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Novel biodegradable metal alloys are increasingly used as implant materials. The implantation can be accompanied by an inflammatory response to a foreign object. For studying inflammation in the implantation area, non-invasive imaging methods are needed. In vivo imaging for the implanted area and its surroundings will provide beneficiary information to understand implant-related inflammation and help to monitor it. Therefore, inflammation-sensitive fluorescent liposomes in rats were tested in the presence of an implant to evaluate their usability in studying inflammation. The sphingomyelin-containing liposomes carrying alpha-melanocyte-stimulating hormone (α-MSH)-peptide were tested in a rat bone implant model. The liposome interaction with implant material (Mg-10Gd) was analyzed with Mg-based implant material (Mg-10Gd) in vitro. The liposome uptake process was studied in the bone-marrow-derived macrophages in vitro. Finally, this liposomal tracer was tested in vivo. It was found that α-MSH coupled sphingomyelin-containing liposomes and the Mg-10Gd implant did not have any disturbing influence on each other. The clearance of liposomes was observed in the presence of an inert and biodegradable implant. The degradable Mg-10Gd was used as an alloy example; however, the presented imaging system offers a new possible use of α-MSH-SM-liposomes as tools for investigating implant responses.
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Liposomas , alfa-MSH , Ratas , Animales , Esfingomielinas , Implantes Absorbibles , InflamaciónRESUMEN
In liposomal delivery, a big question is how to release the loaded material into the correct place. Here, we will test the targeting and release abilities of our sphingomyelin-consisting liposome. A change in release parameters can be observed when sphingomyelin-containing liposome is treated with sphingomyelinase enzyme. Sphingomyelinase is known to be endogenously released from the different cells in stress situations. We assume the effective enzyme treatment will weaken the liposome making it also leakier. To test the release abilities of the SM-liposome, we developed several fluorescence-based experiments. In in vitro studies, we used molecular quenching to study the sphingomyelinase enzyme-based release from the liposomes. We could show that the enzyme treatment releases loaded fluorescent markers from sphingomyelin-containing liposomes. Moreover, the release correlated with used enzymatic activities. We studied whether the stress-related enzyme expression is increased if the cells are treated with radiation as a stress inducer. It appeared that the radiation caused increased enzymatic activity. We studied our liposomes' biodistribution in the animal tumor model when the tumor was under radiation stress. Increased targeting of the fluorescent marker loaded to our liposomes could be found on the site of cancer. The liposomal targeting in vivo could be improved by radiation. Based on our studies, we propose sphingomyelin-containing liposomes can be used as a controlled release system sensitive to cell stress.
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Colorantes Fluorescentes , Liposomas , Neoplasias/diagnóstico , Neoplasias/metabolismo , Esfingomielina Fosfodiesterasa/metabolismo , Esfingomielinas/metabolismo , Estrés Fisiológico/efectos de la radiación , Animales , Catálisis , Línea Celular Tumoral , Modelos Animales de Enfermedad , Activación Enzimática , Colorantes Fluorescentes/química , Liposomas/química , Ratones , Imagen Molecular , Neoplasias/radioterapia , Imagen Óptica , Esfingomielinas/química , Coloración y EtiquetadoRESUMEN
BACKGROUND: The human gastrointestinal (GI) tract microbiota has been a subject of intense research throughout the 3rd Millennium. Now that a general picture about microbiota composition in health and disease is emerging, questions about factors determining development of microbiotas with specific community structures will be addressed. To this end, usage of murine models for colonization studies remains crucial. Optical in vivo imaging of either bioluminescent or fluorescent bacteria is the basis for non-invasive detection of intestinal colonization of bacteria. Although recent advances in in vivo fluorescence imaging have overcome many limitations encountered in bioluminescent imaging of intestinal bacteria, such as requirement for live cells, high signal attenuation and 2D imaging, the method is still restricted to bacteria for which molecular cloning tools are available. RESULTS: Here, we present usage of a lipophilic fluorescent dye together with Katushka far-red fluorescent protein to establish a dual-color in vivo imaging system to monitor GI transit of different bacterial strains, suitable also for strains resistant to genetic labeling. Using this system, we were able to distinguish two different E. coli strains simultaneously and show their unique transit patterns. Combined with fluorescence molecular tomography, these distinct strains could be spatially and temporally resolved and quantified in 3D. CONCLUSIONS: Developed novel method for labeling microbes and identify their passage both temporally and spatially in vivo makes now possible to monitor all culturable bacterial strains, also those that are resistant to conventional genetic labeling.
