RESUMO
Personalized medicine approach in radiotherapy requires the delivery of precise dose to the tumor. The concept is to increase the effectiveness of radiotherapy while sparing the surrounding heathy tissue. This can be achieved by the use of high-Z metal-based nanoparticles (NPs) as radio-enhancers and PET imaging for mapping NPs distribution to guide the irradiation. In the present study, radio-enhancing platinum NPs were radiolabeled and imaged to assess their pharmacokinetics over time. PET imaging of these NPs revealed high enhanced permeation and retention effect. The maximal tumor accumulation (4.8 ± 0.8 %ID/cc) was observed at 24 h post-injection along with persistent accumulation of the NPs, especially at the tumor ring, even after several days. These properties positively suggest the potential clinical use of these NPs.
Assuntos
Nanopartículas Metálicas , Nanopartículas , Neoplasias , Humanos , Platina , Tomografia por Emissão de Pósitrons/métodos , Distribuição TecidualRESUMO
Molecular imaging with PET offers an alternative method to quantify programmed-death-ligand 1 (PD-L1) to accurately select patients for immunotherapies. More and more clinical and preclinical trials involve radiolabeling of antibody fragments for their desirably fast clearance and high tumor penetration. As the radiolabeling strategy can significantly impact pharmacokinetics and biodistribution, we explored in this work a site-specific radiofluorination strategy on an anti-PD-L1 fragment antigen-binding (Fab) and compared the pharmacokinetic and biodistribution properties with the same Fab labeled using stochastic radiolabeling chemistry. We applied an enzymatic bioconjugation mediated by a variant of the lipoic acid ligase (LplA) that promotes the formation of an amide bond between a short peptide cloned onto the C terminus of the Fab. A synthetic analogue of the enzyme natural substrate, lipoic acid, was radiolabeled with fluorine-18 for site-specific conjugation by LplA. We compared the biodistribution of the site-specifically labeled Fab with a stochastically labeled Fab on lysine side chains in tumor-bearing mice. The two methods of fluorination demonstrate a comparable whole-body biodistribution. The 89Zr-labeled Fab had different biodistribution compared to either 18F-labeled Fab. We attribute the difference to [89Zr] metabolism. Fab-LAP-[18F]FPyOctA therefore reflects better the true pharmacokinetic profile of the Fab.
Assuntos
Neoplasias , Ácido Tióctico , Amidas , Animais , Antígeno B7-H1 , Linhagem Celular Tumoral , Radioisótopos de Flúor , Fragmentos de Imunoglobulinas/metabolismo , Ligantes , Ligases/metabolismo , Lisina/metabolismo , Camundongos , Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
AGuIX are emerging radiosensitizing nanoparticles (NPs) for precision radiotherapy (RT) under clinical evaluation (Phase 2). Despite being accompanied by MRI thanks to the presence of gadolinium (Gd) at its surface, more sensitive and quantifiable imaging technique should further leverage the full potential of this technology. In this study, it is shown that 89 Zr can be labeled on such NPs directly for positron emission tomography (PET) imaging with a simple and scalable method. The stability of such complexes is remarkable in vitro and in vivo. Using a glioblastoma orthotopic rat model, it is shown that injected 89 Zr-AGuIX is detectable inside the tumor for at least 1 week. Interestingly, the particles seem to efficiently infiltrate the tumor even in necrotic areas, which places great hope for the treatment of radioresistant tumor. Lastly, the first PET/MR whole-body imaging is performed in non-human primate (NHP), which further demonstrates the translational potential of these bimodal NP.
