Synthetic Aptamer-Polymer Hybrid Constructs for Programmed Drug Delivery into Specific Target Cells
Viruses have evolved specialized mechanisms to efficiently transport nucleic acids and other biomolecules into specific host cells. They achieve this by performing a coordinated series of complex functions, resulting in delivery that is far more efficient than existing synthetic delivery mechanisms. Inspired by these natural systems, we describe a process for synthesizing chemically defined molecular constructs that likewise achieve targeted delivery through a series of coordinated functions. We employ an efficient "click chemistry" technique to synthesize aptamer-polymer hybrids (APHs), coupling cell-targeting aptamers to block copolymers that secure a therapeutic payload in an inactive state. Upon recognizing the targeted cell-surface marker, the APH enters the host cell via endocytosis, at which point the payload is triggered to be released into the cytoplasm. After visualizing this process with coumarin dye, we demonstrate targeted killing of tumor cells with doxorubicin. Importantly, this process can be generalized to yield APHs that specifically target different surface markers.
Additional Information© 2014 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received: August 8, 2014. Published: October 7, 2014. This work was supported by the Institute for Collaborative Biotechnologies through the U.S. Army Research Office (W911NF-09-D-0001) (S.S.O., B.F.L., H.T.S., C.J.H.) and W911NF-10-2-0114 (H.T.S., S.S.O.), the Garland Intitiative (S.S.O., H.T.S.), the MRSEC Program of the National Science Foundation (NSF) under Award DMR-1121053 (F.A.L., M.J.R., C.J.H.) and the National Institutes of Health (NIH) as a Program of Excellence in Nanotechnology (HHSN268201000046C) (N.A.L., C.J.H.). Partial support from the NIH U54 DK093467 (H.T.S., S.S.O.), U01 HL099773-1 (H.T.S., S.S.O.), and the NRI-MCDB Microscopy Facility and the Spectral Laser Scanning Confocal supported by the Office of The Director, the NIH under Award S10OD010610 is gratefully acknowledged. We thank Prof. James A. Thomson, Prof. Patrick S. Daugherty, and Dr. Jack Riefert for their assistance in culturing cells. The authors declare no competing financial interest.
Published - ja5079464.pdf
Supplemental Material - ja5079464_si_001.pdf