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-tetraazacydododecane-1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the beta-particle emitter, Lu-177. 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-pG1u(DOTA)(8)-LA(4)] and determine the elimination and biodistribution of these Lu-177-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 Lu-177-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 Lu-177-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 Lu-177. Our results showed that PEG-pG1u(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-pG1u(Lu-177-DOTA)(8)-LA(4) was the most stable in plasma. Whole body elimination of Lu-177 was most rapid for mice injected with Lu-177-DOTA-PEG-OPSS-AuNP. Urinary excretion accounted for >90% of eliminated Lu-177. All Lu-177-MCP-AuNP accumulated in the liver and spleen. Liver uptake was lowest for PEG-pG1u(Lu-177-DOTA)(8)-LA(4)-AuNP but these AuNP exhibited the greatest spleen uptake. There were differences in Au and Lu-177 in the liver for PEG-pG1u(Lu-177-DOTA)(8)-LA(4)-AuNP. These differences were not correlated with in vitro stability of the Lu-177-MCP-AuNP. We conclude that conjugation of AuNP with PEG-pG1u(Lu-177-DOTA)(8)-LA(4) 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 Lu-177-MCP-AuNP for radiation treatment of breast cancer.