Overexpressed extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDAC) limits drug penetration into the tumor and is associated with poor prognosis. Here, we demonstrate that a pretreatment based on a proteolytic-enzyme nanoparticle system disassembles the dense PDAC collagen stroma and increases drug penetration into the pancreatic tumor. More specifically, the collagozome, a 100 nm liposome encapsulating collagenase, was rationally designed to protect the collagenase from premature deactivation and prolonged its release rate at the target site. Collagen is the main component of the PDAC stroma, reaching 12.8 ± 2.3% vol in diseased mice pancreases, compared to 1.4 ± 0.4% in healthy mice. Upon intravenous injection of the collagozome, ∼1% of the injected dose reached the pancreas over 8 h, reducing the level of fibrotic tissue to 5.6 ± 0.8%. The collagozome pretreatment allowed increased drug penetration into the pancreas and improved PDAC treatment. PDAC tumors, pretreated with the collagozome followed by paclitaxel micelles, were 87% smaller than tumors pretreated with empty liposomes followed by paclitaxel micelles. Interestingly, degrading the ECM did not increase the number of circulating tumor cells or metastasis. This strategy holds promise for degrading the extracellular stroma in other diseases as well, such as liver fibrosis, enhancing tissue permeability before drug administration.
Bibliographical noteFunding Information:
This work was supported by ERC-STG-2015-680242. The authors also acknowledge the support of the Technion Integrated Cancer Center (TICC), the Russell Berrie Nanotechnology Institute, the Lorry I. Lokey Interdisciplinary Center for Life Sciences & Engineering, the Pre-Clinical Research Authority staff, and the Biomedical Core Facility at the Rappaport Faculty of Medicine, as well as the Israel Ministry of Economy for a Kamin Grant (52752); the Israel Ministry of Science Technology and Space, Office of the Chief Scientist (3-11878); the Israel Science Foundation (1778/13, 1421/17); the Israel Cancer Association (2015-0116); the German-Israeli Foundation for Scientific Research and Development for a GIF Young grant (I-2328-1139.10/2012); the European Union FP-7 IRG Program for a Career Integration Grant (908049); the Phospholipid Research Center Grant; and a Mallat Family Foundation Grant. A. Schroeder acknowledges Alon and Taub Fellowships. A. Zinger acknowledges a generous fellowship form the Technion Russell Berrie Nanotechnology Institute (RBNI). N. Krinsky wishes to thank the Baroness Ariane de Rothschild Women Doctoral Program for its generous support. O. Adir wishes to thank the Sherman and Gutwirth Interdisciplinary Graduate School Fellowships. M. Poley wishes to thank the Ministry of Science and Technology for the Shulamit Aloni Doctoral Fellowship. R. Luxenhofer acknowledges support by the Deutsche Forschungsgemeinschaft (project number 398461692) and M. M. Lübtow would like to thank the Evonik Foundation for providing a doctoral fellowship. The authors also acknowledge Dr. R. Shofty, Dr. D. Levin-Ashkenazi, Ms. V. Zlobin, and Mr. N. Amit from the Technion Pre-Clinical Research Authority for their help with the in vivo animal tests, Mr. D. Zagorski and Mrs. K. Filhart for the graphical aid, and Dr. E. Suss Toby, Dr. E. Messer, Mrs. M. Holdengreber, and Ms. O. Schwartz from the Bioimaging Center at the Technion Faculty of Medicine, for their assistance with imaging and image analysis. The help of Mrs. J. Bloch Mendelsohn JD, MPH, in editing this manuscript is greatly appreciated.
© 2019 American Chemical Society.
- extracellular matrix
- paclitaxel micelles
- pancreatic cancer