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

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.

Lipid-Iron Nanoparticle with a Cell Stress Release Mechanism Combined with a Local Alternating Magnetic Field Enables Site-Activated Drug Release

“…The ICG imaging indicated substantially more ICG signals in the AMF treated tumors than in the non-AMF treated tumors or free ICG. These findings show that MESL liposomes with cisplatin and ICG enable better accumulation of the dye and the anticancer drug, allowing efficient imaging and a better medicine homing and thus better therapy outcome due to the better bioavailability of the drug (Figure 4d) [58][59][60].…”

Nanocarriers for pancreatic cancer imaging, treatments, and immunotherapies

“…Various NPs-imaging probes based on iron oxide, carbon oxide, inorganic metal NPs, and liposomes have been evaluated to deliver imaging agents for diverse imaging modalities, including MRI, CT, PET, and SPECT for PDAC 185 , 186 . These have been elegantly reviewed in several recent articles 185 , 187 .…”

Antibody‐Incorporated Nanomedicines for Cancer Therapy

“…[344][345][346][347][348] Therefore, the applications of Fab-conjugated nanoparticulate systems have attracted great interest in cancer-targeted drug delivery. [345][346][347][348][349] For instance, Greene et al utilized a disulfide re-bridging technology to selectively insert strained alkyne handle-conjugated pyridazinedione moieties into the reduced disulfide bonds of non-engineered trastuzumab Fab fragments, for further conjugation with azide-terminated PLGA-PEG nanoparticles by the SPAAC reaction (Figure 8a,b). [350] To endow the linker (3) with site-selective protein reactivity, the strained bicyclononyne moiety (1) was linked to the dibromopyridazinedione (2) because of its superb disulfide reactive selectivity and the good stability of the formed antibody conjugates, as shown in Figure 8a.…”