Integrated hollow mesoporous silica nanoparticles for target drug/siRNA co-delivery

Chemistry. 2013 Nov 11;19(46):15593-603. doi: 10.1002/chem.201302736. Epub 2013 Oct 2.

Abstract

A hollow mesoporous silica nanoparticle (HMSNP) based drug/siRNA co-delivery system was designed and fabricated, aiming at overcoming multidrug resistance (MDR) in cancer cells for targeted cancer therapy. The as-prepared HMSNPs have perpendicular nanochannels connecting to the internal hollow cores, thereby facilitating drug loading and release. The extra volume of the hollow core enhances the drug loading capacity by two folds as compared with conventional mesoporous silica nanoparticles (MSNPs). Folic acid conjugated polyethyleneimine (PEI-FA) was coated on the HMSNP surfaces under neutral conditions through electrostatic interactions between the partially charged amino groups of PEI-FA and the phosphate groups on the HMSNP surfaces, blocking the mesopores and preventing the loaded drugs from leakage. Folic acid acts as the targeting ligand that enables the co-delivery system to selectively bind with and enter into the target cancer cells. PEI-FA-coated HMSNPs show enhanced siRNA binding capability on account of electrostatic interactions between the amino groups of PEI-FA and siRNA, as compared with that of MSNPs. The electrostatic interactions provide the feasibility of pH-controlled release. In vitro pH-responsive drug/siRNA co-delivery experiments were conducted on HeLa cell lines with high folic acid receptor expression and MCF-7 cell lines with low folic acid receptor expression for comparison, showing effective target delivery to the HeLa cells through folic acid receptor meditated cellular endocytosis. The pH-responsive intracellular drug/siRNA release greatly minimizes the prerelease and possible side effects of the delivery system. By simultaneously delivering both doxorubicin (Dox) and siRNA against the Bcl-2 protein into the HeLa cells, the expression of the anti-apoptotic protein Bcl-2 was successfully suppressed, leading to an enhanced therapeutic efficacy. Thus, the present multifunctional nanoparticles show promising potentials for controlled and targeted drug and gene co-delivery in cancer treatment.

Keywords: RNA; drug delivery; gene therapy; multiple drug resistance; nanoparticles; pH-responsive release.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Line
  • Doxorubicin / chemistry*
  • Doxorubicin / pharmacology
  • Doxorubicin / therapeutic use*
  • Drug Delivery Systems / methods*
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Multiple / genetics
  • Genetic Therapy
  • HeLa Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Mice
  • Nanoparticles / chemistry*
  • Porosity
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / chemistry*
  • RNA, Small Interfering / metabolism
  • Silicon Dioxide / chemistry*

Substances

  • Antineoplastic Agents
  • RNA, Small Interfering
  • Silicon Dioxide
  • Doxorubicin