RESUMO
The arrival of cell-based therapies is a revolution in medicine. However, its safe clinical application in a rational manner depends on reliable, clinically applicable methods for determining the fate and trafficking of therapeutic cells in vivo using medical imaging techniquesâknown as in vivo cell tracking. Radionuclide imaging using single photon emission computed tomography (SPECT) or positron emission tomography (PET) has several advantages over other imaging modalities for cell tracking because of its high sensitivity (requiring low amounts of probe per cell for imaging) and whole-body quantitative imaging capability using clinically available scanners. For cell tracking with radionuclides, ex vivo direct cell radiolabeling, that is, radiolabeling cells before their administration, is the simplest and most robust method, allowing labeling of any cell type without the need for genetic modification. This Review covers the development and application of direct cell radiolabeling probes utilizing a variety of chemical approaches: organic and inorganic/coordination (radio)chemistry, nanomaterials, and biochemistry. We describe the key early developments and the most recent advances in the field, identifying advantages and disadvantages of the different approaches and informing future development and choice of methods for clinical and preclinical application.
Assuntos
Rastreamento de Células , Nanoestruturas , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Exosomes or small extracellular vesicles (sEVs) are increasingly gaining attention for their potential as drug delivery systems and biomarkers of disease. Therefore, it is important to understand their in vivo biodistribution using imaging techniques that allow tracking over time and at the whole-body level. Positron emission tomography (PET) allows short- and long-term whole-body tracking of radiolabeled compounds in both animals and humans and with excellent quantification properties compared to other nuclear imaging techniques. In this report, we explored the use of [89Zr]Zr(oxinate)4 (a cell and liposome radiotracer) for direct and intraluminal radiolabeling of several types of sEVs, achieving high radiolabeling yields. The radiosynthesis and radiolabeling protocols were optimized for sEV labeling, avoiding sEV damage, as demonstrated using several characterizations (cryoEM, nanoparticle tracking analysis, dot blot, and flow cytometry) and in vitro techniques. Using pancreatic cancer sEVs (PANC1) in a healthy mouse model, we showed that it is possible to track 89Zr-labeled sEVs in vivo using PET imaging for at least up to 24 h. We also report differential biodistribution of intact sEVs compared to intentionally heat-damaged sEVs, with significantly reduced spleen uptake for the latter. Therefore, we conclude that 89Zr-labeled sEVs using this method can reliably be used for in vivo PET tracking and thus allow efficient exploration of their potential as drug delivery systems.
Assuntos
Vesículas Extracelulares , Neoplasias Pancreáticas , Animais , Linhagem Celular Tumoral , Vesículas Extracelulares/metabolismo , Camundongos , Neoplasias Pancreáticas/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Distribuição Tecidual , ZircônioRESUMO
Nanomaterials offer unique physical, chemical and biological properties of interest for medical imaging and therapy. Over the last two decades, there has been an increasing effort to translate nanomaterial-based medicinal products (so-called nanomedicines) into clinical practice and, although multiple nanoparticle-based formulations are clinically available, there is still a disparity between the number of pre-clinical products and those that reach clinical approval. To facilitate the efficient clinical translation of nanomedicinal-drugs, it is important to study their whole-body biodistribution and pharmacokinetics from the early stages of their development. Integrating this knowledge with that of their therapeutic profile and/or toxicity should provide a powerful combination to efficiently inform nanomedicine trials and allow early selection of the most promising candidates. In this context, radiolabelling nanomaterials allows whole-body and non-invasive in vivo tracking by the sensitive clinical imaging techniques positron emission tomography (PET), and single photon emission computed tomography (SPECT). Furthermore, certain radionuclides with specific nuclear emissions can elicit therapeutic effects by themselves, leading to radionuclide-based therapy. To ensure robust information during the development of nanomaterials for PET/SPECT imaging and/or radionuclide therapy, selection of the most appropriate radiolabelling method and knowledge of its limitations are critical. Different radiolabelling strategies are available depending on the type of material, the radionuclide and/or the final application. In this review we describe the different radiolabelling strategies currently available, with a critical vision over their advantages and disadvantages. The final aim is to review the most relevant and up-to-date knowledge available in this field, and support the efficient clinical translation of future nanomedicinal products for in vivo imaging and/or therapy.
Assuntos
Diagnóstico por Imagem/métodos , Nanoestruturas/química , Compostos Radiofarmacêuticos/química , Animais , Humanos , Nanomedicina , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/metabolismo , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Calcium minerals such as hydroxyapatite (HAp) can be detected noninvasively in vivo using nuclear imaging agents such as [18F]NaF (available from cyclotrons), for positron emission tomography (PET) and 99mTc-radiolabeled bisphosphonates (BP; available from 99mTc generators for single photon emission computed tomography (SPECT) or scintigraphy). These two types of imaging agents allow detection of bone metastases (based on the presence of HAp) and vascular calcification lesions (that contain HAp and other calcium minerals). With the aim of developing a cyclotron-independent PET radiotracer for these lesions, with broad calcium mineral affinity and simple one-step radiolabeling, we developed [68Ga]Ga-THP-Pam. Radiolabeling with 68Ga is achieved using a mild single-step kit (5 min, room temperature, pH 7) to high radiochemical yield and purity (>95%). NMR studies demonstrate that Ga binds via the THP chelator, leaving the BP free to bind to its biological target. [68Ga]Ga-THP-Pam shows high stability in human serum. The calcium mineral binding of [68Ga]Ga-THP-Pam was compared in vitro to two other 68Ga-BPs which have been successfully evaluated in humans, [68Ga]Ga-NO2APBP and [68Ga]Ga-BPAMD, as well as [18F]NaF. Interestingly, we found that all 68Ga-BPs have a high affinity for a broad range of calcium minerals implicated in vascular calcification disease, while [18F]NaF is selective for HAp. Using healthy young mice as a model of metabolically active growing calcium mineral in vivo, we compared the pharmacokinetics and biodistribution of [68Ga]Ga-THP-Pam with [18F]NaF as well as [68Ga]NO2APBP. These studies revealed that [68Ga]Ga-THP-Pam has high in vivo affinity for bone tissue (high bone/muscle and bone/blood ratios) and fast blood clearance (t1/2 < 10 min) comparable to both [68Ga]NO2APBP and [18F]NaF. Overall, [68Ga]Ga-THP-Pam shows high potential for clinical translation as a cyclotron-independent calcium mineral PET radiotracer, with simple and efficient radiochemistry that can be easily implemented in any radiopharmacy.
Assuntos
Cálcio/química , Difosfonatos/química , Radioisótopos de Gálio/química , Tomografia por Emissão de Pósitrons/métodos , Animais , Quelantes/química , Espectroscopia de Ressonância Magnética/métodos , Camundongos , Distribuição TecidualRESUMO
Gammadelta T (γδ-T) cells are strong candidates for adoptive immunotherapy in oncology due to their cytotoxicity, ease of expansion, and favorable safety profile. The development of γδ-T cell therapies would benefit from non-invasive cell-tracking methods and increased targeting to tumor sites. Here we report the use of [89Zr]Zr(oxinate)4 to track Vγ9Vδ2 T cells in vivo by positron emission tomography (PET). In vitro, we showed that 89Zr-labeled Vγ9Vδ2 T cells retained their viability, proliferative capacity, and anti-cancer cytotoxicity with minimal DNA damage for amounts of 89Zr ≤20 mBq/cell. Using a mouse xenograft model of human breast cancer, 89Zr-labeled γδ-T cells were tracked by PET imaging over 1 week. To increase tumor antigen expression, the mice were pre-treated with PEGylated liposomal alendronate. Liposomal alendronate, but not placebo liposomes or non-liposomal alendronate, significantly increased the 89Zr signal in the tumors, suggesting increased homing of γδ-T cells to the tumors. γδ-T cell trafficking to tumors occurred within 48 hr of administration. The presence of γδ-T cells in tumors, liver, and spleen was confirmed by histology. Our results demonstrate the suitability of [89Zr]Zr(oxinate)4 as a cell-labeling agent for therapeutic T cells and the potential benefits of liposomal bisphosphonate treatment before γδ-T cell administration.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/terapia , Tomografia por Emissão de Pósitrons/métodos , Linfócitos T/citologia , Alendronato/uso terapêutico , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Difosfonatos/uso terapêutico , Feminino , Humanos , Imunoterapia Adotiva , Camundongos , Nanomedicina/métodos , Linfócitos T/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
