Investigation of the role of parp inhibitors loaded solid lipid nanoparticles on overcoming drug resistance mechanisms in triple negative breast cancer treatment


Thesis Type: Doctorate

Institution Of The Thesis: Uludağ Üniversitesi, Turkey

Approval Date: 2017

Thesis Language: Turkish

Student: GAMZE GÜNEY ESKİLER

Supervisor: GÜLŞAH ÇEÇENER

Abstract:

Poly-ADP ribose polymerase (PARP) inhibitors have been draw attention as a novel therapeutic treatment strategy for TNBC patients who carrying mutations in the BRCA1/2 genes and/or defective homologous recombination (HR) pathway due to leading to synthetic lethality. However, different mechanisms that have been implicated in the development of resistance to PARP inhibitors present a significant problem in the efficacy treatment of PARP inhibitors. Solid lipid nanoparticles (SLNs) are lipid-based drug delivery systems to overcome the disadvantages of traditional drug delivery systems. It is known that SLNs have a potential therapeutic effect in increasing the therapeutic effect of anti-cancer agents on cancer cells, reducing toxic effects in normal cells and overcoming multidrug resistance (MDR) by providing controlled release of active agent. In the current thesis study, the characterization experiments were carried out by producing BMN 673-SLNs in order to develop pharmacological properties of BMN 673, a PARP inhibitor and to overcome the HR and MDR mechanisms causing the development of resistance to BMN 673. The cytotoxic and apoptotic effects and ultra-structural changes of BMN 673-SLNs compared with BMN 673 were determined on HCC1937BRCA1-/-, HCC1937-R (resistant to BMN 673) TNBC and MCF-10A control epithelial cell lines. In order to determine the therapeutic effect of BMN 673-SLN for overcoming the resistance mechanisms, the effect of mRNA and protein levels of genes related to HR and MDR mechanisms and the expression levels of miRNAs targeting these genes were analyzed both quantitatively and qualitatively. In conclusion, it has been shown that SLNs as an ideal drug delivery system for BMN 673 have a potential therapeutic effect on reducing the disadvantages of BMN 673 (large size, toxic effect, etc.) and overcoming HR and MDR mechanisms causing the development of resistance to BMN 673.