TY - JOUR
T1 - Multimodal Targeted Nanoparticle-Based Delivery System for Pancreatic Tumor Imaging in Cellular and Animal Models
AU - Medina, Oula Penate
AU - Tower, Robert J.
AU - Medina, Tuula Penate
AU - Ashkenani, Fatma
AU - Appold, Lia
AU - Bötcher, Marcus
AU - Huber, Lukas
AU - Will, Olga
AU - Ling, Qi
AU - Hauser, Charlotte
AU - Rohwedder, Arndt
AU - Heneweer, Carola
AU - Peschke, Eva
AU - Hövener, Jan Bernd
AU - Lüdtke-Buzug, Kerstin
AU - Boretius, Susann
AU - Mentlein, Rolf
AU - Kairemo, Kalevi
AU - Glüer, Claus C.
AU - Sebens, Susanne
AU - Kalthoff, Holger
N1 - Funding Information:
This study was supported in part by the Damp Foundation, intramural grants for Oula Penate Medina (FoFö 2012) and Tuula Penate Medina (FoFö 2014) from the faculty of medicine of Kiel University, and the cluster of excellence “precision medicine in inflammation” of the DFG (PMI2167). E.P., J.B.H and L.M.H. acknowledge funding from the DFG, GRK 2154 “Materials4Brain”. The study was supported by DAMP Stiftung, Kiel, Germany. Kiel University and the Medical Faculty are acknowledged for supporting the Molecular Imaging North Competence Center (MOIN CC) as a core facility for imaging in vivo. MOIN CC was founded by a grant of the European Regional Development Fund (ERDF) and the ZukunftsprogrammWirtschaft of Schleswig-Holstein (Project no. 122-09-053). For the technical assistance, we would like to thank Judith Becker, Gabi Trompke and Giesela Refrath.
Publisher Copyright:
© 2022 Bentham Science Publishers.
PY - 2022/2
Y1 - 2022/2
N2 - 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 nomen-clature MUC5AC, an extracellular matrix component excreted by PDAC cells. In this study, we tested the usabil-ity 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 lipo-somes. RA-96 Fab fragment was conjugated to the liposomal surface of the nanoparticle to increase tumor hom-ing 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) photo-acoustic 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.
AB - 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 nomen-clature MUC5AC, an extracellular matrix component excreted by PDAC cells. In this study, we tested the usabil-ity 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 lipo-somes. RA-96 Fab fragment was conjugated to the liposomal surface of the nanoparticle to increase tumor hom-ing 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) photo-acoustic 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.
KW - Indocyanin green (ICG)
KW - Liposome
KW - MPI
KW - MRI
KW - Mucin targeting
KW - Pancreatic tumor
KW - RA-96 antibody
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U2 - 10.2174/1381612826666200717084846
DO - 10.2174/1381612826666200717084846
M3 - Article
C2 - 32679012
AN - SCOPUS:85109375488
SN - 1381-6128
VL - 28
SP - 313
EP - 323
JO - Current Pharmaceutical Design
JF - Current Pharmaceutical Design
IS - 4
ER -