Synthesis and functionalization of protease-activated nanoparticles with tissue plasminogen activator peptides as targeting moiety and diagnostic tool for pancreatic cancer. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Dobiasch, Sophie; Szanyi, Szilard; Kjaev, Aleko; Werner, Jens; Strauss, Albert; Weis, Christian; Grenacher, Lars; Kapilov-Buchman, Katya; Israel, Liron-Limor; Lellouche, Jean-Paul; Locatelli, Erica; Franchini, Mauro; Vandooren, Jennifer; Opdenakker, Ghislain; Felix, Klaus
• Is Part Of: Journal of nanobiotechnology. Volume 14:Issue 1(2016)
• Page Start: 1
• Page End: 18
• Publication Date: 2016-12
• Subjects: Galectins -- Tissue plasminogen activator -- Nanotheranostics -- Pancreatic cancer; Nanotechnology -- Periodicals; Biotechnology -- Periodicals; 660.6
• DOI: 10.1186/s12951-016-0236-3
• Languages: English
• ISSNs: 1477-3155

Abstract

Abstract Background Functionalized nanoparticles (NPs) are one promising tool for detecting specific molecular targets and combine molecular biology and nanotechnology aiming at modern imaging. We aimed at ligand-directed delivery with a suitable target-biomarker to detect early pancreatic ductal adenocarcinoma (PDAC). Promising targets are galectins (Gal), due to their strong expression in and on PDAC-cells and occurrence at early stages in cancer precursor lesions, but not in adjacent normal tissues. Results Molecular probes (10-29 AA long peptides) derived from human tissue plasminogen activator (t-PA) were selected as binding partners to galectins. Affinity constants between the synthesized t-PA peptides and Gal were determined by microscale thermophoresis. The 29 AA-long t-PA-peptide-1 with a lactose-functionalized serine revealed the strongest binding properties to Gal-1 which was 25-fold higher in comparison with the native t-PA protein and showed additional strong binding to Gal-3 and Gal-4, both also over-expressed in PDAC. t-PA-peptide-1 was selected as vector moiety and linked covalently onto the surface of biodegradable iron oxide nanoparticles (NPs). In particular, CAN-doped maghemite NPs (CAN-Mag), promising as contrast agent for magnetic resonance imaging (MRI), were selected as magnetic core and coated with different biocompatible polymers, such as chitosan (CAN-Mag-Chitosan NPs) or polylactic co glycolic acid (PLGA) obtaining polymeric nanoparticles (CAN-Mag@PNPs), already approved for drug delivery applications. The binding efficacy of t-PA-vectorized NPs determined by exposure to different pancreatic cell lines was up to 90%, as assessed by flow cytometry. The in vivo targeting and imaging efficacy of the vectorized NPs were evaluated by applying murine pancreatic tumor models and assessed by 1.5 T magnetic resonance imaging (MRI). The t-PA-vectorized NPs as well as the protease-activated NPs with outer shell decoration (CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac ) showed clearly detectable drop of subcutaneous and orthotopic tumor staining-intensity indicating a considerable uptake of the injected NPs.Post mortem NP deposition in tumors and organs was confirmed by Fe staining of histopathology tissue sections. Conclusions The targeted NPs indicate a fast and enhanced deposition of NPs in the murine tumor models. The CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac interlocking steps strategy of NPs delivery and deposition in pancreatic tumor is promising.