19F-magnetic resonance imaging (MRI) is a promising technique that may allow us to measure the concentration of exogenous fluorinated imaging probes quantitatively in vivo. Here, we describe the synthesis and characterisation of a novel geminal bisphosphonate (19F-BP) that contains chemically-equivalent fluorine atoms that show a single and narrow 19F resonance and a bisphosphonate group that may be used for labelling inorganic materials based in calcium phosphates and metal oxides. The potential of 19F-BP to provide contrast was analysed in vitro and in vivo using 19F-MRI. In vitro studies demonstrated the potential of 19F-BP as an MRI contrast agent in the millimolar concentration range with signal-to-noise ratios (SNR) comparable to previously reported fluorinated probes. The preliminary in vivo MRI study reported here allowed us to visualise the biodistribution of 19F-BP, showing uptake in the liver and in the bladder/urinary system areas. However, bone uptake was not observed. In addition, 19F-BP showed undesirable toxicity effects in mice that prevent further studies with this compound at the required concentrations for MRI contrast. This study highlights the importance of developing 19F MRI probes with the highest signal intensity achievable.
RESUMO
Pretargeted PET imaging using bioorthogonal chemistry is a leading strategy for the tracking of long-circulating agents such as antibodies and nanoparticle-drug delivery systems with short-lived isotopes. Here, we report the synthesis, characterisation and in vitro/vivo evaluation of a new 68Ga-based radiotracer [68Ga]Ga-THP-Tetrazine ([68Ga]Ga-THP-Tz) for bioorthogonal click radiochemistry and in vivo labelling of agents with slow pharmacokinetics. THP-tetrazine (THP-Tz) can be radiolabelled to give [68/67Ga]Ga-THP-Tz at room temperature in less than 15 minutes with excellent radiochemical stability in vitro and in vivo. [68Ga]Ga-THP-Tz was tested in vitro and in vivo for pretargeted imaging of stealth PEGylated liposomes, chosen as a leading clinically-approved platform of nanoparticle-based drug delivery, and for their known long-circulating properties. To achieve this, PEGylated liposomes were functionalised with a synthesised transcyclooctene (TCO) modified phospholipid. Radiolabelling of TCO-PEG-liposomes with [68/67Ga]Ga-THP-Tz was demonstrated in vitro in human serum, and in vivo using both healthy mice and in a syngeneic cancer murine model (WEHI-164 fibrosarcoma). Interestingly in vivo data revealed that [68Ga]Ga-THP-Tz was able to in vivo radiolabel liposomes present in the liver and spleen, and not those in the blood pool or in the tumour. Overall, these results demonstrate the potential of [68Ga]Ga-THP-Tz for pretargeted imaging/therapy but also some unexpected limitations of this system.
RESUMO
Positron emission particle tracking (PEPT) enables 3D localization and tracking of single positron-emitting radiolabelled particles with high spatiotemporal resolution. The translation of PEPT to the biomedical imaging field has been limited due to the lack of methods to radiolabel biocompatible particles with sufficient specific activity and protocols to isolate a single particle in the sub-micrometre size range, below the threshold for capillary embolization. Here we report two key developments: the synthesis and 68Ga-radiolabelling of homogeneous silica particles of 950 nm diameter with unprecedented specific activities (2.1 ± 1.4 kBq per particle), and the isolation and manipulation of a single particle. We have combined these developments to perform in vivo PEPT and dynamic positron emission tomography (PET) imaging of a single radiolabelled sub-micrometre size particle using a pre-clinical positron emission tomography/computed tomography scanner. This work opens possibilities for quantitative assessment of haemodynamics in vivo in real time, at the whole-body level using minimal amounts of injected radioactive dose and material.
