Pancreatic cancer treatment presents one of the most challenges in clinical oncology as majority of the patients with advanced pancreatic cancer do not response to current available chemotherapeutic and radiotherapy and the prognosis of the patients is one of the worst among all cancer types. The objective of this proposed study aims at developing a multi-functional theranostic nanoparticle platform that combines demonstrated imaging capability and receptor specificity of the nanoparticles with novel designs for drug delivery to overcome physical and intrinsic barriers that confer drug resistance in pancreatic cancer. Our extensive research supported by NCI CCNE program led to the development of biodegradable and receptor targeted magnetic iron oxide nanoparticles (lONP) as a molecular imaging probe for MRI of pancreatic cancer. In this project, we will further develop a theranostic nanoparticle platform that combines MRI and drug delivery capabilities with special ability to overcome the barriers causing resistance to therapy in pancreatic cancer tissues and effectively deliver single or multiple therapeutic agents such as chemotherapy drugs and siRNA expressing DNA cassettes into the tumor cells (Aim 1). The drug-nanoparticle complex will be targeted to cellular receptors, such as urokinase plasminogen activator receptor, that are highly expressed in pancreatic cancer cells and active tumor stromal cells to facilitate the intratumoral delivery of the nanoparticles. We will develop novel MRI approaches that are designed and optimized for specific and sensitive detection of the theranostic magnetic nanoparticles in the pancreatic cancer lesions by MRI (Aim 2). We will determine the tumor targeted therapeutic effect, intratumoral distribution of the nanoparticles, and the imaging capability of monitoring response to therapy in orthotopic human pancreatic cancer xenograft and in a mouse transgenic tumor model using MRI and histological analysis of the tumor tissues (Aim 3 and Aim 4). To translate the theranostic magnetic nanoparticles into clinical applications, we will conduct biodistribution, systemic toxicity, and pharmacokinetic studies In normal and tumor bearing mouse models (Aim 5). The development of proposed theranostic nanoparticles that that are capable of targeted delivery of large amounts and multiple drugs into pancreatic cancer cells and tumor environment while providing imaging tools for monitoring drug delivery and response is particularly important for the effective treatment of pancreatic cancer since the cancer patients have a very short median survival time.

Public Health Relevance

;This research project will develop novel tumor targeted nanotechnology therapeutics for improving the treatment of pancreas cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA151810-03
Application #
8312641
Study Section
Special Emphasis Panel (ZCA1-SRLB-X (M1))
Program Officer
Farrell, Dorothy F
Project Start
2010-09-10
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$391,244
Indirect Cost
$182,313
Name
Emory University
Department
Surgery
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Lin, Run; Li, Yuancheng; MacDonald, Tobey et al. (2017) Improving sensitivity and specificity of capturing and detecting targeted cancer cells with anti-biofouling polymer coated magnetic iron oxide nanoparticles. Colloids Surf B Biointerfaces 150:261-270
Zhu, Lei; Zhou, Zhiyang; Mao, Hui et al. (2017) Magnetic nanoparticles for precision oncology: theranostic magnetic iron oxide nanoparticles for image-guided and targeted cancer therapy. Nanomedicine (Lond) 12:73-87
Gao, Ning; Bozeman, Erica N; Qian, Weiping et al. (2017) Tumor Penetrating Theranostic Nanoparticles for Enhancement of Targeted and Image-guided Drug Delivery into Peritoneal Tumors following Intraperitoneal Delivery. Theranostics 7:1689-1704
Zhu, Lei; Staley, Charles; Kooby, David et al. (2017) Current status of biomarker and targeted nanoparticle development: The precision oncology approach for pancreatic cancer therapy. Cancer Lett 388:139-148
Wang, Liya; Huang, Jing; Chen, Hongbo et al. (2017) Exerting Enhanced Permeability and Retention Effect Driven Delivery by Ultrafine Iron Oxide Nanoparticles with T1-T2 Switchable Magnetic Resonance Imaging Contrast. ACS Nano 11:4582-4592
Orza, Anamaria; Wu, Hui; Xu, Yaolin et al. (2017) One-Step Facile Synthesis of Highly Magnetic and Surface Functionalized Iron Oxide Nanorods for Biomarker-Targeted Applications. ACS Appl Mater Interfaces 9:20719-20727
Xie, Huiqiao; Cai, Weixing; Yang, Lily et al. (2016) Reducing radiation dose in grating based x-ray phase contrast CT with twin-peaks in its phase stepping curves. Med Phys 43:5942
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:
Chen, Wei; Yang, Lily (2016) Targeted Delivery with Imaging Assessment of siRNA Expressing Nanocassettes into Cancer. Methods Mol Biol 1372:49-59

Showing the most recent 10 out of 32 publications