Magnetic nano-cyclodexstrin-liposome anti-cancer drug carrier system preparation, characterization and investigation of controlled release behavior

Cancer is one of the deadliest diseases in the 21st century, second only to cardiovascular diseases. It results from uncontrolled division of cells as a result of damage and mutation. Breast cancer is both the most common and the deadliest type of cancer in women worldwide. The most important problem in the treatment of cancerous cells is that the drugs used in chemotherapy show low selectivity for cancer cells and cause many side effects by affecting healthy cells. In order to eliminate this situation, targeted drug delivery systems are primarily studied. Today, drug-loaded delivery systems formed from biocompatible and biodegradable magnetic nanoparticles and magnetic cyclodextrin-liposome together with active targeting methods offer a promising approach in the treatment of breast cancer. By providing continuous drug release in this region, it is aimed not only to increase the therapeutic effect of the drug, but also to reduce the unwanted side effects. Topotecan is an analog of camptothecin, which is one of the most widely used anti-cancer drugs in the treatment of breast cancer and prostate cancer, especially ovarian cancer and small cell lung cancer, and acts as a topoisomerase I inhibitor. The active lactone form under acidic conditions and the inactive carboxylate form by hydrolysis at neutral or alkaline pH dominate. Therefore, it is one of the difficult drugs to study. In this thesis study, magnetic β-cyclodextrin-topotecan (Fe3O4@βCD-TPT) inclusion complexes (hydrophilic topotecan) were prepared and both pure topotecan and its complexes were individually confined to liposomes. It was then evaluated for in vitro cytotoxicity in human breast cancer (MCF-7) cell lines. Optimization of topotecan retention in Fe3O4@β-CD was achieved with magnetically prepared Fe3O4@β-CD-TPT complexes. Inclusion complexes were verified using UV-Vis spectroscopy, transmission electron microscopy (TEM), dynamic light scattering spectrometry (DLS) and Fourier transform infrared spectrometry (FTIR), and high performance liquid chromatography (HPLC). The water solubility of the Fe3O4@β-CD-TPT complexes was significantly improved and successful encapsulation of the complexes into liposomes prepared using the sonication approach was also achieved. Liposomal formulations, topotecan and Fe3O4@β-CD-TPT complex were characterized for particle size, zeta potential, capture efficiency and stability. Topotecan, the Fe3O4@β-CD-TPT complex and their optimized liposomal forms were evaluated for cytotoxicity in breast cancer (MCF-7) cancer cell lines. All tested topotecan-containing forms were found to be effective in inhibiting cell proliferation, as determined by MTT analysis. The median effective dose (IC50) for all topotecan forms was in the low µg/mL range for the breast cancer cell lines tested. Our results confirm that Fe3O4@β-CD inclusion complexes of pH-sensitive drugs such as topotecan can be entrapped in biocompatible vesicles such as liposomes, suggesting that they extend their anticancer activity over a long period of time.