Ovarian cancer is the fifth leading cause of cancer death among women in the United States and the 5-year survival rate is less than 50%. If ovarian cancer is found early, the 5-year survival rate is improved to >90%. Unfortunately, ovarian tumor early detection and treatment is currently being severely hampered by an inability to precisely diagnose and stage disease. Thus far, only 13-21% of the women that undergo surgery to remove adnexal masses actually have ovarian cancer. In patients where tumors are found, up to 90% of patients with apparent stage I or II ovarian cancer do not have optimal surgical staging, and approximately 30% are understaged. These statistics underscore the need to develop more effective strategies for early detection and staging. The overall goal of this proposal is to develop tumor-targeted multifunctional polymersomes for greater accuracy and effectiveness in ovarian cancer early detection, staging, and treatment. In attempt to achieve this goal, a highly sensitive magnetic resonance (MR) imaging probe will be prepared from biodegradable porous polymersomes with encapsulated gadolinium (Gd)-labeled dendrimers. A recombinant antibody (scFv) of human origin that is directed against mesothelin will be conjugated to the polymersome surface to confer specificity for malignant ovarian lesions. Mesothelin is a non-essential protein that is over-expressed by cancer cells from diverse origins, including ovarian and pancreatic adenocarcinomas and mesotheliomas. The hydrophobic anticancer drug paclitaxel will be loaded into the hydrophobic membrane and imaging will be used to accurately assess and monitor dosing. It is envisioned that the use of these multifunctional devices will offer the promise of improved tumor early detection and antitumor efficacy, while reducing drug toxicity, and/or dose. Upon the successful completion of this project, we expect to have a safe and effective nanoplatform available for further clinical evaluation.
The specific aims for this proposal are (1) synthesize Gd-encapsulated, drug- loaded theranostic polymersomes;(2) characterize targeting, uptake and in vitro cytotoxicity of anti-mesothelin- scFV conjugated polymersomes in ovarian cancer cells;and (3) evaluate the contrast enhancement, circulation time, biodistribution, retention and antitumor efficacy of the various polymersomes in ovarian tumor xenografts.

Public Health Relevance

The overall goal of this proposal is to develop tumor-targeted multifunctional polymersomes for greater ovarian cancer early detection, staging, and treatment. A recombinant antibody (scFv) of human origin that is directed against mesothelin will be conjugated to the multifunctional polymersome surface to confer specificity for malignant ovarian lesions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA175480-02
Application #
8720727
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Tandon, Pushpa
Project Start
2013-08-13
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$318,010
Indirect Cost
$99,742
Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Cheng, Zhiliang; Al Zaki, Ajlan; Jones, Ian W et al. (2014) Stabilized porous liposomes with encapsulated Gd-labeled dextran as a highly efficient MRI contrast agent. Chem Commun (Camb) 50:2502-4