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Tracto Gastrointestinal/microbiología , Microscopía Fluorescente/métodos , Coloración y Etiquetado/métodos , Animales , Escherichia coli/metabolismo , Colorantes Fluorescentes/metabolismo , Microbioma Gastrointestinal , Microscopía Intravital/métodos , Proteínas Luminiscentes/metabolismo , Lípidos de la Membrana/metabolismo , Ratones , Tomografía Óptica , Proteína Fluorescente RojaRESUMEN
Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract, resulting in severe symptoms. At the moment, the goal of medical treatments is to reduce inflammation. IBD is treated with systemic anti-inflammatory compounds, but they have serious side effects. The treatment that is most efficient and causes the fewest side effects would be the delivery of the drugs on the disease site. This study aimed to investigate the suitability of sphingomyelin (SM) containing liposomes to specifically target areas of inflammation in dextran sulfate sodium-induced murine colitis. Sphingomyelin is a substrate to the sphingomyelinase enzyme, which is only present outside cells in cell stress, like inflammation. When sphingomyelin consisting of liposomes is predisposed to the enzyme, it causes the weakening of the membrane structure. We demonstrated that SM-liposomes are efficiently taken up in intestinal macrophages, indicating their delivery potential. Furthermore, our studies showed that sphingomyelinase activity and release are increased in a dextran sulfate sodium-induced IBD mouse model. The enzyme appearance in IBD disease was also traced in intestine samples of the dextran sulfate sodium-treated mice and human tissue samples. The results from the IBD diseased animals, treated with fluorescently labeled SM-liposomes, demonstrated that the liposomes were taken up preferentially in the inflamed colon. This uptake efficiency correlated with sphingomyelinase activity.
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The local response of tissue triggered by implantation of degradable magnesium-based implant materials was investigated in vivo in a murine model. Pins (5.0 mm length by 0.5 mm diameter) made of Mg, Mg-10Gd, and Ti were implanted in the leg muscle tissue of C57Bl/6N mice (n = 6). Implantation was generally well tolerated as documented by only a mild short term increase in a multidimensional scoring index. Lack of difference between the groups indicated that the response was systemic and surgery related rather than material dependent. Longitudinal in vivo monitoring utilizing micro-computed tomography over 42 days demonstrated the highest and most heterogeneous degradation for Mg-10Gd. Elemental imaging of the explants by micro X-ray fluorescence spectrometry showed a dense calcium-phosphate-containing degradation layer. In order to monitor resulting surgery induced and/or implant material associated local cell stress, sphingomyelin based liposomes containing indocyanine green were administered. An initial increase in fluorescent signals (3-7 days after implantation) indicating cell stress at the site of the implantation was measured by in vivo fluorescent molecular tomography. The signal decreased until the 42nd day for all materials. These findings demonstrate that Mg based implants are well tolerated causing only mild and short term adverse reactions.
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Implantes Absorbibles , Aleaciones/análisis , Magnesio/análisis , Implantes Absorbibles/efectos adversos , Aleaciones/efectos adversos , Aleaciones/metabolismo , Animales , Imagenología Tridimensional , Implantes Experimentales/efectos adversos , Magnesio/efectos adversos , Magnesio/metabolismo , Ensayo de Materiales , Ratones Endogámicos C57BL , Imagen Óptica , Espectrometría por Rayos XRESUMEN
Imaging techniques have evolved impressively lately, allowing whole new concepts like multimodal imaging, personal medicine, theranostic therapies, and molecular imaging to increase general awareness of possiblities of imaging to medicine field. Here, we have collected the selected (3D) imaging modalities and evaluated the recent findings on preclinical and clinical inflammation imaging. The focus has been on the feasibility of imaging to aid in inflammation precision medicine, and the key challenges and opportunities of the imaging modalities are presented. Some examples of the current usage in clinics/close to clinics have been brought out as an example. This review evaluates the future prospects of the imaging technologies for clinical applications in precision medicine from the pre-clinical development point of view.
