Combinational Therapy Using Multifunctional Nanoparticles for Breast Cancer Therapy

Date

2017

Authors

Shrestha, Binita

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Abstract

The objective of this research was to design and develop multifunctional nanoparticles for selective combinational breast cancer therapy. There have been tremendous advances in cancer biology in past few decades which certainly provided better insight to cancer prevention, detection and treatment however cancer prevalence has not subsided yet. Breast cancer for example is still second leading cause of death in women. It is thus critical to develop effective therapeutic solution to curb cancer. In the wake of major scientific advances in molecular biology, combinational therapy has displayed high potential in development of improved cancer therapy. Combination of gene and chemotherapeutic agent in particular, have grabbed a lot of attention lately. In this project, we designed and developed multifunctional gold nanoparticle (GNPs) mediated drug delivery system for co-delivery of Polo like kinase (PLK1) siRNA and doxorubicin (DOX). DOX was conjugated to GNS via pH sensitive linker for stimulus responsive release. These nanoconjugates demonstrated high DOX loading efficiency (65%). Also, these nanoconjugates displayed controlled release of DOX over the six days period. Polyethyleneimine (PEI) was used to conjugate siRNA. Although it is considered to be a gold standard for gene delivery, cytotoxicity has been a setback for PEI. Here we used minimal PEI just enough for siRNA assembly. We evaluated the toxicity effects of these nanoparticles for seven days period. Our results showed severe toxicity with PEI alone in compare to PEI coated GNS. Further, these nanoconjugates showed effective release of DNA and siRNA. About 70% and 55% of silencing was observed in HEP2 and SKBR3 cells respectively. In case of targeted nanoparticles, there was about 30% reduction in gene silencing in case of HEP2 cells whereas 20% increase in gene silencing was observed in SKBR3 cells. This data clearly illustrated the targeting efficiency of these nanoconjugates in the cells. The reduced protein expression of PLK1 in western blot analysis further confirmed the effective release of siRNA. The therapeutic efficiency of combinational therapy against single therapy was evaluated in 2D and 3D culture systems. The half maximal inhibitory value was used as a measure to determine the therapeutic efficacy of the treatment groups. The reduced IC50 value in both cell culture system indicated synergistic effect of combinational therapy in compare to their single counterparts.

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Keywords

Cancer therapy, Combinational Therapy, Drug delivery, Gene delivery, Gold nanoparticles, Nanomedicine

Citation

Department

Biomedical Engineering