Preparation and Characterization of Doxorubicin Containing Ag/MSN Janus Nanoparticles for Targeted Chemotherapy and Photothermal Therapy in Breast Cancer

Abstract

Background: Drug resistance in cancer treatment, primarily attributed to the overexpression of the multidrug resistance (MDR) gene, significantly hampers the effectiveness of chemotherapy. This mechanism, driven by the increased production of p-glycoprotein (P-gp) efflux pumps, highlights the urgent need for innovative strategies to combat drug resistance in cancer patients. Aims: This study explores the application of antisense technology to suppress MDR gene expression, while addressing the challenges of instability and limited cellular uptake associated with antisense oligonucleotides. Methods: We synthesized Janus silver-mesoporous silica nanoparticles (Ag/MSN JNPs) using a sol-gel method, characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS), revealing uniformly sized, dumbbell-shaped nanoparticles with an average size of 285 ± 5.12 nm. Doxorubicin (DOX) was loaded into the porous structure of the mesoporous silica, and JNPs were functionalized with chitosan (CS) to incorporate p-gp antisense and a MUC-1 aptamer, serving as a pH-responsive gatekeeper. The cellular uptake of aptamer-conjugated nanoparticles was evaluated using flow cytometry. The cytotoxic effects of the synthesized nanoparticles on both the normal cell line (MCF-7) and the drug-resistant breast cancer cell line (MCF-7/ADR) were assessed through the MTT assay. Furthermore, to determine the effectiveness of the antisense, a Western blot analysis was conducted to detect P-gp protein levels.Results: Our findings indicate that the Ap-As-DOX-JNPs achieved a remarkable 89 ± 0.59% cell death in drug-resistant MCF-7/ADR cells after 48 hours, alongside an 80% reduction in P-gp expression. The combination of DOX, antisense technology, and photothermal therapy utilizing these JNPs demonstrates a promising strategy to effectively overcome drug resistance. Notably, normal MCF-7 cells exhibited reduced viability from 39.11 ± 1.12% to 30.05 ± 1.07% when treated with DOX-JNPs under near-infrared (NIR) irradiation. The cellular uptake of aptamer-functionalized nanoparticles demonstrated a significant increase compared to nanoparticles without aptamers in the MCF-7 cell line.Conclusion: These results underscore the potential of utilizing MUC-1 aptamer-conjugated Janus nanoparticles in conjunction with chitosan as a gatekeeper to enhance the efficacy of chemotherapy, photothermal therapy, and gene therapy in overcoming multidrug resistance in cancer treatment.