Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of any malignancy. As no therapy over he past 50 years has substantially altered the median survival of 6 months, a paradigm shift is required to mprove outcomes. Through highly multidisciplinary studies, this proposal outlines an innovative strategy to reat PDAC using local image-guided delivery of multi-functional therapeutic nanoparticles (NPs). This ancreas-directed therapy, termed """"""""nanoembolization"""""""", involves intra-arterial (IA) delivery of molecularly argeted NPs directly into the blood supply of pancreatic tumors, followed by injection of embolic material to emporarily block blood flow. We will combine advanced interventional radiology catheter-based techniques with transcatheter intra-arterial perfusion magnetic resonance imaging (TRIP)-MRI, a method invented by the investigators to verify that tumors will be accurately targeted. Our motivation is to use a) NPs to penetrate the significant barrier of desmoplasia associated with PDAC and b) IA delivery to vastly increase the local uptake of NPs into tumors. IA delivery overcomes the non-target uptake of NPs into the reticuloendothelial ystem (RES) seen with intravenous (IV) injections. Although this project will initially test a therapeutic gold Au)-NP platform, it will provide a pipeline to test other submitted NP platforms.
In Aim 1, we will synthesize ulti-functionalized NPs to target oncogenic KRAS, anti-apoptotic protein survivin, tumor-invasive etalloproteinase MT1-MMP (MMP-14), and to upregulate tumor suppressive microRNA let-7. NPs will be ested in human PDAC cell culture, using standard 2D culture and then embedded within a 3D collagenous atrix to mimic desmoplasia.
For Aim 2, successful platforms will be submitted to the Nanotechnology Characterization Laboratory to verify safety.
In Aim 3, non-toxic platforms will undergo efficacy studies in the Kras[12D] /P53[R172]/ Cre (KPC) mice, the definitive transgenic mouse model of PDAC. We will also assess whether changes in functional diffusion and perfusion MRI parameters can serve as early non-invasive biomarkers to predict survival.
Aim 4 will optimize delivery of therapeutic NPs in the VX2 rabbit model of PDAC, originated by the investigators. In these rabbits, we will determine the benefits of nanoembolization to increase tumor uptake of NPs connpared to IV injections and IA delivery without embolization. This project will provide strong pre-clinical evidence of therapeutic benefit for nanoembolization in PDAC. In future early clinical trials, this novel local pancreas-directed therapy could be applied to patients alone or in combination with other systemic therapies.

Public Health Relevance

This proposal outlines a novel treatment for pancreatic cancer using local image-guided intra-arterial delivery of therapeutic nanoparticle platforms, an approach we have termed nanoembolization. A multi-tiered testing pipeline is proposed that will allow development and confirmation of efficacy for these molecularly targeted nanotherapeutics. Project success will provide critical evidence to support future clinical translation of this new pancreas-directed therapy, which could be used alone or in combination with existing systemic herapies for pancreatic cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
United States
Zip Code
Hong, Bong Jin; Iscen, Aysenur; Chipre, Anthony J et al. (2018) Highly Stable, Ultrasmall Polymer-Grafted Nanobins (usPGNs) with Stimuli-Responsive Capability. J Phys Chem Lett 9:1133-1139
Zavaleta, Cristina; Ho, Dean; Chung, Eun Ji (2018) Theranostic Nanoparticles for Tracking and Monitoring Disease State. SLAS Technol 23:281-293
Sato, Kohei; Hendricks, Mark P; Palmer, Liam C et al. (2018) Peptide supramolecular materials for therapeutics. Chem Soc Rev 47:7539-7551
Rotz, Matthew W; Holbrook, Robert J; MacRenaris, Keith W et al. (2018) A Markedly Improved Synthetic Approach for the Preparation of Multifunctional Au-DNA Nanoparticle Conjugates Modified with Optical and MR Imaging Probes. Bioconjug Chem 29:3544-3549
Lilley, Laura M; Du, Kang; Krzyaniak, Matthew D et al. (2018) Effect of Magnetic Coupling on Water Proton Relaxivity in a Series of Transition Metal GdIII Complexes. Inorg Chem 57:5810-5819
Rink, Jonathan S; Yang, Shuo; Cen, Osman et al. (2017) Rational Targeting of Cellular Cholesterol in Diffuse Large B-Cell Lymphoma (DLBCL) Enabled by Functional Lipoprotein Nanoparticles: A Therapeutic Strategy Dependent on Cell of Origin. Mol Pharm 14:4042-4051
McMahon, Kaylin M; Scielzo, Cristina; Angeloni, Nicholas L et al. (2017) Synthetic high-density lipoproteins as targeted monotherapy for chronic lymphocytic leukemia. Oncotarget 8:11219-11227
Rammohan, Nikhil; Holbrook, Robert J; Rotz, Matthew W et al. (2017) Gd(III)-Gold Nanoconjugates Provide Remarkable Cell Labeling for High Field Magnetic Resonance Imaging. Bioconjug Chem 28:153-160
Scott, Alexander W; Garimella, Viswanadham; Calabrese, Colin M et al. (2017) Universal Biotin-PEG-Linked Gold Nanoparticle Probes for the Simultaneous Detection of Nucleic Acids and Proteins. Bioconjug Chem 28:203-211
Hung, Andy H; Lilley, Laura M; Hu, Fengqin et al. (2017) Magnetic barcode imaging for contrast agents. Magn Reson Med 77:970-978

Showing the most recent 10 out of 223 publications