Meme Kanseri Tedavisinde Aktif Hedeflendirme Amacıyla Kullanılmak Üzere Nano Boyutlu İlaç Taşıyıcı Sistemlerin (Nanofarmasötikler) Tasarımı, İn Vitro/İn Vivo Değerlendirilmesi

Abstract

The aim of an ideal therapy using anticancer molecules is to target tumors selectively without damaging healthy tissues. Tumor specific markers formed by the physiological and morphological changes during the growth of cancer cells are identified by the help of specific ligands. The aim of active targeting, which is developed in this direction, is to protect the normal tissues from the therapy. The lymphatic system plays a critical role in the metastasis of cancer cells, thus lymphatic targeting approach has gained importance for the prevention of cancer metastasis. Laakkonen et al. have identified a cyclic 9-amino-acid (CGNKRTRGC) peptide called LyP-1, which specifically binds to tumor lymphatic vessels using phage-displayed peptide libraries in 2002. Within the scope of this thesis, LyP-1 containing lipid-based nanopharmaceutics (self emulsifying drug delivery systems, SEDDS) were targeted to p32, which is found in high amounts on the surface of breast cancer cells and to which LyP-1 binds and is internalized. Furthermore, the conjugates of the peptide were prepared with doxorubicin hydrochloride, anti-DTPA antibody and fluorescein. The characterization studies were carried out for all prepared formulations. Caco-2, MDA-MB-231 and 4T1 cell lines were used for in vitro evaluation of SEDDS formulations (liquid and solid), as well as in vivo efficacy studies were performed in 4T1 mouse breast cancer model in accordance with the results obtained from in vitro studies. At the end of this thesis, SEDDS formulations of LyP-1 for parenteral and oral use were developed and their potential for the treatment of breast cancer by lymphatic targeting were shown.