Nuclear medicine and biology · 2021
Towards the development of a targeted albumin-binding radioligand: Synthesis, radiolabelling and preliminary in vivo studies.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Driver Cathryn Helena Stanford, Ebenhan Thomas, Szucs Zoltan, Parker Mohammed Iqbal, Zeevaart Jan Rijn, Hunter Roger
Аннотация
INTRODUCTION: The compound named 4-[10-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanamido)decyl]-11-[10-(β,d-glucopyranos-1-yl)-1-oxodecyl]-1,4,8,11-tetraazacyclotetradecane-1,8-diacetic acid is a newly synthesised molecule capable of binding in vivo to albumin to form a bioconjugate. This compound was given the name, GluCAB(glucose-chelator-albumin-binder)-maleimide-1. Radiolabelled GluCAB-maleimide-1 and subsequent bioconjugate is proposed for prospective oncological applications and works on the theoretical dual-targeting principle of tumour localization through the "enhanced permeability and retention (EPR) effect" and glucose metabolism.
METHODS: The precursor, GluCAB-amine-2, and subsequent GluCAB-maleimide-1 was synthesised via sequential regioselective, distal N-functionalisation of a cyclam template with a tether containing a synthetically-derived β-glucoside followed by a second linker to incorporate a maleimide moiety for albumin-binding. GluCAB-amine-2 was radiolabelled with [64Cu]CuCl2 in 0.1 M NH4OAc (pH 3.5, 90 °C, 30 min), purified and converted post-labeling in 0.01 M PBS to [64Cu]Cu-GluCAB-maleimide-1. Serum stability and protein binding studies were completed according to described methods. Healthy BALB/c ice (three groups of n = 5) were injected intravenously with [64Cu]Cu-TETA, [64Cu]Cu-GluCAB-amine-2 or [64Cu]Cu-GluCAB-maleimide-1 and imaged using microPET/CT at 1, 2, 4, 8 and 24 h post-injection. Biodistribution of the compounds were determined ex vivo after 24 h using gamma counting.
RESULTS: GluCAB-maleimide-1 was synthesised in five consecutive steps with an overall yield of 11%. [64Cu]Cu-GluCAB-amine-2 (97% labelling efficiency) was converted to [64Cu]Cu-GluCAB-maleimide-1 (93% conversion; 90% radiochemical purity). Biodistribution analysis indicated that the control compounds were rapidly and almost completely excreted as compared to [64Cu]Cu-GluCAB-maleimide-1 that exhibited a prolonged biological half-life (6-8 h). Both, [64Cu]Cu-GluCAB-maleimide-1 and -amine-2 were excreted through the hepatobiliary system but a higher hepatic presence of the albumin-bound compound was noted. CONCLUSIONS, ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This initial evaluation paves the way for further investigation into the tumour targeting potential of [64Cu]Cu-GluCAB-maleimide-1. An efficient targeted radioligand will allow for further development of a prospective theranostic agent for more personalized patient treatment which potentially improves overall patient prognosis, outcome and health care.
METHODS: The precursor, GluCAB-amine-2, and subsequent GluCAB-maleimide-1 was synthesised via sequential regioselective, distal N-functionalisation of a cyclam template with a tether containing a synthetically-derived β-glucoside followed by a second linker to incorporate a maleimide moiety for albumin-binding. GluCAB-amine-2 was radiolabelled with [64Cu]CuCl2 in 0.1 M NH4OAc (pH 3.5, 90 °C, 30 min), purified and converted post-labeling in 0.01 M PBS to [64Cu]Cu-GluCAB-maleimide-1. Serum stability and protein binding studies were completed according to described methods. Healthy BALB/c ice (three groups of n = 5) were injected intravenously with [64Cu]Cu-TETA, [64Cu]Cu-GluCAB-amine-2 or [64Cu]Cu-GluCAB-maleimide-1 and imaged using microPET/CT at 1, 2, 4, 8 and 24 h post-injection. Biodistribution of the compounds were determined ex vivo after 24 h using gamma counting.
RESULTS: GluCAB-maleimide-1 was synthesised in five consecutive steps with an overall yield of 11%. [64Cu]Cu-GluCAB-amine-2 (97% labelling efficiency) was converted to [64Cu]Cu-GluCAB-maleimide-1 (93% conversion; 90% radiochemical purity). Biodistribution analysis indicated that the control compounds were rapidly and almost completely excreted as compared to [64Cu]Cu-GluCAB-maleimide-1 that exhibited a prolonged biological half-life (6-8 h). Both, [64Cu]Cu-GluCAB-maleimide-1 and -amine-2 were excreted through the hepatobiliary system but a higher hepatic presence of the albumin-bound compound was noted. CONCLUSIONS, ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This initial evaluation paves the way for further investigation into the tumour targeting potential of [64Cu]Cu-GluCAB-maleimide-1. An efficient targeted radioligand will allow for further development of a prospective theranostic agent for more personalized patient treatment which potentially improves overall patient prognosis, outcome and health care.