Synthesis and functionalization of protease-activated nanoparticles with tissue plasminogen activator peptides as targeting moiety and diagnostic tool for pancreatic cancer

Journal of Nanobiotechnology

Research

Mauro Comes Franchini¹  Erica Locatelli¹  Jennifer Vandooren²  Ghislain Opdenakker²  Albert Strauss³  Christian Weis³  Lars Grenacher⁴  Aleko Kjaev⁵  Szilard Szanyi⁵  Klaus Felix⁵  Jens Werner⁶  Sophie Dobiasch⁷  Katya Kapilov-Buchman⁸  Jean-Paul Lellouche⁸  Liron-Limor Israel⁸ 

[1] Department of Industrial Chemistry Toso Montanari, University of Bologna, Bologna, Italy;Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium;Department of Radiology, University of Heidelberg, Heidelberg, Germany;Department of Radiology, University of Heidelberg, Heidelberg, Germany;Diagnostik München, Diagnostic Imaging and Prevention Center, Munich, Germany;Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany;Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany;Department of General-, Visceral-, Transplantations-, Vascular- and Thorax-Surgery LMU Munich, München, Germany;Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany;Department of Radiation Oncology, Technische Universität München, Munich, Germany;Nanomaterials Research Center, Institute for Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat-Gan, Israel;

关键词: Galectins;    Tissue plasminogen activator;    Nanotheranostics;    Pancreatic cancer;   

DOI  :  10.1186/s12951-016-0236-3

 received in 2016-08-31, accepted in 2016-12-03,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundFunctionalized 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.ResultsMolecular 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.ConclusionsThe 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.

【 授权许可】

CC BY   
© The Author(s) 2016