Pancreatic cancer is the fourth leading cause of cancer death in the US and remains the most difficult cancer type to treat with less than 5% of patients surviving 5 years after diagnosis. Chemotherapy and radiotherapy are the only options for these patients. However, the efficacy of systemic chemotherapy is limited by poor efficiency in the delivery and systemic toxicity. Recent research in personalized oncology has concentrated on tumor targeted delivery and controlled release of therapeutic agents with assistances of non-invasive imaging methods to monitor the delivery and accumulation of the drugs in the tumor and to assess the therapeutic response. In this project, we propose to develop and test a multi-functional imaging- delivery magnetic nanoparticle platform that combines the capabilities of demonstrated magnetic resonance imaging (MRI) contrast enhancement, receptor specific tumor targeting and optimized drug loading and release for MRI-guided systemic delivery of chemotherapy drug, gemcitabine, into pancreatic tumors.
Our Specific Aim 1 focuses on the design, preparation and characterization of MRI-capable nanoparticles coated with functionalized anti-fouling "stealth" polymers that can conjugate targeting ligands and may reduce non-specific uptake of nanoparticles by normal tissues for improved tumor targeting efficiency. We will develop methods that can conjugate gemcitabine onto the tumor targeting nanoparticles for enzyme-activated intracellular release. The drug-nanoparticle complex will target the urokinase plasminogen activator receptor (uPAR), a cellular receptor highly expressed in pancreatic cancer and active tumor stromal cells, to facilitate the intratumoral and subcellular delivery of gemcitabine. With the goal of translating the proposed magnetic nanoparticle imaging-delivery platform into clinical applications, we will investigate the biodistribution, systemic toxicity and pharmacokinetics of this delivery platform in normal and tumor bearing mice.
In Aim 2, we will develop novel MRI approaches that are designed for specific and sensitive detection of magnetic nanoparticle delivery vehicles in vivo. For MRI guided drug delivery applications, our objective is to design and test a set of MRI methods, such as ultra-short TE imaging, that not only enable us to track and follow the delivery vehicles with a high sensitivity and better visualization but also provide quantitative information on intra-tumoral delivery efficiency. New MRI methods to assess the tumor response to treatment will also be tested.
In Aim 3, we will evaluate intratumoral distribution of nanoparticles, investigate their tumor targeted therapeutic effect, test and optimize the imaging capabilities of following and quantifying the delivery and accumulation of the drug in the targeted tumors as well as monitoring response to therapy in pancreatic cancer animal models using MRI.

Public Health Relevance

Systemic chemotherapy is a common approach to the chronic management of many cancers. However, its efficacy is limited by poor efficiency in delivery of the therapeutic agent to the tumor and systemic toxicity. In this project, we propose to develop a multi-functional imaging-delivery magnetic nanoparticle platform that combines capabilities of magnetic resonance imaging (MRI), receptor specific tumor targeting and optimized drug loading and release for MRI guided systemic delivery of chemotherapy drugs for the treatment of pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA154846-04
Application #
8677788
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Tandon, Pushpa
Project Start
2011-08-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$379,123
Indirect Cost
$134,527
Name
Emory University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Huang, Jing; Qian, Weiping; Wang, Liya et al. (2016) Functionalized milk-protein-coated magnetic nanoparticles for MRI-monitored targeted therapy of pancreatic cancer. Int J Nanomedicine 11:3087-99
Orza, Anamaria; Yang, Yi; Feng, Ting et al. (2016) A nanocomposite of Au-AgI core/shell dimer as a dual-modality contrast agent for x-ray computed tomography and photoacoustic imaging. Med Phys 43:589
Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M et al. (2016) IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer. Proc SPIE Int Soc Opt Eng 9836:
Huang, Jing; Li, Yuancheng; Orza, Anamaria et al. (2016) Magnetic Nanoparticle Facilitated Drug Delivery for Cancer Therapy with Targeted and Image-Guided Approaches. Adv Funct Mater 26:3818-3836
Huang, Jing; Shu, Qing; Wang, Liya et al. (2015) Layer-by-layer assembled milk protein coated magnetic nanoparticle enabled oral drug delivery with high stability in stomach and enzyme-responsive release in small intestine. Biomaterials 39:105-13
Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M et al. (2015) IGF1 Receptor Targeted Theranostic Nanoparticles for Targeted and Image-Guided Therapy of Pancreatic Cancer. ACS Nano 9:7976-91
Li, Yuancheng; Lin, Run; Wang, Liya et al. (2015) PEG-b-AGE Polymer Coated Magnetic Nanoparticle Probes with Facile Functionalization and Anti-fouling Properties for Reducing Non-specific Uptake and Improving Biomarker Targeting. J Mater Chem B Mater Biol Med 3:3591-3603
Wang, Liya; Zhong, Xiaodong; Qian, Weiping et al. (2014) Ultrashort echo time (UTE) imaging of receptor targeted magnetic iron oxide nanoparticles in mouse tumor models. J Magn Reson Imaging 40:1071-81
Guo, Peng; Huang, Jing; Wang, Liya et al. (2014) ICAM-1 as a molecular target for triple negative breast cancer. Proc Natl Acad Sci U S A 111:14710-5
Huang, Jing; Wang, Liya; Zhong, Xiaodong et al. (2014) Facile non-hydrothermal synthesis of oligosaccharides coated sub-5 nm magnetic iron oxide nanoparticles with dual MRI contrast enhancement effect. J Mater Chem B Mater Biol Med :

Showing the most recent 10 out of 22 publications