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.

Folate receptor-mediated boron-10 containing carbon nanoparticles as potential delivery vehicles for boron neutron capture therapy of nonfunctional pituitary adenomas

“…Furthermore, the FR-mediated uptake of carbon nanoparticles could be inhibited by folic acid, suggesting FR-mediated internalization may be involved in the selective delivery of boron-10 containing carbon nanoparticles to NFPAs. Our results are consistent with previous reports showing that FR-targeted boron compounds could be selectively taken up by FR-expressing tumor cells [28][29][30][31]. In the present study, carbon nanoparticles were surface modified with folate moieties, and therefore could target FR-expressing NFPA cells via a FR-mediated endocytosis process.…”

Folate‐mediated cell uptake of shell‐crosslinked spheres and cylinders

“…26 The synthesis of folate-PEG-amine followed previously reported methods. [23][24][25] The conjugates showed UV absorptions at 363 nm, representative of folate. The extinction coefficient for folate in pH 7.4 PBS buffer at that wavelength is 6197 M À1 cm À1 .…”

“…[23][24][25] Conjugation to the nanostructures was achieved by use of amidation chemistry. SCK solutions prefunctionalized with fluorescein-5-thiosemicarbazide were each placed into a 25-mL round-bottom flask.…”

Vascular endothelial growth factor selectively targets boronated dendrimers to tumor vasculature

“…These macromolecules have large numbers of amino groups that can be linked to receptor-specific targeting agents. The use of decaborate-substituted fourth-or fifth-generation PAMAM dendrimers, or other high-capacity carriers, conjugated to epidermal growth factor (7, 10 -12), monoclonal antibodies (13,14), or bispecific antibodies (15,16) to target brain tumors, or folic acid (17) to target other tumor types have been described. Convection-enhanced delivery was used to improve intracerebral accumulation of these high molecular weight agents while decreasing their uptake by extracranial organs (5,9).…”

“…However, these boron-containing conjugates encounter the same problem as any other antitumor biologicals; that is, they are removed from the bloodstream faster than they can be selectively delivered to tumor cells across the vascular endothelial cell barrier. Development of pegylated boron-containing bioconjugates with longer circulation times is one approach that might alleviate this problem (17).…”