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.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Oncology A (ONCA)
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VA Northern California Health Care System
United States
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Long, Qilai; Lin, Tzu-Yin; Huang, Yee et al. (2018) Image-guided photo-therapeutic nanoporphyrin synergized HSP90 inhibitor in patient-derived xenograft bladder cancer model. Nanomedicine 14:789-799
Gheibi, Pantea; Zeng, Shuxiong; Son, Kyung Jin et al. (2017) Microchamber Cultures of Bladder Cancer: A Platform for Characterizing Drug Responsiveness and Resistance in PDX and Primary Cancer Cells. Sci Rep 7:12277
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
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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
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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