI or the conjugation of fluorophores for bimodal imaging. We have also demonstrated that these branched copolymer nanoparticles are able to noncovalently encapsulate hydrophobic guest molecules, which could allow simultaneous bioimaging and drug delivery.
Assuntos
Materiais Biocompatíveis/química , Meios de Contraste/química , Imageamento por Ressonância Magnética , Polímeros/química , Animais , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Quelantes/química , Sistemas de Liberação de Medicamentos , Feminino , Gadolínio/química , Humanos , Túbulos Renais/metabolismo , Camundongos , Camundongos SCID , Micelas , Nanopartículas/química , PolimerizaçãoRESUMO
In this report, monodispersed ultra-small Gd2O3 nanoparticles capped with hydrophobic oleic acid (OA) were synthesized with average particle size of 2.9 nm. Two methods were introduced to modify the surface coating to hydrophilic for bio-applications. With a hydrophilic coating, the polyvinyl pyrrolidone (PVP) coated Gd2O3 nanoparticles (Gd2O3-PVP) showed a reduced longitudinal T1 relaxation time compared with OA and cetyltrimethylammonium bromide (CTAB) co-coated Gd2O3 (Gd2O3-OA-CTAB) in the relaxation study. The Gd2O3-PVP was thus chosen for its further application study in MRI with an improved longitudinal relaxivity r1 of 12.1 mM(-1) s(-1) at 7 T, which is around 3 times as that of commercial contrast agent Magnevist(®). In vitro cell viability in HK-2 cell indicated negligible cytotoxicity of Gd2O3-PVP within preclinical dosage. In vivo MR imaging study of Gd2O3-PVP nanoparticles demonstrated considerable signal enhancement in the liver and kidney with a long blood circulation time. Notably, the OA capping agent was replaced by PVP through ligand exchange on the Gd2O3 nanoparticle surface. The hydrophilic PVP grants the Gd2O3 nanoparticles with a polar surface for bio-application, and the obtained Gd2O3-PVP could be used as an in vivo indicator of reticuloendothelial activity.
Assuntos
Gadolínio/administração & dosagem , Imageamento por Ressonância Magnética/métodos , Nanopartículas Metálicas , Animais , Linhagem Celular , Xenoenxertos , Humanos , Camundongos , Camundongos SCID , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de SuperfícieRESUMO
An intravascular MRI contrast agent Gd(DO3A-Lys), Gadolinium(III) (2,2',2â³-(10-(3-(5-benzamido-6-methoxy-6-oxohexylamino)-3-oxopropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate), has been studied for tumor angiography based on its high relaxivity and long blood half-life. The preparation procedures of the contrast agent have been modified in order to achieve higher yield and improve the synthetic reproducibility. High relaxivity of Gd(DO3A-Lys) has been confirmed by measurements at 3 T, 7 T and 9.4 T magnetic fields. The relaxivity-dependent albumin binding study indicated that Gd(DO3A-Lys) partially bound to albumin protein. In vitro cell viability in HK2 cell indicated low cytotoxicity of Gd(DO3A-Lys) up to 1.2 mM [Gd] concentration. In vivo toxicity studies demonstrated no toxicity of Gd(DO3A-Lys) on kidney tissues up to 0.2 mM [Gd]. While the toxicity on liver tissue was not observed at low dosage (1.0 mM [Gd]), Gd(DO3A-Lys) cause certain damage on hepatic tissue at high dosage (2.0 mM [Gd]). The DO3A-Lys has been labeled with (68)Ga radioisotope for biodistribution studies. (68)Ga(DO3A-Lys) has high uptake in both HT1080 and U87MG xenograft tumors, and has high accumulation in blood. Contrast-enhanced MR angiography (CE-MRA) in mice bearing U87MG xenograft tumor demonstrated that Gd(DO3A-Lys) could enhance vascular microenvironment around the tumor, and displays promising characteristics of an MRI contrast agent for tumor angiography.