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Inflamación/diagnóstico por imagen , Animales , Diagnóstico por Imagen , HumanosRESUMEN
X-ray-based analytics are routinely applied in many fields, including physics, chemistry, materials science, and engineering. The full potential of such techniques in the life sciences and medicine, however, has not yet been fully exploited. We highlight current and upcoming advances in this direction. We describe different X-ray-based methodologies (including those performed at synchrotron light sources and X-ray free-electron lasers) and their potentials for application to investigate the nano-bio interface. The discussion is predominantly guided by asking how such methods could better help to understand and to improve nanoparticle-based drug delivery, though the concepts also apply to nano-bio interactions in general. We discuss current limitations and how they might be overcome, particularly for future use in vivo.
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Nanopartículas , Sincrotrones , Rayos Láser , Radiografía , Rayos XRESUMEN
Matrix metalloproteinases (MMPs) are enzymes that can hydrolyze almost all constituents of extracellular matrix. An MMP subgroup, the gelatinases, has been focused during last years, since over-expression of gelatinase A (MMP-2) and gelatinase B (MMP-9) has been linked with severe homeostasis disorders such as tumor growth, metastasis formation, and chronic inflammation. In this study, a phage display library-derived novel antigelatinolytic decapeptide, the CTT-peptide, was expressed as a carboxyl terminal, histidine-tagged fusion with the green fluorescent protein (CTT-GFP) in Escherichia coli. In addition, a biologically intact chimera, in which residues in the CTT-peptide critical for gelatinase binding were replaced with alanine (Ala-CTT-GFP), was constructed. The GFP-fusion proteins were purified to homogeneity with a simple one-step procedure utilizing nickel affinity chromatography. The purified chimeras were tested for their binding properties to 4beta-phorbol-12,13-butyrate (PdBu) activated, MMP-9 expressing THP-1 cells, and it was demonstrated that the CTT-GFP strongly bound to the cells, whereas Ala-CTT-GFP lacked the binding ability. Furthermore, the adherence of the CTT-GFP to MMP-9 expressing cells was demonstrated to be mediated by the CTT-moiety, since the binding could be dose-relatedly inhibited with increasing concentrations of synthetic soluble CTT-peptide. In conclusion, this novel tool, combining the gelatinase binding ability of the CTT-peptide with the fluorescing property of the GFP, should clearly improve both experimental and clinical studies of the role and function of gelatinases.
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Proteínas Fluorescentes Verdes/metabolismo , Proteínas Inmovilizadas/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Péptidos Cíclicos/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Alanina/metabolismo , Sustitución de Aminoácidos , Línea Celular Tumoral , Cromatografía de Afinidad , Electroforesis en Gel de Poliacrilamida , Escherichia coli , Proteínas Fluorescentes Verdes/química , Proteínas Fluorescentes Verdes/genética , Humanos , Proteínas Inmovilizadas/química , Proteínas Inmovilizadas/genética , Leucemia Monocítica Aguda/metabolismo , Péptidos Cíclicos/química , Péptidos Cíclicos/genética , Unión Proteica , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genéticaRESUMEN
BACKGROUND: The purpose of our study was to find a novel targeted imaging and drug delivery vehicle for inflammatory bowel disease (IBD). IBD is a common and troublesome disease that still lacks effective therapy and imaging options. As an attempt to improve the disease treatment, we tested αMSH for the targeting of nanoliposomes to IBD sites. αMSH, an endogenous tridecapeptide, binds to the melanocortin-1 receptor (MC1-R) and has anti-inflammatory and immunomodulating effects. MC1-R is found on macrophages, neutrophils and the renal tubule system. We formulated and tested a liposomal nanoparticle involving αMSH in order to achieve a specific targeting to the inflamed intestines. METHODS: NDP-αMSH peptide conjugated to Alexa Fluor™ 680 was linked to the liposomal membrane via NSuccinyl PE and additionally loaded into the lumen of the liposomes. Liposomes without the αMSH-conjugate and free NDP-αMSH were used as a control. The liposomes were also loaded with ICG to track them. The liposomes were tested in DSS treated mice, which had received DSS via drinking water order to develop a model IBD. Inflammation severity was assessed by the Disease Activity Index (DAI) score and ex vivo histological CD68 staining of samples taken from different parts of the intestine. The liposome targeting was analyzed by analyzing the ICG and ALEXA 680 fluorescence in the intestine compared to the biodistribution. RESULTS: NPD-αMSH was successfully labeled with Alexa and retained its biological activity. Liposomes were identified in expected regions in the inflamed bowel regions and in the kidneys, where MC1-R is abundant. In vivo liposome targeting correlated with the macrophage concentration at the site of the inflammation supporting the active targeting of the liposomes through αMSH. The liposomal αMSH was well tolerated by animals. CONCLUSION: This study opens up the possibility to further develop an αMSH targeted theranostic delivery to different clinically relevant applications in IBD inflammation but also opens possibilities for use in other inflammations like lung inflammation in Covid 19.
