Yook Simmyung, Lu Yijie, Jeong Jenny Jooyoung, Cai Zhongli, Tong Lemuel, Alwarda Ramina, Pignol Jean-Philippe, Winnik Mitchell A, Reilly Raymond M
Department of Radiation Oncology, Erasmus MC Cancer Institute , Rotterdam, The Netherlands.
Toronto General Research Institute and Joint Department of Medical Imaging, University Health Network , Toronto, Ontario, Canada.
Biomacromolecules. 2016 Apr 11;17(4):1292-302. doi: 10.1021/acs.biomac.5b01642. Epub 2016 Mar 25.
We are studying a novel radiation nanomedicine approach to treatment of breast cancer using 30 nm gold nanoparticles (AuNP) modified with polyethylene glycol (PEG) metal-chelating polymers (MCP) that incorporate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the β-particle emitter, (177)Lu. Our objective was to compare the stability of AuNP conjugated to MCP via a single thiol [DOTA-PEG-ortho-pyridyl disulfide (OPSS)], a dithiol [DOTA-PEG-lipoic acid (LA)] or multithiol end-group [PEG-pGlu(DOTA)8-LA4] and determine the elimination and biodistribution of these (177)Lu-labeled MCP-AuNP in mice. Stability to aggregation in the presence of thiol-containing dithiothreitol (DTT), L-cysteine or glutathione was assessed and dissociation of (177)Lu-MCP from AuNP in human plasma measured. Elimination of radioactivity from the body of athymic mice and excretion into the urine and feces was measured up to 168 h post-intravenous (i.v.) injection of (177)Lu-MCP-AuNP and normal tissue uptake was determined. ICP-AES was used to quantify Au in the liver and spleen and these were compared to (177)Lu. Our results showed that PEG-pGlu(DOTA)8-LA4-AuNP were more stable to aggregation in vitro than DOTA-PEG-LA-AuNP and both forms of AuNP were more stable to thiol challenge than DOTA-PEG-OPSS-AuNP. PEG-pGlu((177)Lu-DOTA)8-LA4 was the most stable in plasma. Whole body elimination of (177)Lu was most rapid for mice injected with (177)Lu-DOTA-PEG-OPSS-AuNP. Urinary excretion accounted for >90% of eliminated (177)Lu. All (177)Lu-MCP-AuNP accumulated in the liver and spleen. Liver uptake was lowest for PEG-pGlu((177)Lu-DOTA)8-LA4-AuNP but these AuNP exhibited the greatest spleen uptake. There were differences in Au and (177)Lu in the liver for PEG-pGlu((177)Lu-DOTA)8-LA4-AuNP. These differences were not correlated with in vitro stability of the (177)Lu-MCP-AuNP. We conclude that conjugation of AuNP with PEG-pGlu((177)Lu-DOTA)8-LA4 via a multithiol functional group provided the greatest stability in vitro and lowest liver uptake in vivo and is, therefore, the most promising for constructing (177)Lu-MCP-AuNP for radiation treatment of breast cancer.
我们正在研究一种新型的放射纳米医学方法，用于治疗乳腺癌，该方法使用经聚乙二醇（PEG）金属螯合聚合物（MCP）修饰的30纳米金纳米颗粒（AuNP），其中MCP包含1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）螯合剂，用于络合β粒子发射体（177）Lu。我们的目标是比较通过单硫醇[DOTA-PEG-邻吡啶基二硫化物（OPSS）]、二硫醇[DOTA-PEG-硫辛酸（LA）]或多硫醇端基[PEG-pGlu（DOTA）8-LA4]与MCP共轭的AuNP的稳定性，并确定这些（177）Lu标记的MCP-AuNP在小鼠体内的消除和生物分布。评估了在含硫醇的二硫苏糖醇（DTT）、L-半胱氨酸或谷胱甘肽存在下的聚集稳定性，并测量了人血浆中（177）Lu-MCP从AuNP的解离情况。在静脉注射（177）Lu-MCP-AuNP后长达168小时，测量了无胸腺小鼠体内放射性的消除以及尿液和粪便中的排泄情况，并确定了正常组织的摄取。使用电感耦合等离子体原子发射光谱法（ICP-AES）对肝脏和脾脏中的金进行定量，并将其与（177）Lu进行比较。我们的结果表明，PEG-pGlu（DOTA）8-LA4-AuNP在体外比DOTA-PEG-LA-AuNP更稳定，两种形式的AuNP对硫醇攻击都比DOTA-PEG-OPSS-AuNP更稳定。PEG-pGlu（（177）Lu-DOTA）8-LA4在血浆中最稳定。对于注射了（177）Lu-DOTA-PEG-OPSS-AuNP的小鼠，（177）Lu的全身消除最快。尿液排泄占消除的（177）Lu的>90%。所有（177）Lu-MCP-AuNP都在肝脏和脾脏中积累。PEG-pGlu（（177）Lu-DOTA）8-LA4-AuNP的肝脏摄取最低，但这些AuNP在脾脏中的摄取最大。PEG-pGlu（（177）Lu-DOTA）8-LA4-AuNP在肝脏中的金和（177）Lu存在差异。这些差异与（177）Lu-MCP-AuNP的体外稳定性无关。我们得出结论，通过多硫醇官能团将AuNP与PEG-pGlu（（177）Lu-DOTA）8-LA4共轭在体外提供了最大的稳定性，在体内肝脏摄取最低，因此，对于构建用于乳腺癌放射治疗的（177）Lu-MCP-AuNP最有前景。
