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Multimodal Targeted Nanoparticle-Based Delivery System for Pancreatic Tumor Imaging in Cellular and Animal Models

Author(s):

Oula Penate Medina*, Robert J. Tower, Tuula Penate Medina, Fatma Ashkenani, Lia Appold, Marcus Bötcher, Lukas Huber, Olga Will, Qi Ling, Charlotte Hauser, Arndt Rohwedder, Carola Heneweer, Eva Peschke, Jan-Bernd Hövener, Kerstin Lüdtke-Buzug, Susann Boretius , Rolf Mentlein*, Kalevi Kairemo, Claus C. Glüer, Susanne Sebens and Holger Kalthoff   Pages 1 - 11 ( 11 )

Abstract:


Background: Pancreatic ductal adenocarcinoma (PDAC), which ranks forth on the cancer-related death statistics still is both a diagnostic and a therapeutic challenge. Adenocarcinoma of the exocrine human pancreas originates in most instances from malignant transformation of ductal epithelial cells, alternatively by Acinar-Ductal Metaplasia (ADM). RA96 antibody targets to a mucin M1, according to the more recent nomenclature MUC5AC, an extracellular matrix component excreted by PDAC cells. In this study, we tested the usability of multimodal nanoparticle carrying covalently coupled RA96 Fab fragments for pancreatic tumor imaging.

Methods: In order to make and evaluate a novel, better targeting, theranostic nanoparticle, iron nanoparticles and the optical dye indocyanin green (ICG) were encapsulated into the cationic sphingomyelin (SM) consisting liposomes. RA-96 Fab fragment was conjugated to the liposomal surface of the nanoparticle to increase tumor homing ability. ICG and iron nanoparticle-encapsulated liposomes were studied in vitro with cells and (i) their visibility in magnetic resonance imaging (MRI), (ii) optical, (iii) Magnetic particle spectroscopy (MPS) and (iv) photoacoustic settings was tested in vitro and also in in vivo models. The targeting ability and MRI and photoacoustic visibility of the RA-96-nanoparticles were first tested in vitro cell models where cell binding and internalization was studied. In in vivo experiments liposomal nanoparticles were injected into a tail vain using an orthotopic pancreatic tumor xenograft model and subcutaneous pancreas cancer cell xenografts bearing mice to determine in vivo targeting abilities of RA-96-conjugated liposomes.

Results: Multimodal liposomes could be detected by MRI, MPS and by photoacoustic imaging in addition to optical imaging showing a wide range of imaging utility. The fluorescent imaging of ICG in pancreatic tumor cells Panc89 and Capan-2 revealed increased association of ICG-encapsulated liposomes carrying RA-96 Fab fragments in vitro compared to the control liposomes without covalently linked RA-96. Fluorescent molecular tomography (FMT) studies showed increased accumulation of the RA96-targeted nanoparticles in the tumor area compared to non-targeted controls in vivo. Similar accumulation in the tumor sites could be seen with liposomal ferric particles in MRI. Fluorescent tumor signal was confirmed by using an intraoperative fluorescent imaging system which showed fluorescent labeling of pancreatic tumors.

Conclusion: These results suggest that RA-96-targeted liposomes encapsulating ICG and iron nanoparticles can be used to image pancreatic tumors with a variety of optical and magnetic imaging techniques. Additionally, they might be a suitable drug delivery tool to improve treatment of PDAC patients.

Keywords:

RA-96 antibody, mucin targeting, indocyanin green (ICG), liposome, pancreatic tumor, MPI, MRI

Affiliation:

Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein (UKSH), Kiel University, Kiel, Germany; MOIN CC - Am Botanischen Garten 14 24118 Kiel , Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein (UKSH), Kiel University, Kiel, Germany; MOIN CC - Am Botanischen Garten 14 24118 Kiel , Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein (UKSH), Kiel University, Kiel, Germany; MOIN CC - Am Botanischen Garten 14 24118 Kiel , Institut für Experimentelle Tumorforschung (IET), Arnold-Heller-Str. 3, Haus U30 24105 Kiel, Institut für Experimentelle Tumorforschung (IET), Arnold-Heller-Str. 3, Haus U30 24105 Kiel, Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein (UKSH), Kiel University, Kiel, Germany; MOIN CC - Am Botanischen Garten 14 24118 Kiel , Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein (UKSH), Kiel University, Kiel, Germany; MOIN CC - Am Botanischen Garten 14 24118 Kiel , Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein (UKSH), Kiel University, Kiel, Germany; MOIN CC - Am Botanischen Garten 14 24118 Kiel , Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Klinik für Allgemeine, Viszeral-, Thorax-, Transplantationsund Kinderchirurgie, Arnold-Heller-Straße 24105 Kiel, Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein (UKSH), Kiel University, Kiel, Germany; MOIN CC - Am Botanischen Garten 14 24118 Kiel , Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein (UKSH), Kiel University, Kiel, Germany; MOIN CC - Am Botanischen Garten 14 24118 Kiel , Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein (UKSH), Kiel University, Kiel, Germany; MOIN CC - Am Botanischen Garten 14 24118 Kiel , Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein (UKSH), Kiel University, Kiel, Germany; MOIN CC - Am Botanischen Garten 14 24118 Kiel , Anatomisches Institut, Olshausenstr. 40, 24118 Kiel, Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein (UKSH), Kiel University, Kiel, Germany; MOIN CC - Am Botanischen Garten 14 24118 Kiel , Anatomisches Institut, Olshausenstr. 40, 24118 Kiel, Department of Nuclear Medicine - The University of Texas MD Anderson Cancer Center, Houston, TX, Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Department of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein (UKSH), Kiel University, Kiel, Germany; MOIN CC - Am Botanischen Garten 14 24118 Kiel , Institut für Experimentelle Tumorforschung (IET), Arnold-Heller-Str. 3, Haus U30 24105 Kiel, Institut für Experimentelle Tumorforschung (IET), Arnold-Heller-Str. 3, Haus U30 24105 Kiel



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