Dendrimer-based multivalent methotrexates as dual acting nanoconjugates for cancer cell targeting

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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65 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)560-572
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Issue number1
Publication statusPublished - 1 Jan 2012
Externally publishedYes


  • Dual activity
  • Folate receptor
  • Methotrexate
  • Multivalent binding
  • Poly(amidoamine) dendrimer
  • Targeted drug delivery

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