Glutathione-sensitive hollow mesoporous silica nanoparticles for controlled drug delivery

J Control Release. 2018 Jul 28:282:62-75. doi: 10.1016/j.jconrel.2018.04.032. Epub 2018 Apr 19.

Abstract

Tunable glutathione (GSH)-sensitive hollow mesoporous silica nanoparticles (HMSiO2 NPs) were developed using a structural difference-based selective etching strategy. These organosilica hollow nanoparticles contained disulfide linkages (S-S) in the outer shell which were degraded by GSH. The particles were compared with their nonGSH-sensitive tetraethyl orthosilicate (TEOS) HMSiO2 counterparts in terms of their synthesis method, characterization, doxorubicin (DOX) release profile, and in vitro cytotoxicity in MCF-7 breast cancer cells. Transmission electron microscopy (TEM) of the particles indicated that the fabricated HMSiO2 NPs had an average diameter of 130 ± 5 nm. Thermogravimetric analysis (TGA) revealed that GSH-sensitive particles had approximately 5.3% more weight loss than TEOS HMSiO2 NPs. Zeta potential of these redox-responsive particles was -23 ± 1 mV at pH 6 in deionized (DI) water. Nitrogen adsorption-desorption isotherm revealed that the surface area of the hollow mesoporous nanoreservoirs was roughly 446 ± 6 m2 g-1 and the average diameter of the pores was 2.3 ± 0.5 nm. TEM images suggest that the nanoparticles started to lose mass integrity from Day 1. The particles showed a high loading capacity for DOX (8.9 ± 0.5%) as a model drug, due to the large voids existing in the hollow structures. Approximately 58% of the incorporated DOX released within 14 days in phosphate buffered saline (PBS) at pH 6 and in the presence of 10 mM of GSH, mimicking intracellular tumor microenvironment while release from TEOS HMSiO2 NPs was only c.a. 18%. The uptake of these hollow nanospheres by MCF-7 cells and RAW 264.7 macrophages was evaluated using TEM and confocal microscopy. The nanospheres were shown to accumulate in the endolysosomal compartments after incubation for 24 h with the maximum uptake of c.a. 2.1 ± 0.3% and 5.2 ± 0.4%, respectively. Cytotoxicity of the nanospheres was investigated using CCK-8 assay. Results indicate that intact hollow particles (both GSH-sensitive and TEOS HMSiO2 NPs) were nontoxic to MCF-7 cells after incubation for 24 h within the concentration range of 0-1000 μg ml-1. DOX-loaded GSH-sensitive nanospheres containing 6 μg ml-1 of DOX killed c.a. 51% of MCF-7 cells after 24 h while TEOS HMSiO2 NPs killed c.a. 20% with the difference being statistically significant. Finally, cytotoxicity data in RAW 264.7 macrophages and NIH 3 T3 fibroblasts shows that intact GSH-sensitive HMSiO2 NPs did not show any toxic effects on these cells with the concentrations equal or <125 μg ml-1.

Keywords: Degradable; GSH-sensitive; High loading capacity; Hollow mesoporous silica nanoparticles; Structural difference; Tunable.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / administration & dosage*
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Antibiotics, Antineoplastic / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Cell Survival / drug effects
  • Delayed-Action Preparations / chemistry
  • Delayed-Action Preparations / metabolism*
  • Delayed-Action Preparations / toxicity
  • Doxorubicin / administration & dosage*
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / pharmacology
  • Female
  • Glutathione / metabolism*
  • Humans
  • MCF-7 Cells
  • Mice
  • NIH 3T3 Cells
  • Nanoparticles / chemistry
  • Nanoparticles / metabolism*
  • Nanoparticles / toxicity
  • Porosity
  • RAW 264.7 Cells
  • Silicon Dioxide / chemistry
  • Silicon Dioxide / metabolism*
  • Silicon Dioxide / toxicity

Substances

  • Antibiotics, Antineoplastic
  • Delayed-Action Preparations
  • Silicon Dioxide
  • Doxorubicin
  • Glutathione