Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

General Research Article

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

Volume 28, Issue 4, 2022

Published on: 17 July, 2020

Page: [313 - 323] Pages: 11

DOI: 10.2174/1381612826666200717084846

Price: $65


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.

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

Sebens S, Kalthoff H. Emerging therapeutic targets and agents for pancreatic cancer therapy-where are we and where we have to go? Anticancer Agents Med Chem 2011; 11(5): 408-10.
[] [PMID: 21492077]
Bernstorff WV, Glickman JN, Odze RD, et al. Fas (CD95/APO-1) and Fas ligand expression in normal pancreas and pancreatic tumors. Implications for immune privilege and immune escape. Cancer 2002; 94(10): 2552-60.
[] [PMID: 12173320]
Hinz S, Pagerols-Raluy L, Oberg HH, et al. Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res 2007; 67(17): 8344-50.
[] [PMID: 17804750]
Gajiwala S, Torgeson A, Garrido-Laguna I, Kinsey C, Lloyd S. Combination immunotherapy and radiation therapy strategies for pancreatic cancer-targeting multiple steps in the cancer immunity cycle. J Gastrointest Oncol 2018; 9(6): 1014-26.
[] [PMID: 30603120]
Cubilla AL, Fitzgerald PJ. Surgical pathology of tumors of the exocrine pancreas Tumors of the Pancreas. Baltimore, London: William & Wilkens 1980; pp. 159-93.
Klöppel G. Pancreatic cancer Verh Dtsch Ges Pathol 1987; 71: 187-201.
[PMID: 3326329]
Klöppel G, Lingenthal G, von Bülow M, Kern HF. Histological and fine structural features of pancreatic ductal adenocarcinomas in relation to growth and prognosis: studies in xenografted tumours and clinico-histopathological correlation in a series of 75 cases. Histopathology 1985; 9(8): 841-56.
[] [PMID: 2997015]
Kalthoff H, Kreiker C, Schmiegel WH, Greten H, Thiele HG. Characterization of CA 19-9 bearing mucins as physiological exocrine pancreatic secretion products. Cancer Res 1986; 46(7): 3605-7.
[PMID: 3708591]
Augenlicht LH, Augeron C, Yander G, Laboisse C. Overexpression of ras in mucus-secreting human colon carcinoma cells of low tumorigenicity. Cancer Res 1987; 47(14): 3763-5.
[PMID: 3594436]
Janine Ring J, Ogirala A, Cosgrave L, Kalthoff H, Grimm J. Mucin related mRa96 antibody as a potential target for multimodality imaging of pancreatic ductal adenocarcinoma (PDAC). Nucl Med 2012; 53(Suppl. 1): 1731.
Matzku S, Tilgen W, Kalthoff H, Schmiegel WH, Bröcker EB. Dynamics of antibody transport and internalization. Int J Cancer Suppl 1988; 2: 11-4.
[] [PMID: 3162438]
Kalthoff H, Holl K, Schmiegel W, Klöppel G, Arndt R, Matzku S. A new mucin reacting monoclonal antibody for serum diagnosis and radioimmunoscintigraphy of pancreatic cancer. J Tumor Marker Oncol 1987; 2: 75.
Matzku S, Tilgen W, Bihl H, Schwechheimer K, Kalthoff H, Schmiegel W. Tumor imaging: role of the target antigen lectins and glycoconjugates in oncology. Springer 1988; pp. 67-76.
Pagès F, Galon J, Dieu-Nosjean MC, Tartour E, Sautès-Fridman C, Fridman WH. Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 2010; 29(8): 1093-102.
[] [PMID: 19946335]
Cui JH, Krüger U, Vogel I, et al. Intact tissue of gastrointestinal cancer specimen orthotopically transplanted into nude mice. Hepatogastroenterology 1998; 45(24): 2087-96.
[PMID: 9951870]
Kapischke M, Fischer T, Tiessen K, et al. Characterisation of a novel matrix metalloproteinase inhibitor on pancreatic adenocarcinoma cells in vitro and in an orthotopic pancreatic cancer model in vivo. Int J Oncol 2008; 32(1): 273-82.
[] [PMID: 18097568]
Lüdtke-Buzug K, Haegele J, Biederer S, et al. Comparison of commercial iron oxide-based MRI contrast agents with synthesized high-performance MPI tracers. Biomed Tech (Berl) 2013; 58(6): 527-33.
Lüdtke-Buzug K. From Synthesis to clinical Application. Magnetic Nanoparticles. Chemie in unserer Zeit 2012; 46(1): 32-9.
Boman NL, Cullis PR, Mayer LD, Bally MB, Webb MS. Liposomal vincristine: the central role of drug retention in defining therapeutically optimized anticancer formulations Long circulating liposomes: old drugs, new therapeutics. Berlin: Springer-Verlag and Landes Bioscience 1998; pp. 29-49.
Boman NL, Masin D, Mayer LD, Cullis PR, Bally MB. Liposomal vincristine which exhibits increased drug retention and increased circulation longevity cures mice bearing P388 tumors. Cancer Res 1994; 54(11): 2830-3.
[PMID: 8187061]
Boman NL, Mayer LD, Cullis PR. Optimization of the retention properties of vincristine in liposomal systems. Biochim Biophys Acta 1993; 1152(2): 253-8.
[] [PMID: 8218326]
Thurston G, McLean JW, Rizen M, et al. Cationic liposomes target angiogenic endothelial cells in tumors and chronic inflammation in mice. J Clin Invest 1998; 101(7): 1401-13.
[] [PMID: 9525983]
Dellian M, Yuan F, Trubetskoy VS, Torchilin VP, Jain RK. Vascular permeability in a human tumour xenograft: molecular charge dependence. Br J Cancer 2000; 82(9): 1513-8.
[PMID: 10789717]
Reimhult E. Nanoparticle-triggered release from lipid membrane vesicles. N Biotechnol 2015; 32(6): 665-72.
[] [PMID: 25534673]
Peñate Medina O, Pillarsetty N, Glekas A, et al. Optimizing tumor targeting of the lipophilic EGFR-binding radiotracer SKI243 using a Liposomal Nanoparticle Delivery System J Controlled Release 2011; 149: 292-8.
Medina OP, Zhu Y, Kairemo K. Targeted liposomal drug delivery in cancer. Curr Pharm Des 2004; 10(24): 2981-9.
[] [PMID: 15379663]
Peñate-Medina T, Kraas E, Luo K, et al. Utilizing ICG spectroscopical properties for real-time nanoparticle release quantification in vitro and in vivo in imaging setups. Curr Pharm Des 2020.
[] [PMID: 32188378]
Suojanen J, Vilen ST, Nyberg P, et al. Selective gelatinase inhibitor peptide is effective in targeting tongue carcinoma cell tumors in vivo. Anticancer Res 2011; 31(11): 3659-64.
[PMID: 22110184]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy