Targeting and Inhibition of Cell Growth by an Engineered Dendritic Nanodevice

Thommey P. Thomas,* Istvan J. Majoros, Alina Kotlyar, Jolanta F. Kukowska-Latallo, Anna Bielinska, Andrzej Myc, and James R. Baker, Jr.
Center for Biologic Nanotechnology, University of Michigan Medical School, 9220 MSRB III, Ann Arbor, Michigan 48109-0648
J. Med. Chem., 2005, 48 (11), pp 3729–3735
DOI: 10.1021/jm040187v
Publication Date (Web): April 23, 2005
Copyright © 2005 American Chemical Society
*

 Corresponding author. Tel:  734-615-3594. Fax:  734-936-2990. E-mail:  thommey@umich.edu. Website:  www.nano.med.umich.edu.

Abstract

Abstract Image

The cellular uptake and cytotoxicity of an engineered multifunctional dendritic nanodevice containing folic acid (FA) as the targeting molecule, methotrexate (MTX) as the chemotherapeutic drug, and fluorescein (FI) as the detecting agent were studied in vitro. FI and FA were conjugated to the generation 5 poly(amidoamine) (G5) dendrimer carrier through a thiourea and amide linkage and MTX was conjugated through an ester linkage to the carrier to generate the trifunctional dendritic device, G5−FI−FA−MTX. This trifunctional dendrimer−drug conjugate bound to FA receptor-expressing KB cells in a dose-dependent and saturable manner. Confocal microscopic analysis demonstrated cellular internalization of the conjugate. G5−FI−FA−MTX induced a time- and dose-dependent inhibition of cell growth in KB cells. The targeted dendrimer conjugates G5−FI−FA−MTX and G5−FA−MTX inhibited cell growth in KB cells, whereas the nontargeted G5−MTX failed to induce growth inhibition. These studies show the potential of G5−FI−FA−MTX or G5−FA−MTX for targeting and growth suppression of tumor cells that overexpress FA-receptors.

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History

  • Published In Issue June 02, 2005
  • Received October 18, 2004

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