Nanoparticle targeting of cathepsin-L inhibitor and doxorubicin in breast cancer

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$128,350.00
Award Year:
2007
Program:
STTR
Phase:
Phase I
Contract:
1R41CA128152-01A1
Award Id:
85436
Agency Tracking Number:
CA128152
Solicitation Year:
n/a
Solicitation Topic Code:
n/a
Solicitation Number:
n/a
Small Business Information
5 FOX GLOVE COURT, WYNANTSKILL, NY, 12198
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
196257591
Principal Investigator:
SHAKER MOUSA
(518) 694-7397
SHAKER.MOUSA@ACPHS.EDU
Business Contact:
MAWAHEB EL
() -
Research Institution:
CHILDREN'S MEMORIAL HOSPITAL O

NORTHWESTERN UNIVERSITY
750 N. Lake Shore Drive, 7TH
CHICAGO, IL, 60611-2680

Nonprofit college or university
Abstract
DESCRIPTION (provided by applicant): The development of resistance to chemotherapy represents an adaptive biological response by tumor cells that leads to treatment failure and patient relapse. There is an urgent need to overcome this problem if treatments are to be successful in eradicating tumors. Tumor cell irreversible growth arrest (senescence) is an early cellular response to the stress of exposure to chemotherapeutic agents. Those cells that are able to bypass senescence ultimately exhibit resistance to chemotherapy. Recent reports provide a persuasive rationale for studying the role of cathepsin L in the process of chemotherapeutic drug resistance. We showed that specific targeting of cathepsin L using chemical inhibitors or siRNA to this molecule fo rced cancer cells into a state of irreversible growth arrest and suppressed development of resistance to drugs. We also demonstrated the ability of cathepsin L inhibitor to reverse drug resistance in vivo utilizing nude mice bearing xenografts of doxorubic in resistant neuroblastoma cell line SKN-SH/R drug resistant tumors. Because many chemotherapeutic agents show systemic toxicities, and because cathepsin L inhibitors to be used in these studies are peptides subject to biodegradation, we will address these limitations by encapsulation of agents using PEG-PLGA nanoparticles targeted to either the sites of tumor neovascularization (1v integrin) or to MCF7 tumor cells via HER2 antibody. Female nude mice will have drug-resistant MCF7 human breast cancer cells i mplanted orthotopically into the fourth mammary gland. We will study two commercially available Cathepsin L inhibitors, Z-Phe-Try (t-Bu)-diazomethylketone and 1-Naphthalenesulfonyl-Ile-Trp- Aldehyde given either alone or with doxorubicin with respect to th eir effects on tumor cell growth and drug-resistance. Specific Aim 1: Prior to performance of nanoparticle-targeted therapy studies in nude mice, preliminary experiments to determine optimum formulations of nanoparticles will be performed in vivo in the ch ick chorioallantoic membrane (CAM) tumor implant model of tumor angiogenesis and growth. This model permits in vivo pre-screening for bioactivity while limiting the use of more sentient and costly murine species. Specific Aim 2: Nanoparticle formulations t hat show optimum anti-tumor and anti-angiogenesis activity in the CAM model will be tested in the mouse breast cancer model. In these studies, we will evaluate the effectiveness of cathepsin L inhibitors in reducing doxorubicin resistance as evidenced by i mproved anti-tumor activities. Comparisons will be made between non-targeted and targeted therapies with respect to anti-tumor efficacy and doxorubicin-associated toxicities. Cancer cells have the unique ability to develop resistance to chemotherapeutic dr ugs, and so research on ways to reverse this phenomenon would have significant value in the treatment of cancer patients. This project will use a combination of two drugs, one of which impairs the cancer cell's ability to develop drug resistance, in a mous e model of breast cancer. A novel technology, the use of nanoparticles to encapsulate the test drugs, will be tested to determine whether these nanoparticles can improve the delivery of drugs and minimize the associated toxicities.

* information listed above is at the time of submission.

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