Assuntos
Tomografia por Emissão de Pósitrons , Animais , Tomografia por Emissão de Pósitrons/métodos , Radioisótopos de Gálio/química , Camundongos , Dióxido de Silício/química , Tamanho da Partícula , Nanopartículas/química , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodosRESUMO
Direct delivery to the lung via inhalation is arguably one of the most logical approaches to treat lung cancer using drugs. However, despite significant efforts and investment in this area, this strategy has not progressed in clinical trials. Imaging drug delivery is a powerful tool to understand and develop novel drug delivery strategies. In this review we focus on imaging studies of drug delivery by the inhalation route, to provide a broad overview of the field to date and attempt to better understand the complexities of this route of administration and the significant barriers that it faces, as well as its advantages. We start with a discussion of the specific challenges for drug delivery to the lung via inhalation. We focus on the barriers that have prevented progress of this approach in oncology, as well as the most recent developments in this area. This is followed by a comprehensive overview of the different imaging modalities that are relevant to lung drug delivery, including nuclear imaging, X-ray imaging, magnetic resonance imaging, optical imaging and mass spectrometry imaging. For each of these modalities, examples from the literature where these techniques have been explored are provided. Finally the different applications of these technologies in oncology are discussed, focusing separately on small molecules and nanomedicines. We hope that this comprehensive review will be informative to the field and will guide the future preclinical and clinical development of this promising drug delivery strategy to maximise its therapeutic potential.
Assuntos
Sistemas de Liberação de Medicamentos , Pulmão , Humanos , Sistemas de Liberação de Medicamentos/métodos , Pulmão/diagnóstico por imagem , Preparações Farmacêuticas , Administração por Inalação , Imageamento por Ressonância MagnéticaRESUMO
Radiolabelled bisphosphonates (BPs) and [18F]NaF (18F-fluoride) are the two types of radiotracers available to image calcium mineral (e.g. bone), yet only [18F]NaF has been widely explored for the non-invasive molecular imaging of extraosseous calcification (EC) using positron emission tomography (PET) imaging. These two radiotracers bind calcium mineral deposits via different mechanisms, with BPs chelating to calcium ions and thus being non-selective, and [18F]NaF being selective for hydroxyapatite (HAp) which is the main component of bone mineral. Considering that the composition of EC has been reported to include a diverse range of non-HAp calcium minerals, we hypothesised that BPs may be more sensitive for imaging EC due to their ability to bind to both HAp and non-HAp deposits. We report a comparison between the 68Ga-labelled BP tracer [68Ga]Ga-THP-Pam and [18F]NaF for PET imaging in a rat model of EC that develops macro- and microcalcifications in several organs. Macrocalcifications were identified using preclinical computed tomography (CT) and microcalcifications were identified using µCT-based 3D X-ray histology (XRH) on isolated organs ex vivo. The morphological and mineral analysis of individual calcified deposits was performed using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). PET imaging and ex vivo analysis results demonstrated that while both radiotracers behave similarly for bone imaging, the BP-based radiotracer [68Ga]Ga-THP-Pam was able to detect EC more sensitively in several organs in which the mineral composition departs from that of HAp. Our results strongly suggest that BP-based PET radiotracers such as [68Ga]Ga-THP-Pam may have a particular advantage for the sensitive imaging and early detection of EC by being able to detect a wider array of relevant calcium minerals in vivo than [18F]NaF, and should be evaluated clinically for this purpose.
