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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA151880-05
Application #
8710061
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$163,548
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Calabrese, Colin M; Merkel, Timothy J; Briley, William E et al. (2015) Biocompatible infinite-coordination-polymer nanoparticle-nucleic-acid conjugates for antisense gene regulation. Angew Chem Int Ed Engl 54:476-80
Chinen, Alyssa B; Guan, Chenxia M; Mirkin, Chad A (2015) Spherical nucleic acid nanoparticle conjugates enhance G-quadruplex formation and increase serum protein interactions. Angew Chem Int Ed Engl 54:527-31
Rubert Pérez, Charles M; Stephanopoulos, Nicholas; Sur, Shantanu et al. (2015) The powerful functions of peptide-based bioactive matrices for regenerative medicine. Ann Biomed Eng 43:501-14
Xi, Guifa; Robinson, Erik; Mania-Farnell, Barbara et al. (2014) Convection-enhanced delivery of nanodiamond drug delivery platforms for intracranial tumor treatment. Nanomedicine 10:381-91
Heffern, Marie C; Matosziuk, Lauren M; Meade, Thomas J (2014) Lanthanide probes for bioresponsive imaging. Chem Rev 114:4496-539
Moyer, Tyson J; Finbloom, Joel A; Chen, Feng et al. (2014) pH and amphiphilic structure direct supramolecular behavior in biofunctional assemblies. J Am Chem Soc 136:14746-52
Kuhn, Misty L; Zemaitaitis, Bozena; Hu, Linda I et al. (2014) Structural, kinetic and proteomic characterization of acetyl phosphate-dependent bacterial protein acetylation. PLoS One 9:e94816
Kurepa, Jasmina; Nakabayashi, Ryo; Paunesku, Tatjana et al. (2014) Direct isolation of flavonoids from plants using ultra-small anatase TiOýýý nanoparticles. Plant J 77:443-53
Cabezas, Maria D; Eichelsdoerfer, Daniel J; Brown, Keith A et al. (2014) Combinatorial screening of mesenchymal stem cell adhesion and differentiation using polymer pen lithography. Methods Cell Biol 119:261-76
Shabbir, Shagufta H; Cleland, Megan M; Goldman, Robert D et al. (2014) Geometric control of vimentin intermediate filaments. Biomaterials 35:1359-66

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