A tunable delivery platform to provide local chemotherapy for pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating and painful cancers. It is often highly resistant to therapy owing to inherent chemoresistance and the desmoplastic response that creates a barrier of fibrous tissue preventing transport of chemotherapeutics into the tumor. The growth of the tumor in pancreatic cancer often leads to invasion of other organs and partial or complete biliary obstruction, inducing intense pain for patients and necessitating tumor resection or repeated stenting. Here, we have developed a delivery device to provide enhanced palliative therapy for pancreatic cancer patients by providing high concentrations of chemotherapeutic compounds locally at the tumor site. This treatment could reduce the need for repeated procedures in advanced PDAC patients to debulk the tumor mass or stent the obstructed bile duct. To facilitate clinical translation, we created the device out of currently approved materials and drugs. We engineered an implantable poly(lactic-co-glycolic)-based biodegradable device that is able to linearly release high doses of chemotherapeutic drugs for up to 60 days. We created five patient-derived PDAC cell lines and tested their sensitivity to approved chemotherapeutic compounds. These in vitro experiments showed that paclitaxel was the most effective single agent across all cell lines. We compared the efficacy of systemic and local paclitaxel therapy on the patient-derived cell lines in an orthotopic xenograft model in mice (PDX). In this model, we found up to a 12-fold increase in suppression of tumor growth by local therapy in comparison to systemic administration and reduce retention into off-target organs. Herein, we highlight the efficacy of a local therapeutic approach to overcome PDAC chemoresistance and reduce the need for repeated interventions and biliary obstruction by preventing local tumor growth. Our results underscore the urgent need for an implantable drug-eluting platform to deliver cytotoxic agents directly within the tumor mass as a novel therapeutic strategy for patients with pancreatic cancer.

Introduction

Pancreatic cancer is one of the most lethal adult cancers, having a 5-year overall survival rate less than 6%. At the time of diagnosis, only 20% of patients have localized disease that can be successfully treated by surgical resection. The vast majority of PDAC patients have locally advanced disease, which limits the therapeutic options to radiation and systemic chemotherapies. By invading the surrounding vital organs, locally advanced tumors cause excruciating symptoms in patients including intense abdominal pain, anorexia, nausea, vomiting and jaundice. A major source of suffering for pancreatic cancer patients is the development of biliary obstruction due to the growth of the tumor into the biliary duct. This obstruction often requires repeated procedures to clear the duct through resection or stenting.

An additional issue with treatment of pancreatic cancer is the development of chemotherapeutic resistance. Pancreatic cancer is often highly resistant to chemotherapy due to intrinsic cellular chemoresistance, hypovascularity [1], [2], [3], [4] and an extensive desmoplastic reaction that creates a barrier of fibrous tissue preventing drug transport into the tumor [5], [6] (Fig. 1A). Many mechanisms of intrinsic cellular chemoresistance have been reported, but a common theme has been linked to the process of epithelial-mesenchymal transition (EMT). Several studies have shown that in many solid tumors EMT is correlated with chemoresistance, tumor aggressiveness and worsened survival [7], [8], [9], [10], [11]. These extrinsic and intrinsic chemoresistance mechanisms can synergize and dramatically attenuate the efficacy of systemically administered drugs, resulting in the poor efficacy of systemic chemotherapy often observed in PDAC patients. There is growing evidence that overcoming such drug delivery barriers can sensitize PDAC cancer cells to conventional chemotherapies, producing a beneficial impact on patient outcomes [1], [2], [3], [12]. Therefore, we hypothesized that a localized delivery approach would provide a new therapeutic option for palliative care of pancreatic cancer patients to enhance chemotherapy efficacy and reduce the intense suffering associated with their disease.

By integrating established biomaterial-science knowledge, cutting-edge technologies, computational modeling and patient-relevant cancer biology models, we engineered an implantable device that can safely deliver high concentrations of drugs inside the tumor mass to effectively inhibit tumor progression and control its dissemination in nearby vital organs. Our overall goal was to create a local delivery system for PDAC patients that could be rapidly translated into clinical practice. Consequently, we restricted our studies to FDA-approved drugs and biomaterial release systems. Poly(lactic-co-glycolic) (PLGA) is one of the most safe and well-characterized drug-eluting polymers and can be specifically modified to produce tunable local delivery platform for clinical application in pancreatic cancer settings. We first created several new patient-derived PDAC cell lines and tested their sensitivity to approved chemotherapeutic agents. After finding the cell lines were most sensitive to paclitaxel, we used a computational model to predict drug concentrations for the compound under different release scenarios. A final formulation for the paclitaxel-eluting device (PED) was obtained and we tested the efficacy of the local therapy in two orthotopic patient-derived pancreatic xenograft (PDX) mouse models with a comparison to systemic therapy. Local therapy was superior in inhibiting tumor growth and local dissemination of the cancer cells while reducing accumulation of paclitaxel in other healthy organs, like the liver. Moreover, only local delivery of the compound was able to overcome the chemoresistance and induce large areas of necrosis within the tumor mass.

Overall, we have developed a drug-eluting device that was highly effective in treating human tumors in mice by providing increased drug concentrations inside the neoplastic lesions. The device composition provides a generalizable platform consisting of clinically approved materials that can deliver local chemotherapy to PDAC patients based on the chemosensitivity of their cancer.

This drug-eluting platform has broad implications in many solid tumors with the potential to redefine new therapeutic paradigms to treat patients with cancer. By enhancing the effect of existing chemotherapeutic agents or releasing compounds that are not currently deliverable with systemic administration, our local delivery approach has the ability to improve the quality of life and revolutionize patient outcomes by potentially converting locally advanced inoperable tumors into resectable lesions.