title: Dual-Function Polymeric HPMA Prodrugs for the Delivery of miRNA.
abstract: An HPMA-based polymeric prodrug of a CXCR4 antagonist, AMD3465 (P-SS-AMD), was developed as a dual-function carrier of therapeutic miRNA. P-SS-AMD was synthesized by a copolymerization of HPMA with a methacrylamide monomer in which the AMD3465 was attached via a self-immolative disulfide linker. P-SS-AMD showed effective release of the parent AMD3465 drug following treatment with intracellular levels of glutathione (GSH). The AMD3465 was released in the cells and exhibited functional CXCR4 antagonism, demonstrated by inhibition of the CXCR4-mediated cancer cell invasion. Due to its cationic character, P-SS-AMD could form polyplexes with miRNA and mediate efficient transfection of miR-200c mimics to downregulate expression of a downstream target ZEB-1 in cancer cells. The combined P-SS-AMD/miR-200c polyplexes showed improved ability to inhibit cancer cell migration when compared with individual treatments. The reported findings validate P-SS-AMD as a dual-function delivery vector that can simultaneously deliver a therapeutic miRNA and function as a polymeric prodrug of CXCR4 antagonist.
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: Zheng-Hong
authors.identifier: 0000-0001-9783-5108
authors.initials: ZH
authors.lastname: Peng
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: David
authors.identifier: 0000-0003-4710-861X
authors.initials: D
authors.lastname: Oupický
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D008689:Methacrylates / Q000737:chemistry*; D035683:MicroRNAs / Q000737:chemistry* / Q000235:genetics; D011355:Prodrugs / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D008689:Methacrylates; D035683:MicroRNAs; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D011355:Prodrugs; D011725:Pyridines; D019718:Receptors, CXCR4; C032802:hydroxypropyl methacrylate
keywords: CXCR4 antagonist; miRNA delivery; polymeric prodrug; polyplexes; self-immolative linker