Two-step synthesis of multivalent cancer-targeting constructs.
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.
Stukel
Jill M
JM
School of Biological and Health Systems Engineering, Center for Interventional Biomaterials, Arizona State University, Tempe, Arizona, USA.
Li
Ronald C
RC
Maynard
Heather D
HD
Caplan
Michael R
MR
D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001672:Biocompatible Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion; D002470:Cell Survival; D003952:Diagnostic Imaging; D016503:Drug Delivery Systems; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D039121:Integrin alpha6beta1 / Q000378:metabolism*; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding
D001672:Biocompatible Materials; D039121:Integrin alpha6beta1; D011108:Polymers