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Enfermedades Inflamatorias del Intestino/diagnóstico por imagen , Liposomas , Nanopartículas , Receptor de Melanocortina Tipo 1/química , alfa-MSH/química , Animales , Colorantes Fluorescentes/química , Ratones , Distribución TisularRESUMEN
Few reports quantitatively compare the performance of photoacoustic tomography (PAT) versus fluorescence molecular tomography (FMT) in vivo. We compared both modalities for the detection of signals from injected ICG liposomes in the tibial medullary space of 10 BALB/c mice in vivo and ex vivo. Signals significantly correlated between modalities (R²â¯=â¯0.69) and within each modality in vivo versus ex vivo (PAT: R²â¯=â¯0.70, FMT: R²â¯=â¯0.76). Phantom studies showed that signals at 4â¯mm depth are detected down to 3.3â¯ng ICG by PAT and 33â¯ng by FMT, with a nominal spatial resolution below 0.5â¯mm in PAT and limited to 1â¯mm in FMT. Our study demonstrates comparable in vivo sensitivity, but superior ex vivo sensitivity and in vivo resolution for our ICG liposomes of the VevoLAZR versus the FMT2500. PAT provides a useful new tool for the high-resolution imaging of bone marrow signals, for example for monitoring drug delivery.
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BACKGROUND: Nanoparticle imaging and tracking the release of the loaded material from the nanoparticle system have attracted significant attention in recent years. If the release of the loaded molecules could be monitored reliably in vivo, it would speed up the development of drug delivery systems remarkably. METHODS: Here, we test a system that uses indocyanine green (ICG) as a fluorescent agent for studying release kinetics in vitro and in vivo from the lipid iron nanoparticle delivery system. The ICG spectral properties like its concentration dependence, sensitivity and the fluctuation of the absorption and emission wavelengths can be utilized for gathering information about the change of the ICG surrounding. RESULTS: We have found that the absorption, fluorescence, and photoacoustic spectra of ICG in lipid iron nanoparticles differ from the spectra of ICG in pure water and plasma. We followed the ICG containing liposomal nanoparticle uptake into squamous carcinoma cells (SCC) by fluorescence microscopy and the in vivo uptake into SCC tumors in an orthotopic xenograft nude mouse model under a surgical microscope. CONCLUSION: Absorption and emission properties of ICG in the different solvent environment, like in plasma and human serum albumin, differ from those in aqueous solution. Photoacoustic spectral imaging confirmed a peak shift towards longer wavelengths and an intensity increase of ICG when bound to the lipids. The SCC cells showed that the ICG containing liposomes bind to the cell surface but are not internalized in the SCC-9 cells after 60 minutes of incubation. We also showed here that ICG containing liposomal nanoparticles can be traced under a surgical camera in vivo in orthotopic SCC xenografts in mice.
