Two-step synthesis of multivalent cancer-targeting constructs

Biomacromolecules
Jill M StukelMichael R Caplan

Abstract

Selective targeting of constructs to pathological cells by conjugating one or more ligands for an overexpressed receptor has been proposed to enhance the delivery of therapeutics to and imaging of specific cells of interest. Previous work in our lab has demonstrated the efficacy of targeting glioblastoma cells with a multivalent, biomacromolecular construct targeted to the alpha(6)beta(1)-integrin. However, solid-phase synthesis of this construct was inefficient in terms of cost and number of steps. Here we show proof-of-concept of a two-step synthesis that can be used to create similar constructs targeted to glioblastoma cells. Specifically, a well-defined aldehyde side chain polymer was synthesized and oxime chemistry was employed to conjugate ligands specific for the alpha(6)beta(1)-integrin. These constructs were then tested in competitive binding, fluorescence binding, and toxicity assays, through which we demonstrate that constructs are multivalent, preferentially target glioblastoma cells, and are nontoxic. Rapid, potentially low-cost synthesis of targeting constructs will enable their use in the clinic and for personalized medicine.

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Citations

Nov 24, 2011·Biomacromolecules·Vijayakameswara Rao NRaja Shunmugam
Jan 14, 2011·Chemical Communications : Chem Comm·Rebecca M BroyerHeather D Maynard
Oct 11, 2011·Therapeutic Delivery·Chuda ChittasuphoCory Berkland
Jul 24, 2010·Journal of Oncology·Jessie ZhongGeraldine M O'Neill
Jul 14, 2011·Angewandte Chemie·Boris ObermeierHolger Frey
Dec 5, 2013·Chemistry : a European Journal·Sébastien UlrichPascal Dumy
Dec 2, 2010·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Eleni MarkoutsaSophia G Antimisiaris
Nov 5, 2016·Nanomedicine : Nanotechnology, Biology, and Medicine·Maria GregoriDavid Allsop
Feb 23, 2021·Angewandte Chemie·Emma E BrothertonSteven P Armes
Jul 31, 2016·ACS Omega·Sayantani BhattacharyaRaja Shunmugam

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