title: Matrix metalloproteinase-9 (MMP-9) as an activator of nanosystems for targeted drug delivery in pancreatic cancer.
abstract: Specific cancer cell targeting is a pre-requisite for efficient drug delivery as well as for high-resolution imaging and still represents a major technical challenge. Tumor-associated enzyme-assisted targeting is a new concept that takes advantage of the presence of a specific activity in the tumor entity. MMP-9 is a protease found to be upregulated in virtually all malignant tumors. Consequently, we hypothesized that its presence can provide a de-shielding activity for targeted delivery of drugs by nanoparticles (NPs) in pancreatic cancer. Here, we describe synthesis and characterization of an optimized MMP-9-cleavable linker mediating specific removal of a PEG shield from a PLGA-b-PEG-based polymeric nanocarrier (Magh@PNPs-PEG-RegaCP-PEG) leading to specific uptake of the smaller PNPs with their cargo into cells. The specific MMP-9-cleavable linker was designed based on the degradation efficiency of peptides derived from the collagen type II sequence. MMP-9-dependent uptake of the Magh@PNPs-PEG-RegaCP-PEG was demonstrated in pancreatic cancer cells in vitro. Accumulation of the Magh@PNPs-PEG-RegaCP-PEG in pancreatic tissues in the clinically relevant KPC mouse model of pancreatic cancer, as a proof-of-concept, was tumor-specific and MMP-9-dependent, indicating that MMP-9 has a strong potential as a specific mediator of PNP de-shielding for tumor-specific uptake. Pre-treatment of mice with Magh@PNPs-PEG-RegaCP-PEG led to reduction of liver metastasis and drastically decreased average colony size. In conclusion, the increased tumor-specific presence and activity of MMP-9 can be exploited to deliver an MMP-9-activatable NP to pancreatic tumors specifically, effectively, and safely.
authors.affiliation: Institut für Molekulare Immunologie und Experimentelle Onkologie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675 München, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Grünwald
authors.affiliation: Rega Institute for Medical Research, Department Microbiology and Immunology, KU Leuven, Belgium.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Vandooren
authors.affiliation: Department of Industrial Chemistry "Toso Montanari", University of Bologna, Viale Risorgimento 4, 40136 Bologna, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Locatelli
authors.affiliation: Rega Institute for Medical Research, Department Microbiology and Immunology, KU Leuven, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fiten
authors.affiliation: Rega Institute for Medical Research, Department Microbiology and Immunology, KU Leuven, Belgium.
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
authors.affiliation: Rega Institute for Medical Research, Department Microbiology and Immunology, KU Leuven, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Proost
authors.affiliation: Institut für Molekulare Immunologie und Experimentelle Onkologie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675 München, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Krüger
authors.affiliation: Nanomaterials Research Center, Institute of Nanotechnology & Advanced Materials, Bar-Ilan University, Ramat-Gan 5290002, Israel.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Lellouche
authors.affiliation: Nanomaterials Research Center, Institute of Nanotechnology & Advanced Materials, Bar-Ilan University, Ramat-Gan 5290002, Israel.
authors.forename: Liron Limor
authors.initials: LL
authors.lastname: Israel
authors.affiliation: Department of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Louis
authors.initials: L
authors.lastname: Shenkman
authors.affiliation: Department of Industrial Chemistry "Toso Montanari", University of Bologna, Viale Risorgimento 4, 40136 Bologna, Italy. Electronic address: mauro.comesfranchini@unibo.it.
authors.forename: Mauro
authors.initials: M
authors.lastname: Comes Franchini
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000008:administration & dosage* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000008:administration & dosage* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Drug delivery; MMP-9; Nanoparticles; Pancreatic cancer; Targeting