RESUMEN
Recent advances and large-scale use of hybrid imaging modalities like PET-CT have led to the necessity of improving nano-drug carriers that can facilitate both functional and metabolic screening in nuclear medicine applications. In this study, we focused on the evaluation of four potential imaging nanoparticle structures labelled with the 68Ga positron emitter. For this purpose, we functionalized NHS-activated PEG-gold nanoparticles with 68Ga-DOTA-Neuromedin B, 68Ga-DOTA-PEG(4)-BBN(7-14), 68Ga-DOTA-NT and 68Ga-DOTA-Neuromedin N. In vitro binding kinetics and specific binding to human HT-29 colon carcinoma cells and DU-145 prostate carcinoma cells respectively were assessed, over 75% retention being obtained in the case of 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP in prostate tumour cells and over 50% in colon carcinoma cells. Biodistribution in NU/J mice highlighted a three-fold uptake increase in tumours at 30 min post-injection of 68Ga-DOTA-NT-AuNP and 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP compared to 68Ga-DOTA-NT and 68Ga-DOTA-PEG(4)-BBN(7-14) respectively, therewith fast distribution in prostate and colon tumours and minimum accumulation in non-targeted tissues.
Asunto(s)
Neoplasias del Colon/diagnóstico por imagen , Oro/administración & dosificación , Neuroquinina B/análogos & derivados , Neurotensina/química , Fragmentos de Péptidos/química , Péptidos/química , Neoplasias de la Próstata/diagnóstico por imagen , Animales , Disponibilidad Biológica , Bombesina/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Radioisótopos de Galio/administración & dosificación , Radioisótopos de Galio/química , Radioisótopos de Galio/farmacocinética , Oro/química , Oro/farmacocinética , Células HT29 , Humanos , Masculino , Nanopartículas del Metal/química , Ratones , Trasplante de Neoplasias , Neuroquinina B/química , Péptidos/administración & dosificación , Péptidos/farmacocinética , Tomografía de Emisión de Positrones , Neoplasias de la Próstata/metabolismo , Receptores de Bombesina/metabolismo , Receptores de Neurotensina/metabolismoRESUMEN
The neurotensin is a tridecapeptide involved in the proliferation of colon cancer, the overexpression of neurotensin receptors occurring at an early stage development of many tumours. Targeting neurotensin receptors by using the same biological active molecule is an effective approach for both imaging quantification and treatment. The present work aimed to demonstrate the ability of radiolabelled neurotensin to specifically target colon cancer cells, and substantiate its usefulness in targeted imaging and radiotherapy, depending on the emission of the coupled radioisotope. Syntheses of 68Ga-DOTA-NT and 177Lu-DOTA-NT were developed to obtain a level of quality suitable for preclinical use with consistent high synthesis yields. Radiochemical purity meets the pharmaceutical requirements, and it is maintained 4 h for 68Ga-DOTA-NT and 48 h for 177Lu-DOTA-NT. Extensive in vitro studies were conducted to assess the uptake and retention of 68Ga-DOTA-NT, the amount of non-specific binding of neurotensin and the effect of 177Lu-DOTA-NT on HT-29 cells. In vivo biodistribution of 68Ga-DOTA-NT revealed significant uptake at the tumour site, along with fast clearance evidenced by decreasing activity in kidneys and blood after 60 min p.i. 177Lu-DOTA-NT exhibited similar uptake in the tumour, but also a significant uptake at 14 days p.i. in the bone marrow was reported. These results successfully demonstrated the potential of neurotensin to deliver imaging/therapeutic 68Ga/177Lu radioisotopes pair, but also the need for further evaluation of the possible radiotoxicity effects on the liver, kidneys or bone marrow.