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

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.

Cite this article as:

Medina Penate Oula *, Tower J. Robert , Medina Penate Tuula , Ashkenani Fatma , Appold Lia , Bötcher Marcus , Huber Lukas, Will Olga , Ling Qi , Hauser Charlotte , Rohwedder Arndt , Heneweer Carola , Peschke Eva , Hövener Jan-Bernd , Lüdtke-Buzug Kerstin , Boretius Susann , Mentlein Rolf *, Kairemo Kalevi , Glüer C. Claus , Sebens Susanne and Kalthoff Holger , Multimodal Targeted Nanoparticle-Based Delivery System for Pancreatic Tumor Imaging in Cellular and Animal Models, Current Pharmaceutical Design 2022; 28 (4) . https://dx.doi.org/10.2174/1381612826666200717084846