Glutathione-sensitive hollow mesoporous silica nanoparticles for controlled drug delivery

• Published in: Journal of controlled release 2018-07, Vol.282, p.62-75
• Main Authors: Hadipour Moghaddam, Seyyed Pouya, Yazdimamaghani, Mostafa, Ghandehari, Hamidreza
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacokinetics; Antibiotics, Antineoplastic - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cell Survival - drug effects; Degradable; Delayed-Action Preparations - chemistry; Delayed-Action Preparations - metabolism; Delayed-Action Preparations - toxicity; Doxorubicin - administration & dosage; Doxorubicin - pharmacokinetics; Doxorubicin - pharmacology; Female; Glutathione - metabolism; GSH-sensitive; High loading capacity; Hollow mesoporous silica nanoparticles; Humans; MCF-7 Cells; Mice; Nanoparticles - chemistry; Nanoparticles - metabolism; Nanoparticles - toxicity; NIH 3T3 Cells; Porosity; RAW 264.7 Cells; Silicon Dioxide - chemistry; Silicon Dioxide - metabolism; Silicon Dioxide - toxicity; Structural difference; Tunable
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2018.04.032

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 ce