title: Stability and Biodistribution of Thiol-Functionalized and (177)Lu-Labeled Metal Chelating Polymers Bound to Gold Nanoparticles.
abstract: 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.
authors.forename: Simmyung
authors.initials: S
authors.lastname: Yook
authors.forename: Yijie
authors.initials: Y
authors.lastname: Lu
authors.forename: Jenny Jooyoung
authors.initials: JJ
authors.lastname: Jeong
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Cai
authors.forename: Lemuel
authors.initials: L
authors.lastname: Tong
authors.forename: Ramina
authors.initials: R
authors.lastname: Alwarda
authors.affiliation: Department of Radiation Oncology, Erasmus MC Cancer Institute , Rotterdam, The Netherlands.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pignol
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Winnik
authors.affiliation: Toronto General Research Institute and Joint Department of Medical Imaging, University Health Network , Toronto, Ontario, Canada.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Reilly
mesh_terms: D000818:Animals; D001610:Beta Particles / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000532:radiotherapy*; D005260:Female; D006046:Gold / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D008187:Lutetium / Q000737:chemistry / Q000627:therapeutic use*; D053768:Metal Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D050997:Nanomedicine / Q000379:methods*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D011868:Radioisotopes / Q000737:chemistry / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000627:therapeutic use*; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D011108:Polymers; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D013438:Sulfhydryl Compounds; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D008187:Lutetium; D006046:Gold