Assuntos
Glioblastoma , Nanopartículas , Animais , Meios de Contraste , Glioblastoma/diagnóstico por imagem , Humanos , Macaca , Imageamento por Ressonância Magnética , Imagem Multimodal , RatosRESUMO
Rationale: MQ1, a snake toxin which targets with high nanomolar affinity and absolute selectivity for the type 2 vasopressin receptor (V2R), is a drug candidate for renal diseases and a molecular probe for imaging cells or organs expressing V2R. Methods: MQ1's pharmacological properties were characterized and applied to a rat model of hyponatremia. Its PK/PD parameters were determined as well as its therapeutic index. Fluorescently and radioactively labeled MQ1 were chemically synthesized and associated with moderate loss of affinity. MQ1's dynamic biodistribution was monitored by positron emission tomography. Confocal imaging was used to observe the labeling of three cancer cell lines. Results: The inverse agonist property of MQ1 very efficiently prevented dDAVP-induced hyponatremia in rats with low nanomolar/kg doses and with a very large therapeutic index. PK (plasma MQ1 concentrations) and PD (diuresis) exhibited a parallel biphasic decrease. The dynamic biodistribution showed that MQ1 targets the kidneys and then exhibits a blood and kidney biphasic decrease. Whatever the approach used, we found a T1/2α between 0.9 and 3.8 h and a T1/2ß between 25 and 46 h and demonstrated that the kidneys were able to retain MQ1. Finally, the presence of functional V2R expressed at the membrane of cancer cells was, for the first time, demonstrated with a specific fluorescent ligand. Conclusion: As the most selective V2 binder, MQ1 is a new promising drug for aquaresis-related diseases and a molecular probe to visualize in vitro and in vivo V2R expressed physiologically or under pathological conditions.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Hiponatremia/tratamento farmacológico , Receptores de Vasopressinas/metabolismo , Venenos de Serpentes/farmacologia , Água/metabolismo , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Desamino Arginina Vasopressina/administração & dosagem , Diabetes Insípido Nefrogênico/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Hiponatremia/induzido quimicamente , Hiponatremia/diagnóstico , Hiponatremia/metabolismo , Rim/diagnóstico por imagem , Rim/metabolismo , Masculino , Imagem Molecular/métodos , Tomografia por Emissão de Pósitrons , Ratos , Eliminação Renal/efeitos dos fármacos , Venenos de Serpentes/uso terapêutico , Sódio/sangue , Distribuição TecidualRESUMO
Epidermal growth factor receptor (EGFR), involved in cell proliferation and migration, is overexpressed in ~50% of glioblastomas. Anti-EGFR based strategies using monoclonal antibodies (mAb) such as cetuximab (CTX) have been proposed for central nervous system (CNS) cancer therapy. However, the blood-brain barrier (BBB) drastically restricts their brain penetration which limits their efficacy for the treatment of glioblastomas. Herein, a longitudinal PET imaging study was performed to assess the relevance and the impact of focused ultrasound (FUS)-mediated BBB permeabilization on the brain exposure to the anti-EGFR mAb CTX over time. For this purpose, FUS permeabilization process with microbubbles was applied on intact BBB mouse brain before the injection of 89Zr-labeled CTX for longitudinal imaging monitoring. FUS induced a dramatic increase in mAb penetration to the brain, 2 times higher compared to the intact BBB. The transfer of 89Zr-CTX from blood to the brain was rendered significant by FUS (kuptake = 1.3 ± 0.23 min-1 with FUS versus kuptake = 0 ± 0.006 min-1 without FUS). FUS allowed significant and prolonged exposure to mAb in the brain parenchyma. This study confirms the potential of FUS as a target delivery method for mAb in CNS.
Assuntos
Barreira Hematoencefálica , Microbolhas , Animais , Encéfalo , Cetuximab , Sistemas de Liberação de Medicamentos , Cinética , CamundongosRESUMO
PURPOSE: Heavy-metal chelators and inorganic nanoparticles (NPs) have been examined as potential radioenhancers to increase the efficacy of external beam radiation therapy for various cancers. Most of these agents have, unfortunately, displayed relatively poor pharmacokinetic properties, which limit the percentage of injected dose (%ID/g) that localizes to tumors and which shorten the window for effective radiation enhancement due to rapid tumor washout. METHODS AND MATERIALS: To address these challenges, we sought to conjugate gadolinium-based ultrasmall (<5 nm) NPs to an antibody directed against the oncogenic MUC1-C subunit that is overexpressed on the surface of many different human cancer types. The binding of the anti-MUC1-C antibody 3D1 to MUC1-C on the surface of a cancer cell is associated with its internalization and, thereby, to effective intracellular delivery of the antibody-associated payload, promoting its effective tumor retention. As such, we examined whether systemically administered anti-MUC1-C antibody-conjugated, gadolinium-based NPs (anti-MUC1-C/NPs) could accumulate within cell-line xenograft models of MUC1-C-expressing (H460) lung and (E0771) breast cancers to improve the efficacy of radiation therapy (XRT). RESULTS: The %ID/g of anti-MUC1-C/NPs that accumulated within tumors was found to be similar to that of their unconjugated counterparts (6.6 ± 1.4 vs 5.9 ± 1.7 %ID/g, respectively). Importantly, the anti-MUC1-C/NPs demonstrated prolonged retention in in vivo tumor microenvironments; as a result, the radiation boost was maintained during the course of fractionated therapy (3 × 5.2 Gy). We found that by administering anti-MUC1-C/NPs with XRT, it was possible to significantly augment tumor growth inhibition and to prolong the animals' overall survival (46.2 ± 3.1 days) compared with the administration of control NPs with XRT (31.1 ± 2.4 days) or with XRT alone (27.3 ± 1.6 days; P < .01, log-rank). CONCLUSIONS: These findings suggest that anti-MUC1-C/NPs could be used to enhance the effectiveness of radiation therapy and potentially to improve clinical outcomes.
