Development of a targeted Drug Delivery System for treatment of Pancreatic Ductal Adenocarcinom

Sammanfattning: Pancreatic cancer is the fourth leading cause of cancer-related death with a 5-year survival of less than 6%. The only potential cure for pancreatic cancer is by surgical removal of the tumor. However, most patients present with an advanced and metastasized disease at the time of diagnosis, leaving only around 15% of patients eligible for surgery. For the majority of patients, palliative chemotherapeutic treatment is the only option.Gemcitabine, a nucleoside analogue, has been the standard chemotherapeutic treatment for pancreatic cancer in both the palliative and adjuvant settings. However, the use of gemcitabine is problematic, as it presents several drawbacks such as a short half-life (~15 min), drug resistance, deficient drug delivery, poorcellular uptake and hence, a suboptimal therapeutic response.The aim of this thesis was to develop a nanoparticle-based drug delivery system for a targeted and improved delivery of gemcitabine for treatment of pancreatic ductal adenocarcinoma. To address this issue, we used a liposomal drug delivery system as the delivery system of choice. In a first stage, we developed and extensively characterized the liposomal system by use of several measurement techniques, such as DLS, cryo-TEM, nES GEMMA and AF4, evaluated the system stability and studied thebiodistribution profile of the liposomal system by use of radiolabeled liposomes and SPECT/CT imaging. In a second stage, we proceeded to develop a targeted treatment. We first identified a potential targeting protein, MUC4, which is highly expressed in pancreatic cancer but not expressed in the healthy pancreas and studied its clinical impact on resected pancreatic cancer patients. Finally, we developed a MUC4-targeted immunoliposome (iGemLip). iGemLip showed a significantly higher binding affinity, cellular uptake and antiproliferative effect on a MUC4-positive pancreatic cancer cell line, Capan-1, compared to both free and liposomal gemcitabine.