Redox-Responsive Mesoporous Silica Nanoparticles: A Physiologically Sensitive Codelivery Vehicle for siRNA and Doxorubicin

Ma, X., Teh, C., Zhang, Q., Borah, P., Choong, C., Korzh, V., and Zhao, Y.
Antioxidants & redox signaling   21(5): 707-22 (Journal)
Registered Authors
Korzh, Vladimir, Teh, Cathleen
MeSH Terms
  • Antineoplastic Agents/administration & dosage*
  • Antineoplastic Agents/chemistry
  • Antineoplastic Agents/metabolism
  • Antineoplastic Agents/pharmacology
  • Doxorubicin/administration & dosage*
  • Doxorubicin/metabolism
  • Doxorubicin/pharmacology
  • Drug Carriers/chemistry*
  • HeLa Cells
  • Humans
  • Nanoparticles/chemistry*
  • Neoplasms/drug therapy*
  • Neoplasms/genetics
  • Neoplasms/metabolism
  • Neoplasms/pathology
  • Oxidation-Reduction
  • Particle Size
  • Porosity
  • RNA, Small Interfering/administration & dosage
  • RNA, Small Interfering/chemistry*
  • Silicon Dioxide/chemistry*
  • Surface Properties
23931896 Full text @ Antioxid. Redox Signal.

Aims: Efficient siRNA/drug co-delivery carriers can offer great promises to cancer treatment on account of synergistic effect provided from cancer-associated gene and anticancer drugs. In this work, a redox-responsive drug/siRNA co-delivery vehicle based on mesoporous silica nanoparticles was fabricated to simultaneously deliver siRNA and doxorubicin in vitro and in vivo. Results: The nanoparticle surface was functionalized with the adamantane units. Formation of stable host-guest complex between disulfide bond linked adamantane and ethylenediamine modified β-cyclodextrin is capable of fully blocking drugs inside the nanopores, while amino groups can complex with siRNA via electrostatic interaction. Relatively high concentration of glutathione in biophysical environment provides natural reducing agent to trigger drug/siRNA release by cleaving pre-introduced disulfide bonds. Bcl-2 siRNA was co-delivered to silence Bcl-2 protein expression in HeLa cells, resulting in enhanced chemotherapy efficacy in vitro. In vivo delivery experiment carried out in transgenic zebrafish larvae indicates that the delivery of doxorubicin inhibits the development of choroid plexus in a dose-dependent manner, leading to successful decrease of GFP transcription in choroid plexus. Reduction of liver tumor was also demonstrated after injection of doxorubicin-loaded nanoparticles. Innovation: We successfully demonstrated that functional nanoparticles could serve as an efficient carrier for the delivery of Bcl-2siRNA and doxorubicin in HeLa cells and in transgenic zebrafish larvae, leading to enhanced therapeutic efficacy. Conclusion: Enhanced cytotoxicity caused by simultaneous delivery of Bcl-2 siRNA and doxorubicin was observed in HeLa cells. Drug-loaded nanoparticles were internalized in vivo, inhibiting the development of choroid plexus and the progression of liver tumor.

Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes