Stability and Biodistribution of Thiol-Functionalized and 177Lu-Labeled Metal Chelating Polymers Bound to Gold Nanoparticles

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• 作者：Simmyung Yook ; Yijie Lu ; Jenny Jooyoung Jeong ; Zhongli Cai ; Lemuel Tong ; Ramina Alwarda ; Jean-Philippe Pignol ; Mitchell A. Winnik ; Raymond M. Reilly
• 刊名：Biomacromolecules
• 出版年：2016
• 出版时间：April 11, 2016
• 年：2016
• 卷：17
• 期：4
• 页码：1292-1302
• 全文大小：627K
• 年卷期：0
• ISSN：1526-4602

文摘

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, ¹⁷⁷Lu. 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 ¹⁷⁷Lu-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 ¹⁷⁷Lu-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 ¹⁷⁷Lu-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 ¹⁷⁷Lu. Our results showed that PEG-pGlu(DOTA)₈-LA_4-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(¹⁷⁷Lu-DOTA)₈-LA₄ was the most stable in plasma. Whole body elimination of ¹⁷⁷Lu was most rapid for mice injected with ¹⁷⁷Lu-DOTA-PEG-OPSS-AuNP. Urinary excretion accounted for >90% of eliminated ¹⁷⁷Lu. All ¹⁷⁷Lu-MCP-AuNP accumulated in the liver and spleen. Liver uptake was lowest for PEG-pGlu(¹⁷⁷Lu-DOTA)₈-LA₄-AuNP but these AuNP exhibited the greatest spleen uptake. There were differences in Au and ¹⁷⁷Lu in the liver for PEG-pGlu(¹⁷⁷Lu-DOTA)₈-LA₄-AuNP. These differences were not correlated with in vitro stability of the ¹⁷⁷Lu-MCP-AuNP. We conclude that conjugation of AuNP with PEG-pGlu(¹⁷⁷Lu-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 ¹⁷⁷Lu-MCP-AuNP for radiation treatment of breast cancer.