Küçük Hücreli Dışı Akciğer Kanser Hücrelerine Hedeflendirilmiş Kombine İlaç İçeren Teranostik Lipozomların Etkinliğinin İzlenmesi


Thesis Type: Doctorate

Institution Of The Thesis: Hacettepe University, Sağlık Bilimleri Enstitüsü, Radyofarmasi A.B.D., Turkey

Approval Date: 2019

Thesis Language: Turkish

Student: MERVE KARPUZ

Principal Supervisor (For Co-Supervisor Theses): Mine Silindir Günay

Supervisor: Asuman Yekta Özer

Abstract:

Overall, cancer is a fundamental health issue all around the world. In particular, lung cancer is the type that has the highest incidence and mortality rate. Although several methods including chest x-rays, computed tomography, magnetic resonance and nuclear imaging methods are routinely employed in the diagnosis and imaging of lung cancer; these techniques fall short of sufficient when it comes to early diagnosis. On the other hand, the most frequently used treatment methods for lung cancer are surgery, radiotherapy and chemotherapy. Among these, surgery is the most effective method in treating lung cancer; however, it can only be practiced in the early stages of the disease. While radiotherapy is the treatment method of choice for the patients with early-stage lung cancer that’s not suitable for surgical procedures; chemotherapy is utilized in the treatment of advanced-stage patients.  The fact that chemotherapeutic drugs are not tumor-specific and cause serious, systemic, toxic effects constitutes one of the biggest problems in the treatment. Combination therapy, is frequently used in cancer treatment, has various advantages including reducing of toxic effects of monotherapy and targeting of different mechanisms.

Taking these facts into consideration, in our study; nanosized liposome formulations were prepared. While doing so; paclitaxel was encapsulated in the lipid bilayer and vinorelbin was encapsulated in the hydrophilic core of the same liposomes. These formulations were targeted actively and/or passively at the folate receptors in the non-small cell lung cancer cells and labelled with 99mTc radionuclide. In the subsequent characterization studies, the suitability of the profiles of liposomes for in vitro studies has been proven by their particle size (about 150nm for passive targeted ones and about 180 nm for active targeted ones) and encapsulation efficiency of 15% for PCX and 20% for VNB as well as their zeta potential of about -10 mV. The results of the stability studies showed that the liposome formulations remained stable in tightly sealed containers for about 45 days at 4oC. The cytotoxicity profiles of these liposome formulations and the results of the in vitro uptake studies were evaluated in the A549, H1299 and LLC-1 cell lines. According to the results of flow cytometry and MTT analyses, liposomes were uptaken and showed high cytotoxic effects in cells.

By the results of biodistribution studies performed in mice bearing lung cancer, radiolabeled with 99mTc, actively folate targeted, co-drug encapsulated liposomes formulations were uptaken in tumuor tissue compared to non-actively targeted one. In addition, the treatment efficiency of actively folate targeted, co-drug encapsulated liposomes formulations were found as higher than free drug combination and no-drug encapsulated liposome formulation as control group. Furthermore, liposomal formulations showed lower toxicity compared to free drug combinations in the toxicity study considering body weight.