title: Self-immolative nanoparticles for simultaneous delivery of microRNA and targeting of polyamine metabolism in combination cancer therapy.
abstract: Combination of anticancer drugs with therapeutic microRNA (miRNA) has emerged as a promising anticancer strategy. However, the promise is hampered by a lack of desirable delivery systems. We report on the development of self-immolative nanoparticles capable of simultaneously delivering miR-34a mimic and targeting dysregulated polyamine metabolism in cancer. The nanoparticles were prepared from a biodegradable polycationic prodrug, named DSS-BEN, which was synthesized from a polyamine analog N1,N11-bisethylnorspermine (BENSpm). The nanoparticles were selectively disassembled in the cytoplasm where they released miRNA. Glutathione (GSH)-induced degradation of self-immolative linkers released BENSpm from the DSS-BEN polymers. MiR-34a mimic was effectively delivered to cancer cells as evidenced by upregulation of intracellular miR-34a and downregulation of Bcl-2 as one of the downstream targets of miR-34a. Intracellular BENSpm generated from the degraded nanoparticles induced the expression of rate-limiting enzymes in polyamine catabolism (SMOX, SSAT) and depleted cellular natural polyamines. Simultaneous regulation of polyamine metabolism and miR-34a expression by DSS-BEN/miR-34a not only enhanced cancer cell killing in cultured human colon cancer cells, but also improved antitumor activity in vivo. The reported findings validate the self-immolative nanoparticles as delivery vectors of therapeutic miRNA capable of simultaneously targeting dysregulated polyamine metabolism in cancer, thereby providing an elegant and efficient approach to combination nanomedicines.
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xie
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, United States.
authors.forename: Tracy
authors.initials: T
authors.lastname: Murray-Stewart
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Yazhe
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA, United States.
authors.forename: Laurence J
authors.initials: LJ
authors.lastname: Marton
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, United States.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Casero
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, United States. Electronic address: david.oupicky@unmc.edu.
authors.forename: David
authors.initials: D
authors.lastname: Oupický
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D008819:Mice, Nude; D035683:MicroRNAs / Q000008:administration & dosage* / Q000627:therapeutic use; D053758:Nanoparticles / Q000737:chemistry*; D011073:Polyamines / Q000378:metabolism*; D012007:Rectum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013096:Spermine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D035683:MicroRNAs; D011073:Polyamines; C059685:N(1),N(11)-diethylnorspermine; D013096:Spermine
keywords: Bisethylnorspermine; Cancer; Combination delivery; Nanoparticles; Polyamine metabolism; Polyplexes; Self-immolative polymer; miRNA