Tumor-targeted gene delivery using molecularly engineered hybrid polymers functionalized with a tumor-homing peptide.
Before gene therapy can be used in clinical settings, safe and efficient DNA delivery systems must be developed to overcome a range of extra- and intracellular transport barriers. As a step toward the development of a modular, multifunctional gene delivery system to overcome these diverse barriers, we have developed a family of linear-dendritic "hybrid" polymers which contain functionalities for tissue targeting, minimization of nonspecific interactions, endosomal buffering, and DNA binding. Here, we demonstrate the rapid three-step, room-temperature, aqueous synthesis of hybrid polymers, as well as the functionalization of these polymers with a peptide targeting ligand that specifically binds to glucose-regulated protein-78 kDa (GRP-78), a clinically relevant tumor antigen identified in human cancer patients. These polymer systems can condense plasmid DNA into small nanoparticle structures (<210 nm) and transfect cells expressing GRP-78 with efficiencies that exceed that of branched polyethylenimine (bPEI), one of the best commercially available polymers for in vitro transfections. The synthetic approach described here may be useful for the rapid synthesis and optimization of polymer gene delivery systems bearing a range of diverse functional domains, and the specific GRP-78-targeted systems developed in this study may potentially have clinical applications in cancer gene therapy.
Wood
Kris C
KC
Department of Chemical Engineering, Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Azarin
Samira M
SM
Arap
Wadih
W
Pasqualini
Renata
R
Langer
Robert
R
Hammond
Paula T
PT
D018014:Gene Transfer Techniques; D010455:Peptides / Q000008:administration & dosage*; D011108:Polymers / Q000737:chemistry*
D010455:Peptides; D011108:Polymers