Targeted Mesoporous Silica Nanoparticles Delivering Arsenic Trioxide with Environment Sensitive Drug Release for Effective Treatment of Triple Negative Breast Cancer

Abstract

In this study, we report a novel modality of using a mesoporous silica nanoparticles (MSNs)-based drug delivery system with RGD peptide as a targeting ligand to load arsenic trioxide (ATO) (ATO-MSNs-RGD) for treating MDA-MB-231 triple-negative breast cancer. The MSNs, ATO-MSNs, and ATO-MSNs-RGD were characterized by X-ray diffraction (XRD), thermogravimetric analysis (TGA), transmission electron microscopy (TEM), and Brunauer-Emmet-Teller (BET) method. The data indicated that the MSNs possessed MCM-41 type mesopores with high surface area of ∼1021 m 2 /g and pore diameter of ∼2.2 nm. However, both values dramatically decreased after MSNs were encapsulated with ATO or modified with RGD. The amount of surface anchored RGD peptide was determined to be 0.20 mmol/g. Glutathione (GSH) greatly enhanced ATO release from MSNs. Confocal laser microscopy images demonstrated that both ATO-MSNs and ATO-MSNs-RGD had good cellular uptake that improved with longer incubation time and nanoparticle concentration and the ATO-MSNs-RGD showed clearly improved cellular uptake compared with ATO-MSNs. The MSNs, ATO-MSNs, ATO-MSNs-RGD, and ATO were used to treat mice bearing MDA-MB-231 breast tumors every 5 days and the findings suggested that ATO-MSNs-RGD provided superior therapeutic ability over MSNs, ATO-MSNs, and ATO.

Intrinsic and Stable Conjugation of Thiolated Mesoporous Silica Nanoparticles with Radioarsenic

“…Comparison of this value with the number of thiols per gram of thiolated MSN(5 nm pores) (0.4 mmol of –SH/g) shows that this corresponds to a 1:2 molar ratio of As:thiols, implying that at full capacity two sulfhydryl groups are binding to each arsenic atom. This ATO loading capacity is also notably lower than that reported by Wu et al of 120 mg/g 39 and Muhammad et al of 46 mg/g 36 for other thiolated MSN preparations, likely as a result of a lower surface area (580 m 2 /g vs 1021 m 2 /g for Wu et al and 728 m 2 /g for Muhammad et al) and thiol content (0.4 mmol of –SH/g vs 1.1 –SH/g for Wu et al) of the MSN used in this work. Despite this, a loading capacity of 20 mg of ATO per gram of MSN is sufficient to deliver therapeutic quantities of 0.1–1 mg of ATO/kg with MSN doses of <50 mg of MSN/kg, which have been shown to be safe in murine models.…”

“…Recent efforts to increase the therapeutic index of ATO have utilized a variety of nanoparticle-based drug delivery methods including liposomes, 28–31 polymeric nanoparticles, 32–35 and most recently mesoporous silica nanoparticles. 36–39 …”

Mesoporous Silica Nanoparticles for the Treatment of Complex Bone Diseases: Bone Cancer, Bone Infection and Osteoporosis

“…This targeting strategy relies on the overexpression of some receptors only on the membrane of tumoral cells. Examples of this approach include the functionalization of the particles with antibodies [122,123], proteins [69,124], small molecules [125][126][127][128][129] or peptides [77,130,131], among others.…”

Long time release of water soluble drug from hydrophilic nanofibrous material

“…In order to address this issue, we intend to incorporate mesoporous silica nanoparticles (MSNs) into the PVA nanofibrous mats to achieve long time drug release. Lots of previous research studies had demonstrated the potential of MSNs as drug carriers for the controlled release of therapeutics owing to their high surface area, large pore volume, regular and adjustable pore size, and a hydrophilic surface character . The rich pore structure of MSNs enables extraordinarily large loadings of drugs.…”