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Verde de Indocianina , Nanopartículas , Animales , Liposomas , Ratones , Imagen Óptica , Análisis EspectralRESUMEN
Most available cancer chemotherapies are based on systemically administered small organic molecules, and only a tiny fraction of the drug reaches the disease site. The approach causes significant side effects and limits the outcome of the therapy. Targeted drug delivery provides an alternative to improve the situation. However, due to the poor release characteristics of the delivery systems, limitations remain. This report presents a new approach to address the challenges using two fundamentally different mechanisms to trigger the release from the liposomal carrier. We use an endogenous disease marker, an enzyme, combined with an externally applied magnetic field, to open the delivery system at the correct time only in the disease site. This site-activated release system is a novel two-switch nanomachine that can be regulated by a cell stress-induced enzyme at the cellular level and be remotely controlled using an applied magnetic field. We tested the concept using sphingomyelin-containing liposomes encapsulated with indocyanine green, fluorescent marker, or the anticancer drug cisplatin. We engineered the liposomes by adding paramagnetic beads to act as a receiver of outside magnetic energy. The developed multifunctional liposomes were characterized in vitro in leakage studies and cell internalization studies. The release system was further studied in vivo in imaging and therapy trials using a squamous cell carcinoma tumor in the mouse as a disease model. In vitro studies showed an increased release of loaded material when stress-related enzyme and magnetic field was applied to the carrier liposomes. The theranostic liposomes were found in tumors, and the improved therapeutic effect was shown in the survival studies.
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The poor prognosis associated with malignant melanoma has not changed substantially over the past 30 years. Targeted molecular therapies, such as immunotherapy, have shown promise but suffer from resistance and off-target toxicities, underscoring the need for alternative therapeutic strategies that can be used in combination with existing protocols. Moreover, peptides targeting melanoma-specific markers, like the melanocortin-1 receptor (MC1-R), for imaging and therapy exhibit high renal uptake that limits clinical translation. In the current study, the application of ultrasmall fluorescent (Cy5) silica nanoparticles (C' dots), conjugated with MC1-R targeting alpha melanocyte stimulating hormone (αMSH) peptides on the polyethylene glycol (PEG) coated surface, is examined for melanoma-selective imaging. αMSH peptide sequences, evaluated for conjugation to the PEG-Cy5-C' dot nanoparticles, bound to MC1-R with high affinity and targeted melanoma in syngenetic and xenografted melanoma mouse models. Results demonstrated a 10-fold improvement in MC1-R affinity over the native peptide alone following surface attachment of the optimal αMSH peptide. Systematic in vivo studies further demonstrated favorable in vivo renal clearance kinetics as well as receptor-mediated tumor cell internalization of as-developed radiolabeled particle tracers in B16F10 melanoma bearing mice. These findings highlight the ability of αMSH-PEG-Cy5-C' dots to overcome previous hurdles that prevented clinical translation of peptide and antibody-based melanoma probes and reveal the potential of αMSH-PEG-Cy5-C' dots for melanoma-selective imaging, image-guided surgery, and therapeutic applications.
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Nanopartículas , Animales , Humanos , Melanoma , Melanoma Experimental , Ratones , Receptor de Melanocortina Tipo 1 , Dióxido de Silicio , alfa-MSHRESUMEN
BACKGROUND: ß2 Integrins (cluster of differentiation-18, CD18) are expressed only by leukocytes and serve as cell surface receptors, being involved both in inside-out and outside-in signalling, and in cell movement. Therefore, they are interesting targets for therapeutic intervention. Phage display-derived inhibitory peptides against αMß2 integrins (macrophage-1 antigen, Mac-1) have been found to be effective in preventing leukocyte movement in vitro and in vivo but little is known regarding their ability to target leukaemia and lymphoma in vivo. MATERIALS AND METHODS: Athymic nude mice were inoculated with human THP-1 acute monocytic leukemia (AML-M5 variant), U937 diffuse histiocytic lymphoma, and OCI-AML-3 acute-myeloidic leukemia cells, and then treated with Mac-1-inhibiting peptides ADGACILWMDDGWCGAAG (DDGW) or CPCLLGCC fused with green fluorescent protein (LLG-GFP). RESULTS: Mac-1-inhibiting DDGW peptide had no effect on leukemia and lymphoma burden in mice, and LLG-GFP fusion did not home to leukemia cells in vivo. CONCLUSION: Although peptides against Mac-1 are promising drugs and diagnostic tools based on earlier experiments in inflammation they exhibit compromised biological avidity as a therapeutic and diagnostic means for leukaemia and lymphoma.
