eprintid: 22366
rev_number: 13
eprint_status: archive
userid: 1589
dir: disk0/00/02/23/66
datestamp: 2016-12-23 09:42:08
lastmod: 2024-06-28 03:25:07
status_changed: 2016-12-23 09:42:08
type: article
metadata_visibility: show
creators_name: Dobiasch, Sophie
creators_name: Szanyi, Szilard
creators_name: Kjaev, Aleko
creators_name: Werner, Jens
creators_name: Strauß, Albert
creators_name: Weis, Christian
creators_name: Grenacher, Lars
creators_name: Kapilov-Buchman, Katya
creators_name: Israel, Liron-Limor
creators_name: Lellouche, Jean-Paul
creators_name: Locatelli, Erica
creators_name: Franchini, Mauro Comes
creators_name: Vandooren, Jennifer
creators_name: Opdenakker, Ghislain
creators_name: Felix, Klaus
title: Synthesis and functionalization of protease-activated nanoparticles with tissue plasminogen activator peptides as targeting moiety and diagnostic tool for pancreatic cancer
subjects: ddc-610
divisions: i-910200
divisions: i-911400
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.
date: 2016
publisher: BioMed Central
id_scheme: DOI
ppn_swb: 165522462X
own_urn: urn:nbn:de:bsz:16-heidok-223669
language: eng
bibsort: DOBIASCHSOSYNTHESISA2016
full_text_status: public
publication: Journal of Nanobiotechnology
volume: 14
number: 81
place_of_pub: London
pagerange: 1-18
issn: 1477-3155
citation:   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 Comes ; Vandooren, Jennifer ; Opdenakker, Ghislain ; Felix, Klaus  (2016) Synthesis and functionalization of protease-activated nanoparticles with tissue plasminogen activator peptides as targeting moiety and diagnostic tool for pancreatic cancer.  Journal of Nanobiotechnology, 14 (81).  pp. 1-18.  ISSN 1477-3155     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/22366/1/12951_2016_Article_236.pdf