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1.
Bioorg Chem ; 146: 107275, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38493637

RESUMO

Early diagnosis and precise surgical intervention are crucial for cancer patients. We aimed to develop a novel positron emission tomography (PET)/fluorescence dual-modality probe for preoperative diagnosis, intraoperative guidance, and postoperative monitoring of fibroblast activation protein (FAP)-positive tumors. FAPI-FAM was synthesized and labeled with gallium-68. [68Ga]Ga-FAPI-FAM showed favorable in vivo and in vitro characteristics, specific binding affinity, and excellent tumor accumulation in FAP-positive cells and mice xenografts. Excellent tumor-to-background contrast was found owing to high tumor uptake, prolonged retention, and rapid renal clearance of [68Ga]Ga-FAPI-FAM. Moreover, a specific fluorescence signal was detected in FAP-positive tumors during ex vivo fluorescence imaging, demonstrating the feasibility of whole-body tumor detection and intraoperative tumor delineation.


Assuntos
Neoplasias , Quinolinas , Humanos , Camundongos , Animais , Radioisótopos de Gálio , Fluorescência , Tomografia por Emissão de Pósitrons/métodos , Neoplasias/metabolismo , Fibroblastos/metabolismo
2.
Eur J Med Chem ; 264: 115993, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38039792

RESUMO

Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts in more than 90% of epithelial tumors. Several radiotracers targeting FAPs have been used in clinical settings in recent years. However, the number of 18F-labeled FAP tracers is still limited. Herein, we aimed to develop 18F-labeled FAP tracers with optimized pharmacokinetics. Labeling precursors (NOTA-DD-FAPI and NOTA-PD-FAPI) were synthesized and labeled with fluorine-18. The precursors NOTA-DD-FAPI (IC50 = 0.21 ± 0.06 nM) and NOTA -PD-FAPI (IC50 = 0.13 ± 0.07 nM) showed a higher affinity for FAP compared to NOTA-FAPI-42 (IC50 = 0.66 ± 0.19 nM). Novel 18F-labeled FAP tracers showed a specific uptake, high internalized fraction, and low cellular efflux in vitro. Compared to the clinically used tracer [18F]AlF-FAPI-42, both the novel 18F-labeled FAP tracers, and especially the [18F]AlF-PD-FAPI tracer with a higher tumor-to-background ratio demonstrated rapid renal excretion and higher tumor uptake during preclinical evaluation, resulting in images with higher contrast. Thus, [18F]AlF-PD-FAPI shows promise for use as a FAP-targeting tracer for clinical translation.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma , Humanos , Tomografia por Emissão de Pósitrons/métodos , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioisótopos de Gálio , Fibroblastos
3.
Mol Pharm ; 21(2): 883-894, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38155100

RESUMO

Recently, we developed a bivalent prostate-specific membrane antigen (PSMA) radioligand ([18F]AlF-Bi-PSMA), which showed higher tumor uptake and retention in PSMA-positive mouse models than the clinically used radioligands, [68Ga]Ga-PSMA-11 and [18F]PSMA-1007. Here, we developed two 177Lu-labeled bivalent PSMA ligands with (DOTA-Alb-Bi-PSMA) or without an albumin-binding motif (DOTA-Bi-PSMA) to enhance radiotherapeutic efficacy with minimal toxicity. The results demonstrated that both 177Lu-labeled bivalent radioligands showed good stability, high binding affinity, and PSMA-targeting specificity in vitro. Compared with [177Lu]Lu-PSMA-617, both [177Lu]Lu-Bi-PSMA and [177Lu]Lu-Alb-Bi-PSMA showed a higher area under the curve (AUC) of tumor accumulation and superior therapeutic efficacy. However, [177Lu]Lu-Alb-Bi-PSMA exhibited a dose-dependent increase in acute damage to kidneys. In terms of the radionuclide therapy efficacy and side effects, [177Lu]Lu-Bi-PSMA exhibited well-balanced action with high tumor-to-organs AUC ratios, resulting in remarkable therapeutic efficacy and negligible side effects. These promising results warrant further investigations to achieve the clinical translation of [177Lu]Lu-Bi-PSMA.


Assuntos
Próstata , Neoplasias da Próstata , Humanos , Masculino , Animais , Camundongos , Próstata/metabolismo , Radioisótopos de Gálio/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Albuminas/metabolismo , Lutécio/uso terapêutico , Antígeno Prostático Específico/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Ligantes
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