title: Aerosol delivery of stabilized polyester-siRNA nanoparticles to silence gene expression in orthotopic lung tumors.
abstract: Tremendous progress has been made in the development of delivery carriers for small RNA therapeutics. However, most achievements have focused on the treatment of liver-associated diseases because conventional lipid and lipidoid nanoparticles (LNPs) readily accumulate in the liver after intravenous (i.v.) administration. Delivering RNAs to other organs and tumor tissues remains an ongoing challenge. Here, we utilized a 540-member combinatorial functional polyester library to discover nanoparticles (NPs) that enable efficacious siRNA delivery to A549 lung cancer cells in vitro and in vivo. PE4K-A13-0.33C6 and PE4K-A13-0.33C10 NPs were efficiently internalized into A549-Luc cells within 4 h. The addition of PEG 2000 DMG lipid or Pluronic F-127 onto the surface of the polyplexes reduced the surface charge of NPs, resulting in an increase of serum stability. We then explored aerosol delivery of stabilized PE4K-A13-0.33C6 and PE4K-A13-0.33C10 NPs to implanted orthotopic lung tumors. We found that by altering the administration route from i.v. to aerosol, the NPs could avoid liver accumulation and instead be specifically localized only in the lungs. This resulted in significant gene silencing in the A549 orthotopic lung tumors. Due to the ability to deliver siRNA to non-liver targets, this approach provides a privileged route for gene silencing in the lungs.
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Kejin
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Hu
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Miller
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Motea
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Boothman
authors.affiliation: Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States. Electronic address: Li.Liu@UTSouthwestern.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, United States. Electronic address: Daniel.Siegwart@UTSouthwestern.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Siegwart
mesh_terms: D000072283:A549 Cells; D000280:Administration, Inhalation; D000336:Aerosols / Q000008:administration & dosage / Q000138:chemical synthesis; D000818:Animals; D045744:Cell Line, Tumor; D004355:Drug Stability; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D011091:Polyesters / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000336:Aerosols; D053769:Nanocapsules; D011091:Polyesters; D034741:RNA, Small Interfering
keywords: Cancer; Drug delivery; Functional polyesters; Nanoparticles; siRNA