The goal of this project is to develop a nanomicelle drug delivery system that can specifically target bladder cancer. With the funding of the VA Career Development Award-2 (CDA-2, PI: Pan), a bladder cancer-targeting ligand named PLZ4 was developed. PLZ4 binds to both human and dog bladder cancer cell lines and cancer cells from clinical specimens, suggesting that the pre-clinical studies can be performed in dogs with spontaneous bladder cancer. PLZ4 does not bind to normal urothelial cells, inflamed bladder cells, blood cells, vascular endothelial cells an fibroblasts. Recently, Kit Lam, MD, PhD, (Dr. Pan's VA CDA-2 mentor) developed biocompatible and biodegradable nanomicelles. Chemotherapeutic and imaging agents can be loaded inside the nanomicelles. When they are decorated with PLZ4 on surface, these targeting nanomicelles together with the drug load are delivered into bladder cancer cells. Targeting PLZ4-nanomicelles preferentially concentrate at the bladder cancer xenograft sites in vivo and can significantly prolong survival when compared to non-targeting nanomicelles. In this project, we will optimize the structure of the PLZ4-nanomicelles to achieve the maximal drug loading and delivery, and determine the in vivo targeting and drug distribution in mice carrying bladder cancer xenografts developed from human clinical specimens. A pilot study will be conducted in dog patients carrying spontaneous bladder cancer in order to obtain the preliminary toxicity and efficacy data.

Public Health Relevance

This project aims to develop a multi-functional nanomicelle drug delivery system that can specifically deliver the chemotherapeutic drug paclitaxel to bladder cancer. The nanomicelle system can possibly improve treatment efficacy and lower therapy-associated toxicity.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX001784-01A1
Application #
8442030
Study Section
Oncology A (ONCA)
Project Start
2013-10-01
Project End
2017-09-30
Budget Start
2013-10-01
Budget End
2014-09-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
VA Northern California Health Care System
Department
Type
DUNS #
127349889
City
Mather
State
CA
Country
United States
Zip Code
95655
Zeng, Shu-Xiong; Zhu, Yanjun; Ma, Ai-Hong et al. (2017) The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer. Clin Cancer Res 23:6580-6591
Wang, Si-Si; Zimmermann, Maike; Zhang, Hongyong et al. (2017) A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer. Int J Cancer 141:604-613
Lin, Tzu-Yin; Guo, Wenchang; Long, Qilai et al. (2016) HSP90 Inhibitor Encapsulated Photo-Theranostic Nanoparticles for Synergistic Combination Cancer Therapy. Theranostics 6:1324-35
Lin, Tzu-Yin; Li, Yuanpei; Liu, Qiangqiang et al. (2016) Novel theranostic nanoporphyrins for photodynamic diagnosis and trimodal therapy for bladder cancer. Biomaterials 104:339-51
Wang, Sisi; Zhang, Hongyong; Scharadin, Tiffany M et al. (2016) Molecular Dissection of Induced Platinum Resistance through Functional and Gene Expression Analysis in a Cell Culture Model of Bladder Cancer. PLoS One 11:e0146256
Tomlinson, Benjamin K; Thomson, James A; Bomalaski, John S et al. (2015) Phase I Trial of Arginine Deprivation Therapy with ADI-PEG 20 Plus Docetaxel in Patients with Advanced Malignant Solid Tumors. Clin Cancer Res 21:2480-6
Gandara, David R; Mack, Philip C; Bult, Carol et al. (2015) Bridging tumor genomics to patient outcomes through an integrated patient-derived xenograft platform. Clin Lung Cancer 16:165-72
Tomlinson, Ben; Lin, Tzu-yin; Dall'Era, Marc et al. (2015) Nanotechnology in bladder cancer: current state of development and clinical practice. Nanomedicine (Lond) 10:1189-201
Pan, Chong-Xian; Zhang, Hongyong; Tepper, Clifford G et al. (2015) Development and Characterization of Bladder Cancer Patient-Derived Xenografts for Molecularly Guided Targeted Therapy. PLoS One 10:e0134346
Jiang, Shuai; Pan, Amy W; Lin, Tzu-yin et al. (2015) Paclitaxel Enhances Carboplatin-DNA Adduct Formation and Cytotoxicity. Chem Res Toxicol 28:2250-2

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