The overall objective of the proposed research is to utilize a newly discovered, active transendothelial transport pathway, the caveolae pumping system, in order to provide an effective solution to the delivery and toxicity problem of Pt(II)-based chemotherapeutics in breast cancer. Systemic chemotherapy is one of the common forms of breast cancer treatments, however clinical efficacy of Pt(II) antitumor drugs is limited by the significant in vivo barriers inhibit delivery of these drugs into solid tumors, requiring the use of high doses, producing serious side effects and facilitating development of drug resistance. In order to address these problems and significantly improve treatment of breast cancer we propose two novel paradigms: 1) our newly discovered endothelial cell (EC) caveolae targeting system to sidestep passive delivery and dramatically enhance speed and efficiency of tumor penetration, and 2) to design and develop novel platinum(II) supramolecular coordination complexes (Pt(II)-SCCs), the nanoparticles (NPs) that have shown remarkable efficacy in tumor destruction in preclinical breast cancer models while being monodisperse, stable and well-characterized. Our main hypothesis is that immunoconjugates that fully utilize the advantages of caveolae-targeting antibodies will increase Pt(II)-SCCs delivery into tumors for enhanced efficacy and reduced toxicity, potentially resulting in a fundamentally new class of anticancer therapeutics. This hypothesis will be tested by the following specific aims:
In Aim 1, we plan to design and synthesize Pt(II)-SCC immunoconjugates. In this Aim will also design, synthesize and characterize the chemical identity, purity and physicochemical properties of our Pt(II)-SCCs immunoconjugates. We will use caveolae-targeted antibody which we have shown can move the attached cargo from the blood across the EC barrier into solid tumor with unprecedented speed and specificity.
In Aim 2 we will characterize in vivo delivery of Pt(II)-SCC immunoconjugates targeting the EC caveolae in tumors. We will perform dynamic monitoring of antibody-Pt(II)-SCC targeting in real time in live mice with intravital microscopy (IVM) using fluorescence emission of the assembled SCCs.
In Aim 3 we will assess the therapeutic efficacy of the EC-targeting Pt(II)-SCC immunoconjugates. The efficacy of our targeted delivery system will be examined in IVM models using fluorescence microscopy and in non-IVM Her2/Neu tumor models with whole-body animal imaging. The long-term goal of this project is to translate our key basic discoveries into an innovative drug delivery platform in order to improve therapeutic efficacy and reduce toxicity in the breast cancer treatment.

Public Health Relevance

The overall objective of this study is to use our newly discovered mechanism, the caveolae pumping system, in order to provide an effective solution to the drug delivery problem for patients with breast cancer. We discovered the unique mechanism for therapeutics to traverse the blood vessel barrier and designed a strategy that could significantly enhance therapeutic effectiveness while decreasing toxicity of anticancer therapeutics. With the support of this grant application and based on our preliminary results, we plan to design and develop Pt(II)-SCC immunoconjugates, the hitherto unknown drug candidates with excellent therapeutic efficacies and greatly reduced systemic toxicity in breast cancer, ultimately offering delivery platform for safe, effective breast cancer therapy. This grant proposal is relevant to the part of NIH's mission that is focused on fostering applications of fundamental discoveries and innovative research strategies in improving human health.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Fu, Yali
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Proteogenomics Research Institute/Sys/ Med
La Jolla
United States
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