Functionalized Mesoporous Silica Nanoparticles for the Delivery of 3,3'-diindolylmethane to Triple-negative Breast Cancer Cells

Background: Despite advancements in cancer therapy, the delivery of anti-cancer agents remains a significant challenge due to the toxicity of conventional treatments to healthy tissues, and the limited solubility and bioavailability of some therapeutic agents. Delivery systems based on nanoparticles have emerged as an effective way to address these issues. Objectives: The primary goal of this study was to assess the ability of functionalized Mesoporous Silica Nanoparticles (fMSNs) to transport 3,3'-diindolylmethane (DIM), a hydrophobic anticancer drug, to efficiently target Triple-Negative Breast Cancer cells (TNBCs), while posing the least number of adverse effects on cells that are healthy, and to evaluate the mechanism of action and potential cytotoxicity of DIM-fMSNs on TNBC cells. Methods: Functionalized mesoporous silica nanoparticles were synthesized and characterized for uniformity and functionalization. DIM, a hydrophobic indole-based phytochemical, was loaded into the fMSNs to create DIM-fMSNs. The drug delivery system was tested in vitro on TNBC cells to assess its cellular uptake, bioavailability, and cytotoxic effects. Mechanistic studies were conducted to determine the pathways involved in DIM-fMSNs-induced cell death. Results: Our findings demonstrate that the fMSNs effectively delivered drugs to MDA-MB-231 cell lines, resulting in significant suppression of the growth of cancer cells, and enhanced therapeutic efficacy in vitro, whilst demonstrating effective penetration into TNBC cells even at low concentrations. In vitro tests also showed that our nano-formulation was superior to toxic chemotherapy drugs like Doxorubicin in the treatment of TNBC at lower drug concentrations. Mechanistic studies involving the identification of key apoptotic proteins revealed that DIM-fMSNs induced mitochondriamediated apoptosis as the underlying mechanism of cell death in TNBC cells. The formulation demonstrated increased therapeutic efficacy and drug bioavailability with fewer harmful side effects on nearby normal cells and tissues. Conclusion: The study highlights the potential of DIM-loaded fMSNs as a potentially effective therapeutic approach for TNBC treatment. The use of fMSNs improved the solubility, bioavailability, and delivery of DIM, resulting in enhanced efficacy and reduced toxicity, introducing an innovative approach to future cancer therapies.