Format

Send to

Choose Destination
ACS Nano. 2014 Apr 22;8(4):3232-41. doi: 10.1021/nn500704t. Epub 2014 Apr 3.

Bioreducible cationic polymer-based nanoparticles for efficient and environmentally triggered cytoplasmic siRNA delivery to primary human brain cancer cells.

Author information

1
Department of Biomedical Engineering, the Institute for Nanobiotechnology, and the Translational Tissue Engineering Center, The Johns Hopkins University School of Medicine , 400 North Broadway/Smith Building Room 5017, Baltimore, Maryland 21231, United States .

Abstract

siRNA nanomedicines can potentially treat many human diseases, but safe and effective delivery remains a challenge. DNA delivery polymers such as poly(β-amino ester)s (PBAEs) generally cannot effectively deliver siRNA and require chemical modification to enable siRNA encapsulation and delivery. An optimal siRNA delivery nanomaterial needs to be able to bind and self-assemble with siRNA molecules that are shorter and stiffer than plasmid DNA in order to form stable nanoparticles, and needs to promote efficient siRNA release upon entry to the cytoplasm. To address these concerns, we designed, synthesized, and characterized an array of bioreducible PBAEs that self-assemble with siRNA in aqueous conditions to form nanoparticles of approximately 100 nm and that exhibit environmentally triggered siRNA release upon entering the reducing environment of the cytosol. By tuning polymer properties, including bioreducibility and hydrophobicity, we were able to fabricate polymeric nanoparticles capable of efficient gene knockdown (91 ± 1%) in primary human glioblastoma cells without significant cytotoxicity (6 ± 12%). We were also able to achieve significantly higher knockdown using these polymers with a low dose of 5 nM siRNA (76 ± 14%) compared to commercially available reagent Lipofectamine 2000 with a 4-fold higher dose of 20 nM siRNA (40 ± 7%). These bioreducible PBAEs also enabled 63 ± 16% gene knockdown using an extremely low 1 nM siRNA dose and showed preferential transfection of glioblastoma cells versus noncancer neural progenitor cells, highlighting their potential as efficient and tumor-specific carriers for siRNA-based nanomedicine.

PMID:
24673565
PMCID:
PMC4004313
DOI:
10.1021/nn500704t
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center