Active targeting of irinotecan and STAT3 inhibitor loaded PLGA-PEG nanoparticles to small cell lung cancer and In vitro-In vivo evaluation

Lung cancer is the leading cause of death in cancer related deaths and is in the second most common cancer type in both sexes. Around %13-15 of all lung cancer cases consist of small cell lung cancer (SCLC) which advances rapidly and is hard to treat. It is most likely to have formed metastasis in advance of diagnosing the disease. Irinotecan inhibits the topoisomeras-I enzyme which is highly expressed in some cancer types such as breast cancer and lung cancer and thus, induces DNA strand breakage and disturbs DNA replication. In liver and inside the tumor, it transforms to SN-38, which is a 100-1000 fold more active form than irinotecan, mainly by carboxylesterase enzyme. Transformation of irinotecan to SN-38 before reaching the tumor causes heterogeneity in efficacy and toxicity. Research showed that a transcription factor named signal transducer and activator of transcription 3 (STAT3) is constantly active in various human cancer cell lines and is effective in promotion and progression phases. Additionally it contributes to the continuity of cell viability, suppression of the immune system and angiogenesis. Therefore, STAT3 inhibition is currently being investigated as a cancer treatment approach. In our preliminary studies, it was shown that STAT3 pathway is highly active in SCLC cells. In the scope of this thesis, Food and Drug Administration (FDA) approved polyethylene glycol (PEG) modified poly lactic-co-glycolic acid (PLGA) nanoparticles will be prepared and targeted to the tumor by conjugating anti-CD56 monoclonal antibody to their surface. CD56 is a membrane molecule that is highly expressed at the surface of SCLC cells. By encapsulating irinotecan and a suitable STAT3 inhibitor into the nanoparticles; pharmacokinetic properties of irinotecan will be enhanced, side effects to healthy cells and tissues will be eliminated, irinotecan-SN38 transformation will actualize mainly in the tumor by means of targeting and controlled release. Nanoparticles will be characterized in vitro and in vivo. Using a clinically acceptable nanoparticulate system, treatment efficacy of actively targeting a chemotherapeutic agent-inhibitor combination to the clinically most aggressive lung cancer type, SCLC, will be evaluated.