Document Detail

Dendrimer-based multivalent methotrexates as dual acting nanoconjugates for cancer cell targeting.
MedLine Citation:
PMID:  22142685     Owner:  NLM     Status:  MEDLINE    
Cancer-targeting drug delivery can be based on the rational design of a therapeutic platform. This approach is typically achieved by the functionalization of a nanoparticle with two distinct types of molecules, a targeting ligand specific for a cancer cell, and a cytotoxic molecule to kill the cell. The present study aims to evaluate the validity of an alternative simplified approach in the design of cancer-targeting nanotherapeutics: conjugating a single type of molecule with dual activities to nanoparticles, instead of coupling a pair of orthogonal molecules. Herein we investigate whether this strategy can be validated by its application to methotrexate, a dual-acting small molecule that shows cytotoxicity because of its potent inhibitory activity against dihydrofolate reductase and that binds folic acid receptor, a tumor biomarker frequently upregulated on the cancer cell surface. This article describes a series of dendrimer conjugates derived from a generation 5 polyamidoamine (G5 PAMAM) presenting a multivalent array of methotrexate and also demonstrates their dual biological activities by surface plasmon resonance spectroscopy, a cell-free enzyme assay, and cell-based experiments with KB cancer cells.
Ming-Hsin Li; Seok Ki Choi; Thommey P Thomas; Ankur Desai; Kyung-Hoon Lee; Alina Kotlyar; Mark M Banaszak Holl; James R Baker
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-11-23
Journal Detail:
Title:  European journal of medicinal chemistry     Volume:  47     ISSN:  1768-3254     ISO Abbreviation:  Eur J Med Chem     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-01-16     Completed Date:  2012-05-29     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  0420510     Medline TA:  Eur J Med Chem     Country:  France    
Other Details:
Languages:  eng     Pagination:  560-72     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
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MeSH Terms
Antineoplastic Agents / chemistry,  pharmacology
Dendrimers / chemistry*
Folic Acid Antagonists / chemistry,  pharmacology
KB Cells
Methotrexate / chemistry*,  pharmacology*
Molecular Conformation
Molecular Dynamics Simulation
Nanoconjugates / chemistry*
Surface Plasmon Resonance
Tetrahydrofolate Dehydrogenase / metabolism
Grant Support
1 R01 CA119409/CA/NCI NIH HHS; R01 CA119409/CA/NCI NIH HHS; R01 CA119409-01/CA/NCI NIH HHS
Reg. No./Substance:
0/Antineoplastic Agents; 0/Dendrimers; 0/Folic Acid Antagonists; 0/Nanoconjugates; 0/PAMAM Starburst; EC Dehydrogenase; YL5FZ2Y5U1/Methotrexate

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