Abstract

The widespread use of prostate-specific antigen (PSA) screening has led to earlier detection and a dramatic reduction in overall mortality of prostate cancer;however it has also resulted in over diagnosis and over treatment of indolent disease. PSA-triggered biopsies are generally performed to improve specificity, but biopsies have also proven to be inaccurate in the staging of prostate cancer because of the inherent heterogeneity of most tumors. We hypothesize that molecular imaging strategies offer an opportunity for improved differential diagnoses and staging, due to the ability to provide more accurate information on the location, size, extent, and grade of disease. The overall objective of this proposal is to develop tumor-targeted Gd-conjugated dendrimer nanoclusters (DNCs) as an ultra-sensitive T1 magnetic resonance (MR) imaging contrast agents for the specific detection of prostate cancer. DNCs will be conjugated to the scFv of antibody F77, which recognizes a unique glycolipid antigen that is specifically expressed on the cell surface of both androgen-dependent and androgen-independent prostate cancer cells.
The specific aims for the proposal are (1) to synthesize biodegradable, Gd-conjugated DNCs;(2) evaluate the toxicity, specific targeting capabilities, and uptake of tumor-targeted DNCS in culture;and (3) evaluate the ability to detect tumors in orthotopic mouse models of prostate cancer. The long-term goal of this proposal is to develop a contrast agent that can provide improved differential diagnoses and staging of prostate cancer and thus reduce or eliminate the over-treatment of the disease.

Public Health Relevance

The overall objective of this proposal is to develop tumor-targeted Gd-conjugated dendrimer nanoclusters (DNCs) as an ultra-sensitive T1 magnetic resonance (MR) imaging contrast agents for the specific detection of prostate cancer. DNCs will be conjugated to the scFv of antibody F77, which recognizes a unique glycolipid antigen that is specifically expressed on the cell surface of both androgen-dependent and androgen-independent prostate cancer cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA157766-03
Application #
8445382
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Tandon, Pushpa
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2013
Total Cost
$309,388
Indirect Cost
$102,986

  Institution

Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Nwe, Kido; Huang, Ching-Hui; Qu, Feini et al. (2016) Cationic gadolinium chelate for magnetic resonance imaging of cartilaginous defects. Contrast Media Mol Imaging 11:229-35
McQuade, Casey; Al Zaki, Ajlan; Desai, Yaanik et al. (2015) A multifunctional nanoplatform for imaging, radiotherapy, and the prediction of therapeutic response. Small 11:834-43
Yan, Lesan; Higbee, Elizabeth; Tsourkas, Andrew et al. (2015) A simple method for the synthesis of porous polymeric vesicles and their application as MR contrast agents. J Mater Chem B 3:9277-9284
Al Zaki, Ajlan; Hui, James Z; Higbee, Elizabeth et al. (2015) Biodistribution, Clearance, and Toxicology of Polymeric Micelles Loaded with 0.9 or 5 nm Gold Nanoparticles. J Biomed Nanotechnol 11:1836-46
Lajud, Shayanne A; Nagda, Danish A; Qiao, Peter et al. (2015) A novel chitosan-hydrogel-based nanoparticle delivery system for local inner ear application. Otol Neurotol 36:341-7
Ruan, Hang; Hao, Susan; Young, Peter et al. (2015) Targeting Cathepsin B for Cancer Therapies. Horiz Cancer Res 56:23-40
Yan, Lesan; Crayton, Samuel H; Thawani, Jayesh P et al. (2015) A pH-Responsive Drug-Delivery Platform Based on Glycol Chitosan-Coated Liposomes. Small 11:4870-4
Gao, Qiang; Yan, Lesan; Chiorazzo, Michael et al. (2015) PLA2-responsive and SPIO-loaded phospholipid micelles. Chem Commun (Camb) 51:12313-5
de Barros, André Luís Branco; Chacko, Ann-Marie; Mikitsh, John L et al. (2014) Assessment of global cardiac uptake of radiolabeled iron oxide nanoparticles in apolipoprotein-E-deficient mice: implications for imaging cardiovascular inflammation. Mol Imaging Biol 16:330-9
Hui, James Z; Tsourkas, Andrew (2014) Optimization of photoactive protein Z for fast and efficient site-specific conjugation of native IgG. Bioconjug Chem 25:1709-19

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