Synthesis and Biological Evaluation of Folate Receptor-Targeted Boronated PAMAM Dendrimers as Potential Agents for Neutron Capture Therapy

• Published in: Bioconjugate chemistry 2003-01, Vol.14 (1), p.158-167
• Main Authors: Shukla, Supriya, Wu, Gong, Chatterjee, Madhumita, Yang, Weilian, Sekido, Masaru, Diop, Lamine A, Müller, Rainer, Sudimack, Jennifer J, Lee, Robert J, Barth, Rolf F, Tjarks, Werner
• Format: Article
• Language: English
• Subjects: Animals; Biocompatible Materials - chemistry; Biocompatible Materials - pharmacokinetics; Boron Compounds - chemistry; Boron Compounds - pharmacokinetics; Boron Neutron Capture Therapy - methods; Carrier Proteins - metabolism; Dendrimers; Drug Carriers - chemistry; Drug Carriers - pharmacokinetics; Folate Receptors, GPI-Anchored; Folic Acid - chemistry; Folic Acid - pharmacokinetics; Kidney - metabolism; Liver; Liver - metabolism; Mice; Mice, Inbred C57BL; Neoplasm Proteins - metabolism; Neoplasms, Experimental - therapy; Pharmacodynamics; Polyamines - chemistry; Polyamines - pharmacokinetics; Polyethylene Glycols - chemistry; Q1; Receptors, Cell Surface; Structure-Activity Relationship; Tissue Distribution; Tumors
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc025586o

Successful treatment of cancer by boron neutron capture therapy (BNCT) requires the selective delivery of 10B 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 10B 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 PEG2000 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 ∼15 decaborate clusters and ∼1 PEG2000 unit with folic acid attached to the distal end, the other containing ∼13 decaborate clusters, ∼1 PEG2000 unit, and ∼1 PEG800 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.