Assuntos
Gadolínio/uso terapêutico , Imunoconjugados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Neoplasias Pulmonares/radioterapia , Mucina-1/imunologia , Nanopartículas/uso terapêutico , Neoplasias de Mama Triplo Negativas/radioterapia , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/uso terapêutico , Linhagem Celular Tumoral , Dano ao DNA , Fracionamento da Dose de Radiação , Feminino , Gadolínio/metabolismo , Humanos , Imunoconjugados/química , Imunoconjugados/metabolismo , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mucina-1/metabolismo , Nanopartículas/química , Nanopartículas/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Microambiente TumoralRESUMO
We report the first pretargeting in vivo study using the Strain-Promoted Sydnone-Alkyne Cycloaadition (SPSAC) reaction. The injection of a fluorine-18 labeled cyclooctyne three days after cetuximab bearing chlorosydnone moieties allowed a significant detection of the tumor by PET imaging suggesting an efficient click reaction inside the tumoral site. With a kinetic constant superior to 300 M-1 s-1, the SPSAC reaction might be an interesting tool, in addition to tetrazine-cyclooctene ligation, for in vivo chemistry.
Assuntos
Alcinos/química , Química Click/métodos , Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons/métodos , Animais , Ciclização , Xenoenxertos , Humanos , CamundongosRESUMO
AGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck ). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human.
Assuntos
Gadolínio/administração & dosagem , Nanopartículas/administração & dosagem , Radiossensibilizantes/administração & dosagem , Nanomedicina Teranóstica/métodos , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Previsões , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Melanoma/patologia , Melanoma/terapia , Camundongos , Nanomedicina Teranóstica/tendênciasRESUMO
A novel trifunctional imaging probe containing a chelator of radiometal for PET, a NIR heptamethine cyanine dye, and a bioconjugatable handle, has been grafted onto AGuIX® nanoparticles via a Michael addition reaction. The resulting functionalized nanoparticles have been fully characterized, radiolabelled with 64Cu, and evaluated in a mice TSA tumor model using multimodal (PET/MRI/optical) imaging.
RESUMO
Multimodal nanoprobes are highly demanded for biomedical imaging applications to enhance the reliability of the diagnostic results. Among different types of nano-objects, ultrasmall silica gadolinium nanoparticle (SiGdNP) appears as a safe, effective, and versatile platform for this purpose. In this study, a new method to functionalize SiGdNP based on silane chemistry has been reported. Two types of chelating silanes (APTES-DOTAGA and APTES-NODAGA) have been synthesized and grafted on SiGdNP by a simple one-step protocol. This functionalization strategy requires no other reactants or catalyzers and does not compromise the ultrasmall size of the particles. NODAGA-functionalized particle has been labeled with 64Cu isotope and injected intravenously to mice bearing TS/A carcinoma tumor for biodistribution study to demonstrate its potential as a bimodal MRI/PET imaging agent. A fully integrated MRI/PET system was used to simultaneously monitor the distribution of the particle. The results showed that the functionalized particle maintained properties of a renal clearable NP which could rapidly escape through kidneys and had low retention in other organs, especially liver, even though its accumulation in the tumor was modest.
Assuntos
Sondas Moleculares/química , Imagem Multimodal/métodos , Nanopartículas/química , Animais , Linhagem Celular Tumoral , Quelantes , Cobre/farmacocinética , Gadolínio , Xenoenxertos , Humanos , Rim/metabolismo , Imageamento por Ressonância Magnética/métodos , Camundongos , Tomografia por Emissão de Pósitrons/métodos , Silanos , Dióxido de SilícioRESUMO
Ultrasmall silica nanoparticles (NPs), having hydrodynamic diameters under 10 nm are promising inorganic platforms for imaging and therapeutic applications in medicine. Herein is described a new way for synthesizing such kind of NPs in a one-pot scalable protocol. These NPs bear DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) ligands on their surface that can chelate different metals suitable for a wide variety of biomedical applications. By varying the ratio of the precursors, the hydrodynamic diameters of the particles can be controlled over the range of 3 to 15 nm. The resulting NPs have been characterized extensively by complementary techniques like dynamic light scattering (DLS), high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), mass spectrometry (MS), phosphorescence titration, photophysical measurements, relaxometry and elemental analysis to elucidate their structures. Chelation of gadolinium (Gd) allowed its use as an effective intravenous contrast agent in MRI and was illustrated in mice bearing colorectal CT26 tumors. The new particle appears to sufficiently accumulate in the tumors and efficiently clear out of animal bodies through kidneys. This new synthesis is an original, time/material-saving and very flexible process that can be applied for creating versatile ultrasmall multifunctional nanomedicines.
RESUMO
Nanoparticles containing high-Z elements are known to boost the efficacy of radiation therapy. Gadolinium (Gd) is particularly attractive because this element is also a positive contrast agent for MRI, which allows for the simultaneous use of imaging to guide the irradiation and to delineate the tumor. In this study, we used the Gd-based nanoparticles, AGuIX®. After intravenous injection into animals bearing B16F10 tumors, some nanoparticles remained inside the tumor cells for more than 24 hours, indicating that a single administration of nanoparticles might be sufficient for several irradiations. Combining AGuIX® with radiation therapy increases tumor cell death, and improves the life spans of animals bearing multiple brain melanoma metastases. These results provide preclinical proof-of-concept for a phase I clinical trial.