Title:Multimodal Targeted Nanoparticle-Based Delivery System for Pancreatic Tumor Imaging in Cellular and Animal Models
Volume: 28
Issue: 4
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
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 ,Germany
- Anatomisches Institut, Olshausenstr. 40, 24118 Kiel,Germany
Keywords:
RA-96 antibody, mucin targeting, indocyanin green (ICG), liposome, pancreatic tumor, MPI, MRI.
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). RA-96 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 RA-96 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
were studied. In in vivo experiments liposomal nanoparticles were injected into the tail vain using an orthotopic
pancreatic tumor xenograft model and subcutaneous pancreatic 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 an 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.