Assuntos
Calcinose , Radioisótopos de Gálio , Animais , Ratos , Cálcio , Difosfonatos , Tomografia por Emissão de Pósitrons , Cálcio da Dieta , DurapatitaRESUMO
Liposomes are clinically used drug carriers designed to improve the delivery of drugs to specific tissues while minimising systemic distribution. However, liposomes are unable to cross the blood-brain barrier (BBB) and enter the brain, mostly due to their large size (ca. 100 nm). A noninvasive and localised method of delivering liposomes across the BBB is to intravenously inject microbubbles and apply long pulses of ultrasound (pulse length: >1 ms) to a targeted brain region. Recently, we have shown that applying rapid short pulses (RaSP) (pulse length: 5 µs) can deliver drugs with an improved efficacy and safety profile. However, this was tested with a relatively smaller 3-kDa molecule (dextran). In this study, we examine whether RaSP can deliver liposomes to the murine brain in vivo. Fluorescent DiD-PEGylated liposomes were synthesized and injected intravenously alongside microbubbles. The left hippocampus of mice was then sonicated with either a RaSP sequence (5 µs at 1.25 kHz in groups of 10 ms at 0.5 Hz) or a long pulse sequence (10 ms at 0.5 Hz), with each pulse having a 1-MHz centre frequency (0.35 and 0.53 MPa). The delivery and distribution of the fluorescently-labelled liposomes were assessed by fluorescence imaging of the brain sections. The safety profile of the sonicated brains was assessed by histological staining. RaSP was shown to locally deliver liposomes across the BBB at 0.53 MPa with a more diffused and safer profile compared to the long pulse ultrasound sequence. Cellular uptake of liposomes was observed in neurons and microglia, while no uptake within astrocytes was observed in both RaSP and long pulse-treated brains. This study shows that RaSP allows a targeted and safe delivery of liposomal drugs into the murine brain with potential to deliver drugs into neuronal and glial targets.
Assuntos
Lipossomos , Microbolhas , Animais , Barreira Hematoencefálica , Encéfalo/diagnóstico por imagem , Sistemas de Liberação de Medicamentos/métodos , CamundongosRESUMO
BACKGROUND: Manganese porphyrins have several therapeutic/imaging applications, including their use as radioprotectants (in clinical trials) and as paramagnetic MRI contrast agents. The affinity of porphyrins for lipid bilayers also makes them candidates for cell/liposome labelling. We hypothesised that metalation with the positron emission tomography (PET) radionuclide 52Mn (t1/2 = 5.6 d) would allow long-term in vivo biodistribution studies of Mn-porphyrins, as well as a method to label and track cells/liposomes, but methods for fast and efficient radiolabelling are lacking. RESULTS: Several porphyrins were produced and radiolabelled by addition to neutralised [52Mn]MnCl2 and heating using a microwave (MW) synthesiser, and compared with non-MW heating. MW radiosynthesis allowed >95 % radiochemical yields (RCY) in just 1 h. Conversely, non-MW heating at 70 °C for 1 h resulted in low RCY (0-25 % RCY) and most porphyrins did not reach radiolabelling completion after 24 h. Formation of the 52Mn-complexes were confirmed with radio-HPLC by comparison with their non-radioactive 55Mn counterparts. Following this, several [52Mn]Mn-porphyrins were used to radiolabel liposomes resulting in 75-86 % labelling efficiency (LE). Two lead [52Mn]Mn-porphyrins were taken forward to label MDA-MB-231 cancer cells in vitro, achieving ca. 11 % LE. After 24 h, 32-45 % of the [52Mn]Mn-porphyrins was retained in cells. CONCLUSIONS: In contrast to standard methods, MW heating allows the fast synthesis of [52Mn]Mn-porphyrins with >95 % radiochemical yields that avoid purification. [52Mn]Mn-porphyrins also show promising cell/liposome labelling properties. Our reported technique can potentially be exploited for the in vivo imaging of Mn-porphyrin therapeutics, as well as for the accurate in vivo quantification of Mn-porphyrin MRI agents.
