Non-Hodgkin Lenfoma Tedavisinde İlaç Direncini Yenmek Amacıyla Aktif Hedeflendirilmiş, Çoklu İlaç Yüklü Nanopartiküllerin Geliştirilmesi ve İn Vitro-İn Vivo Etkinlik ve Güvenliliğinin Değerlendirilmesi

Abstract

Demirturk, N., Development and in vitro-in vivo Evaluation of Active Targeted Multidrug Loaded Nanoparticles to Overcome Drug Resistance in the Treatment of Non-Hodgkin Lymphoma, Hacettepe University Graduate School Health Sciences Pharmacy Department of Pharmaceutical Technology Doctor of Philosophy Thesis, Ankara, 2024. Currently, the first-line treatment for Non-Hodgkin Lymphoma (NHL) involves a "4-drug regimen" known as R-CHOP, which includes anticancer agents such as cyclophosphamide, doxorubicin, and vincristine, as well as prednisone and the monoclonal antibody rituximab. However, due to anticancer drug resistance, the desired level of success is not always achieved. This thesis aims to enhance the effectiveness of R-CHOP therapy, reduce side effects, and overcome emerging drug resistance by using nanoparticles made from amphiphilic and polymeric cyclodextrins containing "guanidine groups" that target mitochondria. In the first phase of the thesis, the safety of cyclodextrin derivatives was demonstrated through studies on hemolysis, stability in biological fluids, and complement activation. Subsequently, HPLC methods were validated for quantifying each anticancer drug. Following this, rituximab-targeted, multi-drug-loaded nanoparticles were successfully prepared using the nanoprecipitation method. In vitro characterization studies, including particle size, surface charge, drug loading efficiency, and drug release profile, were conducted, followed by 2 and 3-dimentional cell culture studies. The results showed a statistically significant reduction in cell viability in lymphoma cell lines treated with the targeted drug-loaded nanoparticles compared to drug solutions (p<0.05). Finally, in vivo experiments were carried out in Balb/c mice to assess pharmacokinetics, bioavailability, safety, and antitumor efficacy. The study has led to the development of a promising model drug delivery system for overcoming drug resistance.