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WIREs Nanomed Nanobiotechnol
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Methotrexate delivery via folate targeted dendrimer‐based nanotherapeutic platform

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Abstract This paper provides a synopsis of the advancements made in advancing a dendrimer‐based nanomedicine towards human clinical trials by the Michigan Nanotechnology Institute for Medicine and Biological Sciences. A brief description of the synthesis and characterization of a targeted multifunctional therapeutic will demonstrate the simple yet delicate task of producing novel chemotherapeutic agents. The results obtained from in vitro and in vivo studies not only authenticate the potential of using nanoparticles to target therapeutics but also provide valuable insight towards the future directions of this technology. A fundamental, cross‐disciplinary collaboration was necessary to achieve the synthesis and testing of this technology, and was the keystone to establishing this innovative invention. Throughout this paper, we will stress that the unique collaboration that facilitated the evolution of this technology is vital to the success of future developments in nanomedicine. Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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Synthesis pathways leading to three varieties of dendrimer‐based, methotrexate‐conjugated synthetic nanoscale bioconjugates. The superscript e on MTX highlights its conjugation through an ester bond. From left, G5‐Ac‐FA‐OH‐MTXe (without FITC dye) is a clinically applicable device, used for both in vitro and in vivo studies, G5‐Ac‐FITC‐FA‐OH‐MTXe is an experimental device used to study binding efficacy and cytotoxicity in vitro, and G5‐Ac‐FITC‐OH‐MTXe served as a control both for in vitro and in vivo studies.

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Progress of treatment with G5‐Ac‐FA‐OH‐MTXe within a 22‐day period.

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Mice administered either (a) free MTX (15 mg/kg) or (b) G5‐Ac‐FITC‐FA‐OH‐MTXe (3 mg/kg).

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Confocal microscopy of KB cells treated with dendrimer‐conjugates. KB cells were incubated with 250 nM of the indicated dendrimers for 24 h and confocal images were taken. The left and right panels under each treatment represent FITC fluorescence and a differential interference contrast image of the same observation field. (a) PBS, (b) G5‐Ac‐FITC, (c) G5‐Ac‐FITC‐FA, and (d) G5‐Ac‐FITC‐FA‐OH‐MTXe. (Reprinted with permission from Ref 13. Copyright 2005 ACS).

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Effect of free folic acid on the uptake of G5‐Ac‐FITC‐FA and G5‐Ac‐FITC‐FA‐OH‐MTXe in KB cells expressing high and low FAR. KB cells which express high (solid bars) and low (shaded bars) FAR were incubated with 30 nM of the dendrimers for 1 h at 37 °C, rinsed, and the fluorescence of cells was determined by flow cytometric analysis (left panel). Pre‐incubation with 50 µM free FA for 30 min prevents cellular binding and uptake (right panel). (Reprinted with permission from Ref 13. Copyright 2005 ACS).

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Dose‐dependent binding of G5‐Ac‐FITC‐FA‐OH‐MTXe in KB cells. The cells were maintained under FA‐free medium and incubated with different concentrations of the indicated dendrimers for 1 h. The cells were then rinsed and resuspended in PBS and the fluorescence was measured in a flow cytometer. (Reprinted with permission from Ref 13. Copyright 2005 ACS).

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UV spectra of acetylated G5 PAMAM dendrimer carrier, mono‐, bi‐ and tri‐functional devices. (Reprinted with permission from Ref 8. Copyright 2005 ACS).

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UV spectra of free FA, MTX, and FITC. (Reprinted with permission from Ref 8. Copyright 2005 ACS).

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