Assuntos
Lipossomos , Porfirinas , Micro-Ondas , Distribuição Tecidual , Radioisótopos , Compostos RadiofarmacêuticosRESUMO
Porous materials, such as zeolites, have great potential for biomedical applications, thanks to their ability to accommodate positively charged metal-ions and their facile surface functionalization. Although the latter aspect is important to endow the nanoparticles with chemical/colloidal stability and desired biological properties, the possibility for simple ion-exchange enables easy switching between imaging modalities and/or combination with therapy, depending on the envisioned application. In this study, the nanozeolite Linde type L (LTL) with already confirmed magnetic resonance imaging properties, generated by the paramagnetic gadolinium (GdIII) in the inner cavities, was successfully radiolabeled with a positron emission tomography (PET)-tracer zirconium-89 (89Zr). Thereby, exploiting 89Zr-chloride resulted in a slightly higher radiolabeling in the inner cavities compared to the commonly used 89Zr-oxalate, which apparently remained on the surface of LTL. Intravenous injection of PEGylated 89Zr/GdIII-LTL in healthy mice allowed for PET-computed tomography evaluation, revealing initial lung uptake followed by gradual migration of LTL to the liver and spleen. Ex vivo biodistribution confirmed the in vivo stability and integrity of the proposed multimodal probe by demonstrating the original metal/Si ratio being preserved in the organs. These findings reveal beneficial biological behavior of the nanozeolite LTL and hence open the door for follow-up theranostic studies by exploiting the immense variety of metal-based radioisotopes.
RESUMO
Extracellular vesicles (EVs) such as exosomes and microvesicles have gained recent attention as potential biomarkers of disease as well as nanomedicinal tools, but their behaviour in vivo remains mostly unexplored. In order to gain knowledge of their in vivo biodistribution it is important to develop imaging tools that allow us to track EVs over time and at the whole-body level. Radionuclide-based imaging (PET and SPECT) have properties that allow us to do so efficiently, mostly due to their high sensitivity, imaging signal tissue penetration, and accurate quantification. Furthermore, they can be easily translated from animals to humans. In this review, we summarise and discuss the different studies that have used PET or SPECT to study the behaviour of EVs in vivo. With a focus on the different radiolabelling methods used, we also discuss the advantages and disadvantages of each one, and the challenges of imaging EVs due to their variable stability and heterogeneity.
Assuntos
Vesículas Extracelulares/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Humanos , Compostos Radiofarmacêuticos/administração & dosagemRESUMO
BACKGROUND: Advances in immunology and cell-based therapies are creating a need to track individual cell types, such as immune cells (neutrophils, eosinophils, chimeric antigen receptor (CAR) T cells, etc.) and stem cells. As the fate of administered cells remains largely unknown, nuclear imaging could determine the migration and survival of cells in patients. [89Zr]Zr(oxinate)4, or [89Zr]Zr-oxine, is a radiotracer for positron emission tomography (PET) that has been evaluated in preclinical models of cell tracking and could improve on [111In]In-oxine, the current gold standard radiotracer for cell tracking by scintigraphy and single-photon emission computed tomography (SPECT), because of the better sensitivity, spatial resolution and quantification of PET. However, a clinically usable formulation of [89Zr]Zr-oxine is lacking. This study demonstrates a 1-step procedure for preparing [89Zr]Zr-oxine and evaluates it against [111In]In-oxine in white blood cell (WBC) labelling. METHODS: Commercial [89Zr]Zr-oxalate was added to a formulation containing oxine, a buffering agent, a base and a surfactant or organic solvent. WBC isolated from 10 human volunteers were radiolabelled with [89Zr]Zr-oxine following a clinical radiolabelling protocol. Labelling efficiency, cell viability, chemotaxis and DNA damage were evaluated in vitro, in an intra-individual comparison against [111In]In-oxine. RESULTS: An optimised formulation of [89Zr]Zr-oxine containing oxine, polysorbate 80 and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) was developed. This enabled 1-step radiolabelling of oxine with commercial [89Zr]Zr-oxalate (0.1-25 MBq) in 5 min and radiotracer stability for 1 week. WBC labelling efficiency was 48.7 ± 6.3%, compared to 89.1 ± 9.5% (P < 0.0001, n = 10) for [111In]In-oxine. Intracellular retention of 89Zr and cell viability after radiolabelling were comparable to 111In. There were no significant differences in leukocyte chemotaxis or DNA damage between [89Zr]Zr-oxine or [111In]In-oxine. CONCLUSIONS, ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Our results demonstrate that [89Zr]Zr-oxine is a suitable PET alternative to [111In]In-oxine for WBC imaging. Our formulation allows rapid, stable, high-yield, single-step preparation of [89Zr]Zr-oxine from commercially available 89Zr. This will facilitate the clinical translation of cell tracking using [89Zr]Zr-oxine.
