Targeted therapy of breast cancer using methotrexate and indolamine-2,3-dioxygenase inhibitor loaded mesoporous silica magnetic nanoparticles

Abstract

Introduction: Conventional cancer therapeutic agents often are associated with the serious challenge due to adverse effects. Whereases, the emergence of targeted drug delivery vehicles provides an alternative approach for cancer therapy. Recently, cancer immunotherapy agents such as 1-Methyl-D Tryptophan (1-MDT) have been mostly used in cancer therapy. Aim: We established the PEGylated targeted drug delivery system using mesoporous silica magnetic nanoparticles (MSMNPs) for encapsulating 1-Methyl-D Tryptophan (1-MDT) as an immunotherapeutic and investigated its anti-tumor efficiency in combination with methotrexate (MTX) on breast cancer cell lines. Methods: In the present study, the thermal decomposition technique was used to synthesize superparamagnetic iron oxide nanoparticles (SPIONs). In the next step, these SPIONs were coated with mesoporous silica and conjugated with Polyethylene glycol (PEG) 2100 polymer and methotrexate in various steps to achieve MTX-PEG-MSMNPs. Subsequently, 1-MDT was loaded onto the final particles. Prepared NPs were characterized beyond each synthetic step using TEM, SEM, DLS, ATR-FTIR, VSM, BET, and XRD. Thereupon, quantitative RT- PCR was used to investigate the effect of 1-MDT on the expression of indoleamine 2,3 dioxygenase (IDO) on cancer cells. Besides, flow cytometry was performed to evaluate the cellular uptake. Subsequently, the antiproliferative effect of NPs was explored using MTT, NIR, and apoptosis assays in cancer cells. Results: The results revealed that the MTX-PEG-MSMNPs had a uniform size distribution (average size = 68.33, PDI=0.16). The Encapsulation efficiency and Loading capacity respectively were about 71% and 60%. Uptake experiments demonstrated that prepared nanoparticles can target breast cancer cells. RT-PCR data indicated that 1-MDT suppressed the IDO level. Besides, cytotoxic and apoptosis assays further confirmed the efficiency of NPs in cancer cell growth inhibition. Moreover, in-vitro MTT analysis revealed that 1-MDT loaded in MTX-PEG-MSMNPs in combination with NIR declined the cell viability. Conclusion: Overall, the engineered PEGylated MTX- armed mesoporous silica magnetic nanoparticles had potential anti-tumor impacts in vitro.