Prostate cancer is the second leading cause of all cancer-related deaths and the most commonly diagnosed cancer among males in US. Castration-resistant prostate cancer (CRPC) is an incurable and lethal form of the disease. Docetaxel-based chemotherapy is the first-line standard treatment for CRPC. However, the efficacy of systemic chemotherapy is limited by poor efficiency in the delivery, drug resistance and systemic toxicity. The goal of this project is to develop novel stimuli-responsive cross-linked theranostics (SCTs) for image-guided delivery of mechanism-based molecular medicine to circumvent treatment-resistance and systemic toxicity for advanced prostate cancer. SCTs integrate unique stimuli-responsive crosslinking strategies and highly potent av3 integrin targeting ligand (LXW64) into a novel multifunctional nanoporphyrin system with unique architecture-dependent imaging properties. The goal of Aim 1 is to design and synthesize a series of SCTs with boronate, disulfide and protease-cleavable crosslinkers that are responsive to the intrinsic stimuli at the tumor microenvironment, such as acidic pH, reducing agents and proteases, respectively. SCTs will be decorated with LXW64 to enhance their targeting capability to advanced prostate cancer.
In Aim 2, the spatiotemporal distribution of SCTs including pharmacokinetics, biodistribution and intratumoral delivery and drug release, will be quantitatively investigated by multimodal imaging (NIRFI, PET and MRI) in orthotopic prostate cancer xenograft models. The 64Cu signal of SCTs from PET imaging will be measured quantitatively so that the pharmacokinetics and biodistribution of SCTs can be determined. The activation of the MRI and NIRF imaging functions correlates with the level of local stimuli and can be considered as an indication of nanoparticle dissociation and drug release. The imaging results will be validated by inductively coupled plasma mass spectrometry (ICP-MS) for quantitative Gd level, autoradiography and frster resonance energy transfer (FRET) for drug release as well as immunohistochemistry for protease and integrin level.
In Aim 3, SCID mice bearing docetaxel-resistance prostate cancer xenograft will be treated with SCTs that are co-loaded with a new heat shock protein 90 inhibitor (ganetespib) and docetaxel. These novel nano-formulations hold promise for circumventing drug efflux through P-glycoprotein and inhibiting alternative growth pathways, two important mechanisms of resistance to docetaxel. Tumor regression associated with response to therapy will be quantified by molecular imaging, and correlated with molecular changes in tumor microenvironment. Successful development of the proposed theranostic agents will significantly improve the imaging sensitivity for monitoring the therapeutic delivery process, and enhance the delivery of mechanism-based drugs to overcome docetaxel resistance. Results from this study will be significant not only in advancing the development of a novel theranostic nano-platform for effective therapy of advanced prostate cancer, but also in providing a new framework of using stimuli-responsive cross-linked theranostics for image-guided drug delivery.

Public Health Relevance

The proposed novel theranostic agents are expected to improve prostate cancer patient care through: (i) sensitive detection and accurate diagnosis of primary tumors; (ii) sensitive detection of metastases including micro-metastases; (iii) real-time image-guided drug delivery; (iv) overcoming docetaxel resistance; and (v) real- time evaluation of the treatment outcomes. As a result, we expect many patients with advanced prostate cancer will benefit from such novel imaging-based therapeutic approach. This project will have a tremendous impact on quality of life of prostate cancer patients and lead to lower mortality rates.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA199668-03
Application #
9318482
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Farahani, Keyvan
Project Start
2015-09-01
Project End
2020-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Davis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Xue, Xiangdong; Huang, Yee; Wang, Xinshuai et al. (2018) Self-indicating, fully active pharmaceutical ingredients nanoparticles (FAPIN) for multimodal imaging guided trimodality cancer therapy. Biomaterials 161:203-215
Wang, Xin-Shuai; Zhang, Li; Li, Xiaocen et al. (2018) Nanoformulated paclitaxel and AZD9291 synergistically eradicate non-small-cell lung cancers in vivo. Nanomedicine (Lond) 13:1107-1120
Xiao, Kai; Liu, Qiangqiang; Al Awwad, Nasir et al. (2018) Reversibly disulfide cross-linked micelles improve the pharmacokinetics and facilitate the targeted, on-demand delivery of doxorubicin in the treatment of B-cell lymphoma. Nanoscale 10:8207-8216
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
Yuan, Ye; He, Yixuan; Bo, Ruonan et al. (2018) A facile approach to fabricate self-assembled magnetic nanotheranostics for drug delivery and imaging. Nanoscale 10:21634-21639
Xue, Xiangdong; Huang, Yee; Bo, Ruonan et al. (2018) Trojan Horse nanotheranostics with dual transformability and multifunctionality for highly effective cancer treatment. Nat Commun 9:3653
Luo, Yan; Wu, Hao; Feng, Caihong et al. (2017) ""One-Pot"" Fabrication of Highly Versatile and Biocompatible Poly(vinyl alcohol)-porphyrin-based Nanotheranostics. Theranostics 7:3901-3914
Wang, Zhongling; Qiao, Ruirui; Tang, Na et al. (2017) Active targeting theranostic iron oxide nanoparticles for MRI and magnetic resonance-guided focused ultrasound ablation of lung cancer. Biomaterials 127:25-35
Wang, Xin-Shuai; Kong, De-Jiu; Lin, Tzu-Yin et al. (2017) A versatile nanoplatform for synergistic combination therapy to treat human esophageal cancer. Acta Pharmacol Sin 38:931-942
Xiao, Kai; Lin, Tzu-Yin; Lam, Kit S et al. (2017) A facile strategy for fine-tuning the stability and drug release of stimuli-responsive cross-linked micellar nanoparticles towards precision drug delivery. Nanoscale 9:7765-7770

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