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Enhanced penetration and cytotoxicity of metformin and collagenase conjugated gold nanoparticles in breast cancer spheroids

Abdolahinia, Elaheh Dalir, Nadri, Samad, Rahbarghazi, Reza, Barar, Jaleh, Aghanejad, Ayoub, Omidi, Yadollah
Life sciences 2019 v.231 pp. 116545
apoptosis, breast neoplasms, breasts, cell lines, cell proliferation, collagen, collagenase, cytotoxicity, enzyme-linked immunosorbent assay, extracellular matrix, flow cytometry, fluorescent antibody technique, metformin, nanogold, nanoparticles, neoplasm cells, pyruvate kinase, quantitative polymerase chain reaction, stem cells
The extracellular matrix (ECM) within the tumor nest plays a key role in cancer cell proliferation and invasion. It has been proven that the increased density of ECM, especially collagen network, correlates with the poor distribution of gold-nanoparticles (GNPs) to the tumor mass. Here, for the first time, we examined the combined effect of collagenase (COL) with metformin (MET)-conjugated GNPs on mammosphere generated from JIMT-1 breast cell line in vitro.Mammospheres (on days 7 and 14) and monolayer culture were treated with MET, MET-GNPs, and a mixture of COL-GNPs and MET-GNPs for 5 days. To assess the impacts of the engineered nanoparticles (NPs) on the survival/apoptosis of cancer cells and cancer stem cells (CSCs), the amount/activity of collagen and the expression of pyruvate kinase M2, different methods were applied, including MTT, flow cytometry, immunofluorescence, ELISA and real-time PCR analyses. Our results confirmed the enhanced cytotoxic effects of MET-GNPs combined with COL-GNPs on mammospheres compared to the cells treated with MET alone or MET-GNPs.Upon treatment with the mixture of MET-GNPs and COL-GNPs, the population of the apoptotic cells was significantly increased. A marked reduction was found in the number of CD24−/CD44+ CSCs and the amount of collagen in the group received a mixture of MET-GNPs and COL-GNPs.Based on our findings, the use of COL can improve the cellular interaction/penetration of MET-GNPs in mammospheres and its antitumor impacts on the CSCs.