Advancing Treatments for Leukemia and Metastatic Pancreatic Cancer with Targeted, Synchronized Delivery of Drug Combination Stabilized in Nanoparticles

Abstract

Cancer continues to be a leading cause of death for all Americans due to an inability of the treatment drugs to properly target and accumulate at the cancer and tumor sites in the body. Leukemia (blood cancer) treatments that can temper the disease without truly curing it are now common first-line regimens, with some patients even experiencing treatment-free remission (TFR) for up to 10 years after their initial treatment. However, not all patients experience this TFR due to the inability of treatment drug to remain at sufficiently toxic levels in the body over time because of fast clearance, limited distribution of drug in the body, and poor patient compliance. Pancreatic cancer, on the other hand, has not benefited from treatment advances that improve outcomes of patients with leukemia, primarily due to its often-late diagnosis, meaning most patients present metastatic symptoms at diagnosis. Gemcitabine (G) and nab-paclitaxel (T, a protein-based nanoparticle bound paclitaxel) is a leading combination therapy involving the sequential administration of hydrophobic, nanoparticle-bound T followed by hydrophilic, free G in solution. However, GT combination therapy generally only grants a median overall survival of about 9 months from treatment initiation. While somewhat successful relative to other treatments, this limited survival time extension is likely due to insufficiently drug concentrations at the tumor site that related to poorly vascularized tumors with limited drug access and overall high drug clearance from the body. If anticancer small molecule drugs could be assembled and co-localize in cancer laden tissues and cells for an extended duration, some of the current limitations (drug access and retention) for treating both leukemia and pancreatic cancer could be addressed in improving patient outcomes. Following this hypothesis, we first assembled a novel drug combination nanoparticle (DcNP) which carry two novel small molecule drugs, venetoclax and zanubrutinib (VZ-DcNP). The VZ-DcNP tested in mice were shown to prolong the exposure of each drug by 43-fold and 5-fold, respectively. Currently, there is no immune-competent pancreatic tumor mice model that reflects pancreatic cancer development in pancreas. In searching for an experimental pancreatic cancer model, we found that simple intraperitoneal, but not intravenous, inoculation of a pancreatic ductal adenocarcinoma cell Pan02 resulted in development of pancreatic tumors in their pancreases, mimicking pancreatic cancer in humans. The use of intensive survival surgeries, foreign matrices, or unreliable genetic induction events, which typically pose challenges in therapeutic evaluation, is no longer a limitation with this novel Pan02 orthotopic pancreatic tumor model. Pancreatic Pan02 cells were shown to home into the pancreas, resulting in a 100% take-rate of tumors in mice. Following an intraperitoneal administration of drug combination nanoparticles with GT (GT-DcNP) at 20 mg/kg G and 2 mg/kg T, pancreatic tumor-bearing mice had greatly improved overall survival compared to mice receiving intravenous GT-DcNP, intravenous free drug, or no treatment. Further pharmacokinetic analysis of mouse tissue and plasma following intraperitoneal drug administration demonstrates the extended exposure of nanoparticle-bound drugs in blood and enhanced drug exposure in tumor-laden pancreas by GT-DcNP, compared to that dose with equivalent free GT combination. These results and accomplishments described in the thesis serve as the foundation for translating the novel pancreatic tumor models, enabling drug-combination technology for VZ and GT for safer and more effective treatments for leukemia and pancreatic cancer in the future.