期刊
BIOMATERIALS
卷 118, 期 -, 页码 84-93出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2016.12.001
关键词
Functional polyesters; siRNA; Cancer; Drug delivery; Nanoparticles
资金
- Cancer Prevention and Research Institute of Texas (CPRIT) [R1212, RP140110]
- Welch Foundation [I-1855]
- American Cancer Society [ACS-IRG-02-196]
- Friends of the Comprehensive Cancer Center
- UTSW Translational Pilot Program via the National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR001105]
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. (C) 2016 Elsevier Ltd. All rights reserved.
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