Abstract
Objective:The MDR of metastatic breast cancer cells is accompanied by the overexpression of P-gp transporter. This study has been focused to determine whether silencing the expression of P-gp by aptamer-labeled siRNA nanoparticles could enhance the delivery of doxorubicin into breast cancer cells in culture.Methodology:The nanoparticle F-31 was prepared using DOTAP, cholesterol, and PLGA, and then incorporating Mal-PEG to facilitate aptamer-binding. The nanoparticles were surface-functionalized with aptamer A6, which targets Her-2 receptors overexpressed on the surface of breast cancer cells.Results:This study has shown that the uptake of Dox by Dox-resistant 4T1-R is significantly less than Dox-sensitive 4T1-S which is partly attributed to the higher expression of drug-efflux pump P-gp on the surface of the resistant cells. The targeted knockdown of P-gp has been enhanced when the particles carrying P-gp siRNA was labeled with aptamer. Concurrently, the uptake of Dox into the Dox-resistant 4T1-R breast cancer cells has increased significantly when the P-gp was silenced by P-gp siRNA-encapsulated aptamer-labeled nanoparticles.Conclusions:This preliminary study concludes that downregulating P-gp expression by targeted delivery of P-gp siRNA using aptamer-labeled lipid-based hybrid nanoparticles could effectively increase the intracellular trafficking of doxorubicin in Dox-resistant mouse breast cancer cells.
Highlights
Breast cancer incidences have declined in the recent past[1,2], it is still the second leading cause of death in women
The uptake of Dox into the Dox-resistant 4T1-R breast cancer cells has increased significantly when the P-gp was silenced by P-gp siRNA-encapsulated aptamer-labeled nanoparticles
This preliminary study concludes that downregulating P-gp expression by targeted delivery of P-gp siRNA using aptamer-labeled lipid-based hybrid nanoparticles could effectively increase the intracellular trafficking of doxorubicin in Dox-resistant mouse breast cancer cells
Summary
Breast cancer incidences have declined in the recent past (by 37% from 1990– 2013)[1,2], it is still the second leading cause of death in women. Treatment options available at present include surgical excision, adjuvant radiation therapy, adjuvant chemotherapy and hormonal therapy. Chemotherapy involves the application of small molecule drugs like alkylating agents, anti-metabolites, anthracyclines and topoisomerase inhibitors. Over prolong exposure to the chemotherapeutic drug, cancer cells become resistant to a single drug or class of drugs and manifest cross-resistant phenotype to several antineoplastic drugs[4], that are structurally and functionally unrelated[5]. This phenomenon of acquired drug resistance, known as, multidrug resistance or MDR, is a major challenge faced by cancer therapy till today
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