High capacity nanoporous silicon carrier for systemic delivery of gene silencing therapeutics

Jianliang Shen, Rong Xu, Junhua Mai, Han Cheon Kim, Xiaojing Guo, Guoting Qin, Yong Yang, Joy Wolfram, Chaofeng Mu, Xiaojun Xia, Jianhua Gu, Xuewu Liu, Zong Wan Mao, Mauro Ferrari, Haifa Shen

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

Gene silencing agents such as small interfering RNA (siRNA) and microRNA offer the promise to modulate expression of almost every gene for the treatment of human diseases including cancer. However, lack of vehicles for effective systemic delivery to the disease organs has greatly limited their in vivo applications. In this study, we developed a high capacity polycation- functionalized nanoporous silicon (PCPS) platform comprised of nanoporous silicon microparticles functionalized with arginine-polyethyleneimine inside the nanopores for effective delivery of gene silencing agents. Incubation of MDA-MB-231 human breast cancer cells with PCPS loaded with STAT3 siRNA (PCPS/STAT3) or GRP78 siRNA (PCPS/GRP78) resulted in 91 and 83% reduction of STAT3 and GRP78 gene expression in vitro. Treatment of cells with a microRNA-18a mimic in PCPS (PCPS/miR-18) knocked down 90% expression of the microRNA-18a target gene ATM. Systemic delivery of PCPS/STAT3 siRNA in murine model of MDA-MB-231 breast cancer enriched particles in tumor tissues and reduced STAT3 expression in cancer cells, causing significant reduction of cancer stem cells in the residual tumor tissue. At the therapeutic dosage, PCPS/STAT3 siRNA did not trigger acute immune response in FVB mice, including changes in serum cytokines, chemokines, and colony-stimulating factors. In addition, weekly dosing of PCPS/STAT3 siRNA for four weeks did not cause signs of subacute toxicity based on changes in body weight, hematology, blood chemistry, and major organ histology. Collectively, the results suggest that we have developed a safe vehicle for effective delivery of gene silencing agents.

Original languageEnglish (US)
Pages (from-to)9867-9880
Number of pages14
JournalACS Nano
Volume7
Issue number11
DOIs
StatePublished - Nov 26 2013

Keywords

  • cancer therapy
  • delivery
  • microRNA
  • porous silicon
  • siRNA

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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  • Cite this

    Shen, J., Xu, R., Mai, J., Kim, H. C., Guo, X., Qin, G., Yang, Y., Wolfram, J., Mu, C., Xia, X., Gu, J., Liu, X., Mao, Z. W., Ferrari, M., & Shen, H. (2013). High capacity nanoporous silicon carrier for systemic delivery of gene silencing therapeutics. ACS Nano, 7(11), 9867-9880. https://doi.org/10.1021/nn4035316