1. Collagenase Nanoparticles Enhance the Penetration of Drugs into Pancreatic Tumors
- Author
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Yelena Mumblat, Mohammed Alyan, Nadav Noor, Assaf Simon, Omer Adir, Robert Luxenhofer, Jeny Shklover, Nitzan Krinsky, Sivan Ofir, Eran Fridman, Janna Shainsky-Roitman, Ziv Gil, Hadas Gibori, Assaf Zinger, Maria Poley, Tal Dvir, Lilach Koren, Neta Milman, Ronit Satchi-Fainaro, Yoav Binenbaum, Majd Krayem, Lior Liba, Zvi Yaari, Dov Hershkovitz, Avi Schroeder, Michael M. Lübtow, and Shira Kasten
- Subjects
Cell Membrane Permeability ,Paclitaxel ,General Physics and Astronomy ,02 engineering and technology ,Adenocarcinoma ,010402 general chemistry ,01 natural sciences ,Article ,Extracellular matrix ,chemistry.chemical_compound ,Mice ,Circulating tumor cell ,Fibrosis ,Pancreatic tumor ,Pancreatic cancer ,Cell Line, Tumor ,medicine ,Tumor Microenvironment ,Animals ,Humans ,General Materials Science ,Collagenases ,Pancreas ,General Engineering ,021001 nanoscience & nanotechnology ,medicine.disease ,3. Good health ,0104 chemical sciences ,Extracellular Matrix ,Disease Models, Animal ,medicine.anatomical_structure ,chemistry ,Liposomes ,Collagenase ,Cancer research ,Nanoparticles ,Collagen ,0210 nano-technology ,medicine.drug ,Carcinoma, Pancreatic Ductal - Abstract
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.
- Published
- 2019