The vast majority of cancer deaths are due to metastatic disease. While effective interventions (e.g. surgery, radiation) strongly depend on our ability to detect disseminated disease at an early stage, imaging micrometastases hidden in a large population of normal cells presents a unique challenge. We seek to design a dual-ligand nanoparticle capable of 'sensing'the endothelium associated with a metastasis. By selecting two appropriate chemical specificities, a dual-ligand strategy can provide both synergistic amplification of nanoparticle targeting to micrometastases expressing both receptors but also detection of metastatic tumors expressing only one receptor that would be otherwise missed using a single-ligand strategy. Our central hypothesis is that a dual-ligand nanoparticle coupled with a vascular targeting strategy offer an increased likelihood of highly sensitive and specific recognition of micrometastasis. The nanoparticle is comprised of iron oxide nanospheres chemically linked into a linear nanochain. We hypothesize that the dual- ligand strategy will not only enhance the targeting specificity towards regions that express both receptors, but also 'capture'metastatic regions in which only one of the two receptors is predominantly expressed. Since the shape and size of nanoparticles govern their margination and attachment to the vascular bed, we also hypothesize that the aspect ratio and overall dimensions of the nanochain can be optimized, resulting in early and accurate detection of metastatic disease. We will test our hypotheses with the following Specific Aims:
Specific Aim 1 : Optimize the design of dual-ligand nanochains to perform vascular targeting under flow conditions of the microcirculation in vitro. We seek to optimize the design of nanochains in terms of their length, width and density of the two targeting peptides. The margination and targeting avidity of the nanochains will be evaluated in microchannel networks seeded with endothelial and cancer cells at different flow rates.
Specific Aim 2 : Test the ability of the dual-ligand nanochains to recognize the microenvironment of micrometastasis in the 4T1 mammary tumor model in mice. We seek to optimize the dose and timeframe for imaging by quantitatively assessing the accumulation of fluorescently labeled nanochains in metastases in vivo using fluorescence molecular tomography.
Specific Aim 3 : Test the accuracy of the dual-ligand nanochains to detect metastases using MRI. Nanochain- enhanced MRI will be assessed using an analysis of physician perception of metastases. In this blinded study, radiologists will read MR images of healthy and tumor-bearing animals to estimate the diagnostic accuracy. As a case study for the proposed work, detection of triple-negative breast cancer metastases in the liver and lungs was selected, because this cancer subtype is highly metastatic and deadly. However, this technology can be used for many types of cancer, since liver and lungs are common metastatic sites.

Public Health Relevance

The vast majority of cancer deaths are due to metastatic disease. While effective interventions (e.g. surgery, radiation) strongly depend on our ability to detect metastasis at an early stage, imaging metastases hidden in a large population of normal cells presents a unique challenge. To improve the long-term treatment outcome of aggressive cancers, this proposal seeks to develop a contrast agent for early and accurate detection of metastatic tumors using MRI.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA177716-01
Application #
8557669
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Tandon, Pushpa
Project Start
2013-07-01
Project End
2018-05-31
Budget Start
2013-07-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$321,962
Indirect Cost
$114,462
Name
Case Western Reserve University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Toy, Randall; Peiris, Pubudu M; Ghaghada, Ketan B et al. (2014) Shaping cancer nanomedicine: the effect of particle shape on the in vivo journey of nanoparticles. Nanomedicine (Lond) 9:121-34
Peiris, Pubudu M; Toy, Randall; Abramowski, Aaron et al. (2014) Treatment of cancer micrometastasis using a multicomponent chain-like nanoparticle. J Control Release 173:51-8
Toy, Randall; Bauer, Lisa; Hoimes, Christopher et al. (2014) Targeted nanotechnology for cancer imaging. Adv Drug Deliv Rev 76:79-97