Kemik Metastazlarının Tedavisinde Etkili Nanopartikül Formülasyonlarının Geliştirilmesi, Optimizasyonu ve In Vitro Değerlendirilmesi

Abstract

Kozlu, S., Formulation Development, Optimisation and In Vitro Evaluation of Nanoparticles Effective to Bone Methastasis, Hacettepe University Institute of Health Sciences Department of Pharmaceutical Technology Doctor of Philosophy Thesis, Ankara, 2017. Bone metastasis that is often seen on patient with high incidence cancers (egg. breast and prostate) because important complication that lowers the quality of life and even ended with death. Doxorubicin is one of the chemotherapeutics using for the treatment of breast cancer metastasis on bone has some limitation due to its adverse effects primarily cardiotoxicity. In recent years it is known that doxorubicin and celecoxib have synergistic effect. There are some clinical trials that had to be stopped due to adverse effect to other organs. Within this study it is aimed to develop a nanocarrier system that leads the synergic effect of these molecules and promote increasing of drug concentration in the specified tissue. Thus, PLGA nanoparticles has chosen as carrier system, alendronate as targeting ligand due to its chelating properties with calcium ions in bone tissue, doxorubicin and celecoxib have chosen as the active pharmaceutical ingredients. Metastatic breast cancer has chosen as the model disease. At first step, the optimum dose that shows synergic effect is investigated with human breast cancer cell line. The determined optimum synergic dose is incorporated into nanoparticles by the help of statistical experimental design tools. Optimized nanoparticles were characterized with particle size, electron microscopy images, surface charge and in vitro release characteristics. The characterized particles’ affinity to bone tissue has been investigated with in vitro calcium binding capacity assay, hydroxyapatite binding affinity assay and in vitro cell cytotoxicity and uptake studies. Moreover in vivo biodistribution study has been performed with Balb/c mice. It is founded that; the developed nanoparticular system is promising with ability to carry the drugs at desired dose ratio and with affinity to bone tissue.