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Leucemia Monocítica Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Antígeno de Macrófago-1/metabolismo , Péptidos/farmacología , Secuencia de Aminoácidos , Animales , Femenino , Proteínas Fluorescentes Verdes/farmacocinética , Humanos , Leucemia Monocítica Aguda/metabolismo , Leucemia Monocítica Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Ratones , Ratones Desnudos , Datos de Secuencia Molecular , Péptidos/farmacocinética , Proteínas Recombinantes de Fusión/farmacocinética , Células U937 , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We have recently suggested a novel mechanism, autoendocytosis, for the entry of certain microbes into their hosts, with a key role played by the sphingomyelinase-catalyzed topical conversion of sphingomyelin to ceramide, the differences in the biophysical properties of these two lipids providing the driving force. The only requirement for such microbes to utilize this mechanism is that they should have a catalytically active SMase on their outer surface while the target cells should expose sphingomyelin in the external leaflet of their plasma membrane. In pursuit of possible microbial candidates, which could utilize this putative mechanism, we conducted a sequence similarity search for SMase. Because of the intriguing cellular and biochemical characteristics of the poorly understood entry of Chlamydia into its host cells these microbes were of particular interest. SMase activity was measured in vitro from isolated C. pneumoniae elementary bodies (EB) and in the lysate from E. coli cells transfected with a plasmid expressing CPn0300 protein having sequence similarity to SMase. Finally, pretreatment of host cells with exogenous SMase resulting in loss plasma membrane sphingomyelin attenuated attachment of EB.
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BACKGROUND: In immunopathological conditions, clinical diagnosis is commonly made on the basis of patient symptoms, measurement of blood leukocyte levels or proinflammatory biomarkers, non-specific radiological findings and, regarding infection, microbiological analysis. Nevertheless, frequently the exact spatial location of inflammation or even infection cannot be reliably identified, despite the use of up-to-date clinical, laboratory and imaging techniques. For this reason, new tools are warranted for use in advanced diagnosis and therapy targeting in patients. OBJECTIVE: The peptide CPCFLLGCC (LLG), known to bind activated ß2-integrins in vitro, was fused with green fluorescent protein (GFP) to test the ability of LLG fusions to target and bind activated leukocytes in vivo. METHODS: A murine skin scratch inflammation model was chosen for the convenient non-surgical detection of GFP. RESULTS: The murine skin lesion inflammation model demonstrated in vivo targeting of LLG-GFP to sites of inflammation. Targeting by LLG-GFP fusion construct depends on the ability of the LLG-moiety to bind activated leukocytes. Control construct unable to bind ß2-integrins appeared biologically inert. CONCLUSION: The data support the possibility of using this fluorescently labeled peptide as a tool for both the detection of and targeting to inflammatory sites characterized by robust leukocyte activation.
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Antígenos CD18/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Inflamación/inmunología , Leucocitos/citología , Leucocitos/metabolismo , Péptidos/química , Péptidos/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Animales , Antígenos CD18/inmunología , Línea Celular , Modelos Animales de Enfermedad , Humanos , Leucocitos/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
A first-in-human clinical trial of ultrasmall inorganic hybrid nanoparticles, "C dots" (Cornell dots), in patients with metastatic melanoma is described for the imaging of cancer. These renally excreted silica particles were labeled with (124)I for positron emission tomography (PET) imaging and modified with cRGDY peptides for molecular targeting. (124)I-cRGDY-PEG-C dot particles are inherently fluorescent, containing the dye, Cy5, so they may be used as hybrid PET-optical imaging agents for lesion detection, cancer staging, and treatment management in humans. However, the clinical translation of nanoparticle probes, including quantum dots, has not kept pace with the accelerated growth in minimally invasive surgical tools that rely on optical imaging agents. The safety, pharmacokinetics, clearance properties, and radiation dosimetry of (124)I-cRGDY-PEG-C dots were assessed by serial PET and computerized tomography after intravenous administration in patients. Metabolic profiles and laboratory tests of blood and urine specimens, obtained before and after particle injection, were monitored over a 2-week interval. Findings are consistent with a well-tolerated inorganic particle tracer exhibiting in vivo stability and distinct, reproducible pharmacokinetic signatures defined by renal excretion. No toxic or adverse events attributable to the particles were observed. Coupled with preferential uptake and localization of the probe at sites of disease, these first-in-human results suggest safe use of these particles in human cancer diagnostics.
