Development and Testing of Anticancer Drug Conjugates for Lung-Targeted Delivery via the Polyamine Transport System
Project no. 25269 · Status: Kapanmış (Yayın bekleniyor) · 2023
Summary
<p>In this project, polyamine conjugates of cisplatin, docetaxel, and gemcitabine, drugs used in the treatment of lung cancer, were synthesized with the aim of targeting the Polyamine Transport System (PTS), which is substantially more abundant in the membranes of tumor cells than in healthy cells, thereby increasing the intracellular drug dose while reducing systemic toxic effects. The targeting capacities of the conjugates were evaluated in vitro using cell culture models. Their cytotoxic effects were also determined in cell culture and compared with those of the corresponding parent drugs. To evaluate the efficacy of the four synthesized conjugates in vivo, an orthotopic tumor model was established in immunosuppressed nude mice by injecting cancer cells directly into the lung under anesthesia. Human lung cancer cells (A549) were injected, and histopathological analysis in the preliminary experiment demonstrated tumor formation in two of the three animals. Since it was not known which of the four different human lung cancer cell lines available in our laboratory exhibited the highest PTS activity, an additional study was planned as a Master's thesis to characterize the PTS in these cell lines at the gene, protein, and functional activity levels. Based on the functional assessment, A549 cells were found to exhibit high PTS activity and were therefore selected for subsequent experiments. For the subsequent in vivo experiment, luciferase-transfected A549 cells (A549-Luc) were used, and tumor development was evaluated using an IVIS imaging system after three weeks. However, the success achieved in the preliminary experiment could not be reproduced, and tumor formation was detected in only one of the seven animals. The orthotopic tumor model experiments will therefore be repeated for the currently available drug candidates as well as those planned for synthesis. To date, three novel drug conjugates have been synthesized and purified within the scope of the project, and their PTS selectivity ratios have been determined in vitro using cell culture models. The synthesis and purification of a fourth alternative conjugate, a paclitaxel–polyamine conjugate, is planned. In addition, the functional PTS levels of four different human lung cancer cell lines have been determined, while characterization at the gene and protein levels is ongoing. Partial success has also been achieved in establishing a rodent orthotopic lung cancer model. Throughout these studies, the project team has gained substantial experimental experience, and the postdoctoral researchers and Master's student involved in the project have acquired the skills necessary to apply new methods, techniques, and experimental models.</p><p></p><p class="ql-align-justify"><strong>Key words:</strong> Lung cancer, Preclinical study, Drug targeting, Polyamine transport system, polyamine conjugate drug candidates</p>