title: Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted SiRNA Delivery to HER2+ Breast Cancer.
abstract: In vivodelivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. We now describe a new nanoparticle construct that has been engineered for efficient delivery of siRNA to tumors. The construct is comprised of a 47-nm mesoporous silica nanoparticle (MSNP) core coated with a cross-linked PEI-PEG copolymer, carrying siRNA against the HER2 oncogene, and coupled to the anti-HER2 monoclonal antibody (trastuzumab). The construct has been engineered to increase siRNA blood half-life, enhance tumor-specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti-HER2-nanoparticles produced apoptotic death in HER2 positive (HER2+) breast cancer cells grownin vitro, but not in HER2 negative (HER2-) cells. One dose of the siHER2-nanoparticles reduced HER2 protein levels by 60% in trastuzumab-resistant HCC1954 xenografts. Multiple doses administered intravenously over 3 weeks significantly inhibited tumor growth (p < 0.004). The siHER2-nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch-to-batch reproducibility and the production methods are suitable for large-scale production. These results suggest that this siHER2-nanoparticle is ready for clinical evaluation.
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University 3303 SW Bond Ave, Portland, OR 97239.
authors.forename: Worapol
authors.initials: W
authors.lastname: Ngamcherdtrakul
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University 3303 SW Bond Ave, Portland, OR 97239.
authors.forename: Jingga
authors.initials: J
authors.lastname: Morry
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University 3303 SW Bond Ave, Portland, OR 97239.
authors.forename: Shenda
authors.initials: S
authors.lastname: Gu
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University 3303 SW Bond Ave, Portland, OR 97239.
authors.forename: David J
authors.initials: DJ
authors.lastname: Castro
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University 3303 SW Bond Ave, Portland, OR 97239.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Goodyear
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University 3303 SW Bond Ave, Portland, OR 97239.
authors.forename: Thanapon
authors.initials: T
authors.lastname: Sangvanich
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University 3303 SW Bond Ave, Portland, OR 97239.
authors.forename: Moataz M
authors.initials: MM
authors.lastname: Reda
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University 3303 SW Bond Ave, Portland, OR 97239.
authors.forename: Richard
authors.initials: R
authors.lastname: Lee
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University 3303 SW Bond Ave, Portland, OR 97239.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Mihelic
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University 3303 SW Bond Ave, Portland, OR 97239.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Beckman
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University 3303 SW Bond Ave, Portland, OR 97239.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University 3303 SW Bond Ave, Portland, OR 97239.
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University 3303 SW Bond Ave, Portland, OR 97239.
authors.forename: Wassana
authors.initials: W
authors.lastname: Yantasee
keywords: HER2+ breast cancer; cancer nanomedicine; mesoporous silica nanoparticles; siRNA