Development of doxorubicin and elacridar loaded PLGA/silica hybrid nanoparticles and evaluation of activity against breast cancer

Although doxorubicin is efficient alone in cancer treatment, its being a substrate of P-glycoprotein (P-gp) limits its effectiveness. Various approaches have been developed to overcome the growing resistance to these drugs. One of them is the co-administration of P-gp substrate anticancer drugs with another P-gp inhibitor substance. Elacridar which is an inhibitor used for this purpose, has been one of the most studied inhibitors because of the BCRP (breast cancer resistant protein) and P-gp inhibition ability. Another promising approach about overcoming of developed drug resistance is the encapsulation of anticancer drugs into the nanoparticulate drug delivery systems and targeting these systems to the receptors found on cancer cells. In this thesis, folic acid targeted nanoparticles with small size (~50 nm) can penetrate to the cancer cells at a high level were prepared by loading doxorubicin to the mesoporous silica nanoparticles (MSN). Prepared nanoparticles and P-gp inhibitör, elacridar, were co-loaded to the second polymeric system made of PLGA-PEG to ensure the acumulation in desired tissue and extended blood residence time. Developed drug delivery systems were characterized in detail, cytotoxicity, cellular uptake and mechanism of nanoparticles were investigated on T47-D, ZR-5-1 and EMT6/AR1 breast cancer cell lines. The obtained nano-drug delivery system was significantly better than doxorubicin solution and Caelyx® which was the commercially available nano drug. Keywords: PLGA hybrid nanoparticle, elacridar, mesoporous silica nanoparticles, breast cancer, active and passive targeting