Advisor(s)

Ban An Khaw

Contributor(s)

Samuel Gatley, Joel Berniac, Craig Ferris, Richard Duclos

Date of Award

2011

Date Accepted

8-2011

Degree Grantor

Northeastern University

Degree Level

Ph.D.

Degree Name

Doctor of Philosophy

Department or Academic Unit

Bouve School of Health Sciences, Department of Pharmaceutical Sciences

Keywords

pharmaceutical sciences, bipsecific, Bombesin, doxorubicin, GRP receptors, pretargeting, prostate cancer

Disciplines

Pharmacy and Pharmaceutical Sciences

Abstract

Current standard cancer therapies include surgery, chemotherapy and radiation therapy. Although surgery is generally effective in the treatment of primary cancerous lesions, surgical resection of malignant tumors may not result in complete cure. By the time a tumor is detected by the existing diagnostic methods, it can be assumed that metastases may already have occurred and spread. These metastatic sites are not identified at such early stages by existing methods such as X-ray, ultrasound, Computed Tomography (CT) scans or even Nuclear Magnetic Resonance Imaging (MRI) because of poor limit of detection. Small cancerous lesions are difficult to detect in vivo due to high background activity, low target activity and contrast, as well as limited specificity of the targeting agents. Furthermore chemotherapeutic agents lack specificity since normal cells are often also targeted by most of the chemotherapeutic agents. Radiation therapy has also been used to target cancer cells because cancer cells are less able to repair themselves after treatment with radiation. However, radiation cannot be used to treat many cancers because of the damage done to normal cells that surround the cancerous tissue. Thus, the development of combined and improved methods for the diagnosis and treatment of small cancerous lesions is needed.

To overcome the above problems, our objective is to develop diagnostic reagents that have high specific radioactivity, targeting ability and decreased non-target organ activity. This should allow the diagnosis of even very small lesions by delivering high specific radioactivity while keeping the background activity low. In addition, these targeted diagnostic agents may be modified to carry chemotherapeutic agents instead of radioisotopes. When chemotherapeutic drugs are covalently conjugated to the carriers, the resulting drug-conjugates become pro-drug carriers that are expected to be less toxic to normal cells.

To enable specific targeting of these pro-drug carriers, we proposed a pre-targeting approach with bispecific antibodies. A Bispecific Antibody-Ligand Complex (BALC) was constructed via conjugation of a peptide or peptide analog specific for a receptor to a monoclonal antibody or antibody fragment that can specifically capture an effector compound. We used a two-step approach using: i) Bombesin-Anti-DTPA antibody bispecific complex (Bom-bsCx) or Bombesin-Anti-DTPA antibody Fab′ bispecific complex (Bom-bsFCx) for pre-targeting in step 1; and ii) targeted delivery of either Tc-99m/In-111-loaded polylysine (PL) polymers for diagnosis or Doxorubicin (Dox)-loaded polyglutamic acid polymers (D-Dox-PGA) for therapy in step 2. For diagnosis, specific tumor targeting and reduction of non-specific background activity were demonstrated by an in vivo prostate cancer xenograft model. Additionally for therapy, multiple Dox molecules attached to polymers are demonstrated to be less cytotoxic to embryonic cardiocytes relative to free Dox. However, targeting D-Dox-PGA polymers via Bom-bsCx led to enhanced prostate cancer toxicity.

Document Type

Dissertation

Rights Information

copyright 2011

Rights Holder

Vishwesh A. Patil

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