title: Polyvalent dendrimer-methotrexate as a folate receptor-targeted cancer therapeutic.
abstract: Our previous studies have demonstrated that a generation 5 dendrimer (G5) conjugated with both folic acid (FA) and methotrexate (MTX) has a higher chemotherapeutic index than MTX alone. Despite this, batch-to-batch inconsistencies in the number of FA and MTX molecules linked to each dendrimer led to conjugate batches with varying biological activity, especially when scaleup synthesis was attempted. Since the MTX is conjugated through an ester linkage, there were concerns that biological inconsistency could also result from serum esterase activity and differential bioavailability of the targeted conjugate. In order to resolve these problems, we undertook a novel approach to synthesize a polyvalent G5-MTX(n) conjugate through click chemistry, attaching the MTX to the dendrimer through an esterase-stable amide linkage. Surface plasmon resonance binding studies show that a G5-MTX(10) conjugate synthesized in this manner binds to the FA receptor (FR) through polyvalent interaction showing 4300-fold higher affinity than free MTX. The conjugate inhibits dihydrofolate reductase, and induces cytotoxicity in FR-expressing KB cells through FR-specific cellular internalization. Thus, the polyvalent MTX on the dendrimer serves the dual role as a targeting molecule as well as a chemotherapeutic drug. The newly synthesized G5-MTX(n) conjugate may serve as a FR-targeted chemotherapeutic with potential for cancer therapy.
authors: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Thommey P
authors: TP
authors: Thomas
authors: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Baohua
authors: B
authors: Huang
authors: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Seok Ki
authors: SK
authors: Choi
authors: Department of Macromolecular Science and Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Justin E
authors: JE
authors: Silpe
authors: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Alina
authors: A
authors: Kotlyar
authors: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Ankur M
authors: AM
authors: Desai
authors: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Hong
authors: H
authors: Zong
authors: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Jeremy
authors: J
authors: Gam
authors: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Melvin
authors: M
authors: Joice
authors: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: James R
authors: JR
authors: Baker
mesh_terms: D001682:Biological Availability; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry*; D004950:Esterases / Q000097:blood; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism*; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D007624:KB Cells; D008727:Methotrexate / Q000008:administration & dosage / Q000737:chemistry*; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
chemical_list: D050091:Dendrimers; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D004950:Esterases; D008727:Methotrexate