This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Paclitaxel (Taxol) is a standard and effective chemotherapeutic for many cancer types, including breast cancer, ovarian cancer, small cell lung cancer and non-small cell lung cancer. Since paclitaxel (PTX) has very limited solubility in water, the formulation of this drug requires Cremophor EL which causes significant side effects, such as allergic reactions. Consequently, patients receiving PTX require premedication with histamine blockers and steroids. We proposed to use a novel water-soluble nanoparticle-based formulation to enable better drug delivery of PTX. This proprietary formulation has been demonstrated to be safer and more effective in preclinical studies compared to currently available formulations. For example, some tumor-bearing mice exposed to PTX-nanoparticles were cured of cancer, which was not observed for the Cremophor formulation. The goal of this study is to advance the use of PTX-nanoparticles into Phase 0 clinical studies by using 14C-paclitaxel to label the nanoparticles followed by absorption, distribution, metabolism and excretion (ADME) studies in nude mice with human tumor xenografts. The particles will be synthesized according to established protocols which includes addition of the 14C-paclitaxel in the final self-assemble step. Mice will be dosed with PTX-nanoparticles of sufficient specific activity to allow tracing by liquid scintillation counting (LSC). The LSC experiments will allow calculation of the specific activity needed for the studies to be repeated using AMS-based detection of the 14C-paclitaxel. AMS is needed as part of the project in order to predict dose formulations and develop methods for use in clinical studies (to be proposed later). It is anticipated that LSC has sufficient sensitivity for human phase 0 studies, but this needs to be established empirically with the proposed animal studies. If successful, the feasibility study data will be submitted to FDA for an exploratory IND application in order to determine the pharmacokinetics of PTX-nanoparticles in humans in order to justify subsequent Phase 1 studies.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BCMB-K (40))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Lawrence Livermore National Laboratory
Organized Research Units
United States
Zip Code
Wan, Debin; Yang, Jun; Barnych, Bogdan et al. (2017) A new sensitive LC/MS/MS analysis of vitamin D metabolites using a click derivatization reagent, 2-nitrosopyridine. J Lipid Res 58:798-808
Stornetta, Alessia; Zimmermann, Maike; Cimino, George D et al. (2017) DNA Adducts from Anticancer Drugs as Candidate Predictive Markers for Precision Medicine. Chem Res Toxicol 30:388-409
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
Wang, Zhican; Fang, Ying; Teague, Juli et al. (2017) In Vitro Metabolism of Oprozomib, an Oral Proteasome Inhibitor: Role of Epoxide Hydrolases and Cytochrome P450s. Drug Metab Dispos 45:712-720
Kim, Jeffrey; Stewart, Benjamin; Weiss, Robert H (2016) Extraction and Quantification of Tryptophan and Kynurenine from Cultured Cells and Media Using a High Performance Liquid Chromatography (HPLC) System Equipped with an Ultra-Sensitive Diode Array Detector. Bio Protoc 6:
Pan, Amy; Zhang, Hongyong; Li, Yuanpei et al. (2016) Disulfide-crosslinked nanomicelles confer cancer-specific drug delivery and improve efficacy of paclitaxel in bladder cancer. Nanotechnology 27:425103
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
McCartt, A D; Ognibene, T; Bench, G et al. (2015) Measurements of Carbon-14 With Cavity Ring-Down Spectroscopy. Nucl Instrum Methods Phys Res B 361:277-280
Cai, Hong; Scott, Edwina; Kholghi, Abeer et al. (2015) Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice. Sci Transl Med 7:298ra117
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

Showing the most recent 10 out of 123 publications