Collagenase Nanoparticles Enhance the Penetration of Drugs into Pancreatic Tumors

Assaf Zinger, Lilach Koren, Omer Adir, Maria Poley, Mohammed Alyan, Zvi Yaari, Nadav Noor, Nitzan Krinsky, Assaf Simon, Hadas Gibori, Majd Krayem, Yelena Mumblat, Shira Kasten, Sivan Ofir, Eran Fridman, Neta Milman, Michael M. Lübtow, Lior Liba, Jeny Shklover, Janna Shainsky-RoitmanYoav Binenbaum, Dov Hershkovitz, Ziv Gil, Tal Dvir, Robert Luxenhofer, Ronit Satchi-Fainaro, Avi Schroeder*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)11008-11021
Number of pages14
JournalACS Nano
Volume13
Issue number10
DOIs
StatePublished - 22 Oct 2019

Funding

FundersFunder number
European Union FP-7908049
Mallat Family Foundation
Ministry of Science and Technology for the Shulamit Aloni
Pre-Clinical Research Authority
TICC
Technion Integrated Cancer Center
Yale University
Evonik Stiftung
Horizon 2020 Framework Programme680242
Deutsche Forschungsgemeinschaft398461692
German-Israeli Foundation for Scientific Research and DevelopmentI-2328-1139.10/2012
Israel Cancer Association2015-0116
Israel Science Foundation1421/17, 1778/13
Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion-Israel Institute of Technology
Ministry of Science and Technology, Israel
Ministry of Economy52752
Office of the Chief Scientist, Ministry of Economy3-11878

    Keywords

    • collagen
    • extracellular matrix
    • fibrosis
    • liposome
    • nanoparticle
    • paclitaxel micelles
    • pancreatic cancer

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