title: Synthesis and biological evaluation of folate receptor-targeted boronated PAMAM dendrimers as potential agents for neutron capture therapy.
abstract: Successful treatment of cancer by boron neutron capture therapy (BNCT) requires the selective delivery of (10)B to constituent cells within a tumor. The expression of the folate receptor is amplified in a variety of human tumors and potentially might serve as a molecular target for BNCT. In the present study we have investigated the possibility of targeting the folate receptor on cancer cells using folic acid conjugates of boronated poly(ethylene glycol) (PEG) containing 3rd generation polyamidoamine dendrimers to obtain (10)B concentrations necessary for BNCT by reducing the uptake of these conjugates by the reticuloendothelial system. First we covalently attached 12-15 decaborate clusters to 3rd generation polyamidoamine dendrimers. Varying quantities of PEG units with varying chain lengths were then linked to these boronated dendrimers to reduce hepatic uptake. Among all prepared combinations, boronated dendrimers with 1-1.5 PEG(2000) units exhibited the lowest hepatic uptake in C57BL/6 mice (7.2-7.7% injected dose (ID)/g liver). Thus, two folate receptor-targeted boronated 3rd generation polyamidoamine dendrimers were prepared, one containing approximately 15 decaborate clusters and approximately 1 PEG(2000) unit with folic acid attached to the distal end, the other containing approximately 13 decaborate clusters, approximately 1 PEG(2000) unit, and approximately 1 PEG(800) unit with folic acid attached to the distal end. In vitro studies using folate receptor (+) KB cells demonstrated receptor-dependent uptake of the latter conjugate. Biodistribution studies with this conjugate in C57BL/6 mice bearing folate receptor (+) murine 24JK-FBP sarcomas resulted in selective tumor uptake (6.0% ID/g tumor), but also high hepatic (38.8% ID/g) and renal (62.8% ID/g) uptake, indicating that attachment of a second PEG unit and/or folic acid may adversely affect the pharmacodynamics of this conjugate.
authors.affiliation: College of Pharmacy, Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Shukla
authors.forename: Gong
authors.initials: G
authors.lastname: Wu
authors.forename: Madhumita
authors.initials: M
authors.lastname: Chatterjee
authors.forename: Weilian
authors.initials: W
authors.lastname: Yang
authors.forename: Masaru
authors.initials: M
authors.lastname: Sekido
authors.forename: Lamine A
authors.initials: LA
authors.lastname: Diop
authors.forename: Rainer
authors.initials: R
authors.lastname: Müller
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Sudimack
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Barth
authors.forename: Werner
authors.initials: W
authors.lastname: Tjarks
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000493:pharmacokinetics; D001896:Boron Compounds / Q000737:chemistry* / Q000493:pharmacokinetics*; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D002352:Carrier Proteins / Q000378:metabolism*; D050091:Dendrimers; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000737:chemistry / Q000493:pharmacokinetics; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000628:therapy; D011073:Polyamines / Q000737:chemistry / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000737:chemistry; D011956:Receptors, Cell Surface; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D001672:Biocompatible Materials; D001896:Boron Compounds; D002352:Carrier Proteins; D050091:Dendrimers; D004337:Drug Carriers; D058973:Folate Receptors, GPI-Anchored; D009363:Neoplasm Proteins; C104700:PAMAM Starburst; D011073:Polyamines; D011956:Receptors, Cell Surface; D011092:Polyethylene Glycols; D005492:Folic Acid