Contrast agents are commonly used in diagnostic magnetic resonance (MR) imaging to help detect and characterize pathological abnormalities. In fact, it has been estimated that nearly 50 % of all MR examinations involve the use of MR contrast agents. Most clinically relevant Gd-based agents are small, non-targeted compounds that passively distribute into the intravascular and interstitial space. However, there has recently been emerging interest in the development of paramagnetic contrast agents that are capable of probing the molecular profile of tissues via ligand targeting, enzymatic activity and multiplexing. It is envisioned that these agents could be used to acquire a more specific clinical diagnosis and thus improve patient management. The overall goal of this proposal is to develop molecular targeted paramagnetic contrast agents based on Gd- encapsulated porous vesicles for in-vivo tumor imaging. The key features of our MR imaging platform are: a) porous nanovesicles formed from the self assembly of amphiphilic diblock copolymers;b) high Gd payloads encapsulated within the nanovesicle lumen, resulting in a high T1 relaxivity (per particle);and c) tumor- targeting ligands conjugated onto paramagnetic nanovesicles, which serve to localize the contrast agent to the site of interest.
The specific aims for this proposal are (1) to synthesize Gd-encapsulated porous vesicles with various physical and magnetic properties;(2) characterize binding and uptake of anti-HER2-affibody conjugated paramagnetic vesicles in breast cancer cells;and (3) evaluate the MR contrast enhancement in tumor xenografts. The long-term goal of this proposal will be to further develop paramagnetic porous polymersomes into theranostic agents (i.e. combined drug delivery and imaging). MR imaging can then be used to assess biodistribution and therapeutic efficacy, which can impact decisions on dosing and treatment options. When used as a drug delivery vehicle, the hydrophobic domain of polymersomes provides a natural carrier environment for hydrophobic drugs and hydrophilic compounds can be loaded in the aqueous lumen of the nanovesicles.

Public Health Relevance

The overall goal of this proposal is to develop molecular targeted paramagnetic contrast agents based on gadolinium-encapsulated porous polymer vesicles. The paramagnetic porous vesicles will be functionalized with anti-HER2/neu-affibodies and will be used to specifically detect breast cancer cells in vitro and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB013226-02
Application #
8252148
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Liu, Christina
Project Start
2011-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$200,000
Indirect Cost
$75,000
Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Elias, Andrew; Crayton, Samuel H; Warden-Rothman, Robert et al. (2014) Quantitative comparison of tumor delivery for multiple targeted nanoparticles simultaneously by multiplex ICP-MS. Sci Rep 4:5840
Al Zaki, Ajlan; Joh, Daniel; Cheng, Zhiliang et al. (2014) Gold-loaded polymeric micelles for computed tomography-guided radiation therapy treatment and radiosensitization. ACS Nano 8:104-12
Huang, Ching-Hui; Tsourkas, Andrew (2013) Gd-based macromolecules and nanoparticles as magnetic resonance contrast agents for molecular imaging. Curr Top Med Chem 13:411-21
Elias, Drew R; Poloukhtine, Andrei; Popik, Vladimir et al. (2013) Effect of ligand density, receptor density, and nanoparticle size on cell targeting. Nanomedicine 9:194-201
Warden-Rothman, Robert; Caturegli, Ilaria; Popik, Vladimir et al. (2013) Sortase-tag expressed protein ligation: combining protein purification and site-specific bioconjugation into a single step. Anal Chem 85:11090-7
Cheng, Zhiliang; Elias, Drew R; Kamat, Neha P et al. (2011) Improved tumor targeting of polymer-based nanovesicles using polymer-lipid blends. Bioconjug Chem 22:2021-9