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Nanopartículas , Óptica y Fotónica , Tomografía de Emisión de Positrones , Adulto , Anciano , Ensayos Clínicos como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sondas Moleculares , Proyectos de InvestigaciónRESUMEN
Recently, there have been several advancements in material sciences and nanosciences. At the moment these new techniques are slowly entering into clinical settings in drug delivery and imaging. In this review, we will look more closely at the applications that are at the forefront of this translation and examine critical aspects that are involved in the process. Nanoparticles have been increasingly used in clinical settings for drug delivery over the past two decades. Lipid-based nanoparticles are front-runners, but other innovative strategies, such as small inorganic nanoparticles, are entering into the field, particularly for imaging applications. Lipid-based nanoparticles can be metabolized and consumed by the body and are regarded as safe for clinical use. They are usually large with hydrodynamic diameters of approximately 100-200 nm; however, phospholipid-containing particles such as microbubbles with diameters as low as 10 microm in size and micelles with diameters of 10-40 nm can also be used. Hollow liposomes with a large aqueous inner cavity can carry high payloads of drugs and imaging moieties, but are easily trapped by liver kupffer cells and can result in lower tissue penetration rates. New classes of particles with hydrodynamic diameters of < 10 nm, which are cleared by the kidneys, have recently been developed. These particles have been used primarily for imaging applications since they offer only small loading capacities for drugs. However, new strategies such as surface-coupled prodrugs have been developed to facilitate drug delivery in small nanoparticles. We describe different strategies for targeted delivery, imaging and controlled release, and discuss the ability of small inorganic particles as well as larger nanoparticles to be used broadly in human diagnostics and drug delivery.
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Antineoplásicos/administración & dosificación , Portadores de Fármacos , Imagen Molecular/métodos , Nanomedicina , Nanopartículas , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Tecnología Farmacéutica/métodos , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Química Farmacéutica , Composición de Medicamentos , Humanos , Liposomas , Neoplasias/metabolismo , Neoplasias/patología , Tamaño de la PartículaRESUMEN
Dasatinib, a new-generation Src and platelet-derived growth factor receptor (PDGFR) inhibitor, is currently under evaluation in high-grade glioma clinical trials. To achieve optimum physicochemical and/or biologic properties, alternative drug delivery vehicles may be needed. We used a novel fluorinated dasatinib derivative (F-SKI249380), in combination with nanocarrier vehicles and metabolic imaging tools (microPET) to evaluate drug delivery and uptake in a platelet-derived growth factor B (PDGFB)-driven genetically engineered mouse model (GEMM) of high-grade glioma. We assessed dasatinib survival benefit on the basis of measured tumor volumes. Using brain tumor cells derived from PDGFB-driven gliomas, dose-dependent uptake and time-dependent inhibitory effects of F-SKI249380 on biologic activity were investigated and compared with the parent drug. PDGFR receptor status and tumor-specific targeting were non-invasively evaluated in vivo using (18)F-SKI249380 and (18)F-SKI249380-containing micellar and liposomal nanoformulations. A statistically significant survival benefit was found using dasatinib (95 mg/kg) versus saline vehicle (P < .001) in tumor volume-matched GEMM pairs. Competitive binding and treatment assays revealed comparable biologic properties for F-SKI249380 and the parent drug. In vivo, Significantly higher tumor uptake was observed for (18)F-SKI249380-containing micelle formulations [4.9 percentage of the injected dose per gram tissue (%ID/g); P = .002] compared to control values (1.6%ID/g). Saturation studies using excess cold dasatinib showed marked reduction of tumor uptake values to levels in normal brain (1.5%ID/g), consistent with in vivo binding specificity. Using (18)F-SKI249380-containing micelles as radiotracers to estimate therapeutic dosing requirements, we calculated intratumoral drug concentrations (24-60 nM) that were comparable to in vitro 50% inhibitory concentration values. (18)F-SKI249380 is a PDGFR-selective tracer, which demonstrates improved delivery to PDGFB-driven high-grade gliomas and facilitates treatment planning when coupled with nanoformulations and quantitative PET imaging approaches.