Assuntos
Rastreamento de Células/métodos , Compostos Organometálicos/química , Oxiquinolina/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Linhagem Celular Tumoral , Sobrevivência Celular , Composição de Medicamentos , Humanos , Marcação por Isótopo , Leucócitos/citologia , Leucócitos/metabolismo , Oxiquinolina/química , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Computed tomography (CT) is one of the most widespread imaging techniques in clinical use worldwide. CT contrast agents are administered to improve soft tissue contrast and highlight blood vessels. However, the range of CT contrast agents available in the clinic is limited and they suffer from short-circulation times and low k-edge values that result in the need for high doses for in vivo applications. Nanomaterials containing a mixture of electron-dense elements, such as BaYbF5 nanoparticles, have shown promise as more efficient CT contrast agents, but they require biocompatible coatings for biomedical applications. Here, we explore the use of a bifunctional PEG polymer (5 kDa) containing a terminal bisphosphonate (BP) anchor for efficient binding to the surface of BaYbF5 nanomaterials. The resulting PEG(5)-BP-BaYbF5 nanoparticles were synthesized and characterized using TEM, DLS, TGA, XRD and Z-potential measurements. Their in vitro stability was verified and their ability to produce CT contrast in a wide range of X-ray energies, covering preclinical and clinical scanners, was demonstrated. In vitro toxicity studies with PEG(5)-BP-BaYbF5 in the phagocytic pro-monocytic human cell line U937 did not identify toxic effects, even at high concentrations (30 mM). In vivo, PEG(5)-BP-BaYbF5 exhibited efficient CT contrast for angiography imaging, highlighting blood vessels and vascular organs, and long circulation times as expected from the PEG coating. However, at late time points (48 h), in vivo toxicity was observed. While the causes could not be completely elucidated, in vitro studies suggest that decomposition and release of Yb3+ and/or Ba2+ metal ions after decomposition of PEG(5)-BP-BaYbF5 may play a role. Overall, despite the promising CT contrast properties, our results suggest that BaYbF5 nanomaterials may suffer from significant long-term toxicities.
Assuntos
Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Difosfonatos/química , Nanopartículas/química , Polietilenoglicóis/química , Tomografia Computadorizada por Raios X/métodos , Materiais Biocompatíveis/síntese química , Linhagem Celular Tumoral , Técnicas de Química Sintética , HumanosRESUMO
The integration of nuclear imaging with nanomedicine is a powerful tool for efficient development and clinical translation of liposomal drug delivery systems. Furthermore, it may allow highly efficient imaging-guided personalised treatments. In this article, we critically review methods available for radiolabelling liposomes. We discuss the influence that the radiolabelling methods can have on their biodistribution and highlight the often-overlooked possibility of misinterpretation of results due to decomposition in vivo. We stress the need for knowing the biodistribution/pharmacokinetics of both the radiolabelled liposomal components and free radionuclides in order to confidently evaluate the images, as they often share excretion pathways with intact liposomes (e.g. phospholipids, metallic radionuclides) and even show significant tumour uptake by themselves (e.g. some radionuclides). Finally, we describe preclinical and clinical studies using radiolabelled liposomes and discuss their impact in supporting liposomal drug development and clinical translation in several diseases, including personalised nanomedicine approaches.
