title: Protease-mediated release of chemotherapeutics from mesoporous silica nanoparticles to ex vivo human and mouse lung tumors.
abstract: Nanoparticles allow for controlled and targeted drug delivery to diseased tissues and therefore bypass systemic side effects. Spatiotemporal control of drug release can be achieved by nanocarriers that respond to elevated levels of disease-specific enzymes. For example, matrix metalloproteinase 9 (MMP9) is overexpressed in tumors, is known to enhance the metastatic potency of malignant cells, and has been associated with poor prognosis of lung cancer. Here, we report the synthesis of mesoporous silica nanoparticles (MSNs) tightly capped by avidin molecules via MMP9 sequence-specific linkers to allow for site-selective drug delivery in high-expressing MMP9 tumor areas. We provide proof-of-concept evidence for successful MMP9-triggered drug release from MSNs in human tumor cells and in mouse and human lung tumors using the novel technology of ex vivo 3D lung tissue cultures. This technique allows for translational testing of drug delivery strategies in diseased mouse and human tissue. Using this method we show MMP9-mediated release of cisplatin, which induced apoptotic cell death only in lung tumor regions of Kras mutant mice, without causing toxicity in tumor-free areas or in healthy mice. The MMP9-responsive nanoparticles also allowed for effective combinatorial drug delivery of cisplatin and proteasome inhibitor bortezomib, which had a synergistic effect on the (therapeutic) efficiency. Importantly, we demonstrate the feasibility of MMP9-controlled drug release in human lung tumors.
authors.forename: Sabine H
authors.initials: SH
authors.lastname: van Rijt
authors.forename: Deniz A
authors.initials: DA
authors.lastname: Bölükbas
authors.affiliation: ‡Department of Chemistry and Center for NanoScience (CeNS), University of Munich (LMU), Butenandtstrasse 5-13(E), 81377 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Argyo
authors.affiliation: ‡Department of Chemistry and Center for NanoScience (CeNS), University of Munich (LMU), Butenandtstrasse 5-13(E), 81377 Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Datz
authors.forename: Michael
authors.initials: M
authors.lastname: Lindner
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.affiliation: ‡Department of Chemistry and Center for NanoScience (CeNS), University of Munich (LMU), Butenandtstrasse 5-13(E), 81377 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bein
authors.forename: Silke
authors.initials: S
authors.lastname: Meiners
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D065546:Drug Liberation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D016062:Porosity; D012822:Silicon Dioxide / Q000737:chemistry*; D046509:Tissue Culture Techniques
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D000069286:Bortezomib; D012822:Silicon Dioxide; D020780:Matrix Metalloproteinase 9; D002945:Cisplatin
keywords: bortezomib; cisplatin; combination treatment; controlled drug delivery; ex vivo 3D lung tissue cultures; lung cancer; matrix metalloproteinase-9; mesoporous silica nanoparticles; nanomedicine