title: Development of switchable polymers to address the dilemma of stability and cargo release in polycationic nucleic acid carriers.
abstract: Cationic polymer gene delivery vehicles that effectively resist premature serum degradation often have difficulty releasing their nucleic acid cargoes. In this work, we report a pH-sensitive polymer (SP), poly(oligo(ethylene glycol) monomethyl ether methacrylate)-co-poly(2-(dimethylamino)ethyl methacrylate)-block- poly(propargyl methacrylate-graft-propyl-(4-methoxy-benzylidene)-amine) (p(PMA-PMBA)-b-(p(OEGMA-DMAEMA)), for successful in vitro and in vivo gene transfer. In the physiological condition, the hydrophobization of p(OEGMA-DMAEMA) polycations by p(PMA-PMBA) significantly enhanced the stability of its polyplexes counterpart. In endosomes, the polymer undergoes an acid-triggered hydrophilic transition through the cleavage of benzoic imines, thus allowing the vector to quickly release nucleic acid cargo due to the loss of hydrophobic functionalization. Compared to a pH-insensitive polymer (IP), SP exhibited more significant luciferase plasmid delivery efficiency with HeLa cells in vitro and with in vivo intraventricular brain injections. Therefore, the polymer designed here is a good solution to address the dilemma of stability and cargo release in gene delivery, and may have broad potential applications in therapeutic agent delivery.
authors.affiliation: Department of Bioengineering and Molecular Engineering & Sciences Institute, University of Washington, Seattle, WA 98195, United States.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Bioengineering and Molecular Engineering & Sciences Institute, University of Washington, Seattle, WA 98195, United States.
authors.forename: Drew L
authors.initials: DL
authors.lastname: Sellers
authors.affiliation: Department of Bioengineering and Molecular Engineering & Sciences Institute, University of Washington, Seattle, WA 98195, United States.
authors.forename: James-Kevin Y
authors.initials: JY
authors.lastname: Tan
authors.affiliation: Department of Bioengineering and Molecular Engineering & Sciences Institute, University of Washington, Seattle, WA 98195, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Peeler
authors.affiliation: Center for Neuroregeneration and Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX 77030, United States. Electronic address: pjhorner@houstonmethodist.org.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Horner
authors.affiliation: Department of Bioengineering and Molecular Engineering & Sciences Institute, University of Washington, Seattle, WA 98195, United States. Electronic address: spun@u.washington.edu.
authors.forename: Suzie H
authors.initials: SH
authors.lastname: Pun
mesh_terms: D000818:Animals; D005260:Female; D018014:Gene Transfer Techniques; D006367:HeLa Cells; D006801:Humans; D057446:Hydrodynamics; D006863:Hydrogen-Ion Concentration; D008156:Luciferases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009696:Nucleic Acids / Q000737:chemistry*; D011073:Polyamines / Q000737:chemistry*; D000071228:Polyelectrolytes; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D014162:Transfection
chemical_list: D008156:Luciferases; D009696:Nucleic Acids; D011073:Polyamines; D000071228:Polyelectrolytes; D011108:Polymers
keywords: Benzoic imine; Gene delivery; Hydrophobization; pH sensitive