Assuntos
Sistemas de Liberação de Medicamentos , Lipossomos , Radioisótopos , Animais , Diagnóstico por Imagem , Humanos , NanomedicinaRESUMO
Imaging plays a key role in the preclinical evaluation of nanomedicine-based drug delivery systems and it has provided important insights into their mechanism of action and therapeutic effect. Its role in supporting the clinical development of nanomedicine products, however, has been less explored. In this review, we summarize clinical studies in which imaging has provided valuable information on the pharmacokinetics, biodistribution, and target site accumulation of nanomedicine-based drug delivery systems. Importantly, these studies provide convincing evidence on the uptake of nanomedicines in tumors, confirming that the enhanced permeability and retention (EPR) effect is a real phenomenon in patients, albeit with fairly high levels of inter- and intraindividual variability. It is gradually becoming clear that imaging is critically important to help address this high heterogeneity. In support of this notion, a decent correlation between nanomedicine uptake in tumors and antitumor efficacy has recently been obtained in two independent studies in patients, exemplifying that image-guided drug delivery can help to pave the way towards individualized and improved nanomedicine therapies.
Assuntos
Diagnóstico por Imagem , Sistemas de Liberação de Medicamentos , Nanomedicina , Animais , Ensaios Clínicos como Assunto , Humanos , Imagem Corporal TotalRESUMO
The magnetic properties and safety of dextran-coated superparamagnetic iron oxide nanoparticles (SPIONs) have facilitated their clinical use as MRI contrast agents and stimulated research on applications for SPIONs in particle imaging and magnetic hyperthermia. The wider clinical potential of SPIONs, however, has been limited by their rapid removal from circulation via the reticuloendothelial system (RES). We explored the possibility of extending SPION circulatory time using fucoidan, a seaweed-derived food supplement, to inhibit RES uptake. The effects of fucoidan on SPION biodistribution were evaluated using ferucarbotran, which in its pharmaceutical formulation (Resovist) targets the RES. Ferucarbotran was radiolabeled at the iron oxide core with technetium-99m (99mTc; t1/2 = 6 h) or zirconium-89 (89Zr; t1/2 = 3.3 days). Results obtained with 99mTc-ferucarbotran demonstrated that administration of fucoidan led to a 4-fold increase in the circulatory half-life (t1/2 slow) from 37.4 to 150 min (n = 4; P < 0.0001). To investigate whether a longer circulatory half-life could lead to concomitant increased tumor uptake, the effects of fucoidan were tested with 89Zr-ferucarbotran in mice bearing syngeneic subcutaneous (GL261) tumors. In this model, the longer circulatory half-life achieved with fucoidan was associated with a doubling in tumor SPION uptake (n = 5; P < 0.001). Fucoidan was also effective in significantly increasing the circulatory half-life of perimag-COOH, a commercially available SPION with a larger hydrodynamic size (130 nm) than ferucarbotran (65 nm). These findings indicate successful diversion of SPIONs away from the hepatic RES and show realistic potential for future clinical applications.
RESUMO
Lipid nanocapsules (LNCs) are semi-rigid spherical capsules with a triglyceride core that present a promising formulation option for the pulmonary delivery of drugs with poor aqueous solubility. Whilst the biodistribution of LNCs of different size has been studied following intravenous administration, the fate of LNCs following pulmonary delivery has not been reported. We investigated quantitatively whether lung inflammation affects the clearance of 50nm lipid nanocapsules, or is exacerbated by their pulmonary administration. Studies were conducted in mice with lipopolysaccharide-induced lung inflammation compared to healthy controls. Particle deposition and nanocapsule clearance kinetics were measured by single photon emission computed tomography/computed tomography (SPECT/CT) imaging over 48 h. A significantly lower lung dose of (111)In-LNC50 was achieved in the lipopolysaccharide (LPS)-treated animals compared with healthy controls (p<0.001). When normalised to the delivered lung dose, the clearance kinetics of (111)In-LNC50 from the lungs fit a first order model with an elimination half-life of 10.5±0.9h (R(2)=0.995) and 10.6±0.3h (R(2)=1.000) for healthy and inflamed lungs respectively (n=3). In contrast, (111)In-diethylene triamine pentaacetic acid (DTPA), a small hydrophilic molecule, was cleared rapidly from the lungs with the majority of the dose absorbed within 20min of administration. Biodistribution to lungs, stomach-intestine, liver, trachea-throat and blood at the end of the imaging period was unaltered by lung inflammation. This study demonstrated that lung clearance and whole body distribution of lipid nanocapsules were unaffected by the presence of acute lung inflammation.