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.
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.
|Seo, Soyoung E; Wang, Mary X; Shade, Chad M et al. (2016) Modulating the Bond Strength of DNA-Nanoparticle Superlattices. ACS Nano 10:1771-9|
|Thaner, Ryan V; Eryazici, Ibrahim; Macfarlane, Robert J et al. (2016) The Significance of Multivalent Bonding Motifs and "Bond Order" in DNA-Directed Nanoparticle Crystallization. J Am Chem Soc 138:6119-22|
|Thaxton, C Shad; Rink, Jonathan S; Naha, Pratap C et al. (2016) Lipoproteins and lipoprotein mimetics for imaging and drug delivery. Adv Drug Deliv Rev 106:116-131|
|Culver, Kayla S B; Shin, Yu Jin; Rotz, Matthew W et al. (2016) Shape-Dependent Relaxivity of Nanoparticle-Based T1 Magnetic Resonance Imaging Contrast Agents. J Phys Chem C Nanomater Interfaces 120:22103-22109|
|Moore, Laura; Yang, Junyu; Lan, Thanh T Ha et al. (2016) Biocompatibility Assessment of Detonation Nanodiamond in Non-Human Primates and Rats Using Histological, Hematologic, and Urine Analysis. ACS Nano 10:7385-400|
|Barnaby, Stacey N; Perelman, Grant A; Kohlstedt, Kevin L et al. (2016) Design Considerations for RNA Spherical Nucleic Acids (SNAs). Bioconjug Chem 27:2124-31|
|Hung, Andy H; Lilley, Laura M; Hu, Fengqin et al. (2016) Magnetic barcode imaging for contrast agents. Magn Reson Med :|
|Wang, Xiao; Hao, Liangliang; Bu, Heng-Fu et al. (2016) Spherical nucleic acid targeting microRNA-99b enhances intestinal MFG-E8 gene expression and restores enterocyte migration in lipopolysaccharide-induced septic mice. Sci Rep 6:31687|
|Holbrook, Robert J; Rammohan, Nikhil; Rotz, Matthew W et al. (2016) Gd(III)-Dithiolane Gold Nanoparticles for T1-Weighted Magnetic Resonance Imaging of the Pancreas. Nano Lett 16:3202-9|
|Angeloni, Nicholas L; McMahon, Kaylin M; Swaminathan, Suchitra et al. (2016) Pathways for Modulating Exosome Lipids Identified By High-Density Lipoprotein-Like Nanoparticle Binding to Scavenger Receptor Type B-1. Sci Rep 6:22915|
Showing the most recent 10 out of 197 publications