Analytical and Phartriacokinetics Core In vitro and in vivo PK studies of nanocarrier formulations of siRNA, cisplatin and paditaxel will be performed by the Analytical and PK Core. In vitro studies will be performed to evaluate the stability and released characteristics ofthe nanoparticle formulations of siRNA, cisplatin, and paditaxel in saline and plasma. In vivo studies will evaluate the PK disposition of the nanoparticle encapsulated, released and sum total (encapsulated + released) siRNA, cisplatin, and paditaxel in plasma and sum total in tumor and tissues. The evaluation of encapsulated and released drug in plasma will be evaluated using SPS, Dr. Zamboni's lab currently has an Inductively Coupled Plasma Mass Spectrometry (ICP-MS) assay for cisplatin and carboplatin in plasma, tumor and tissues. His group has also used SPS methods to evaluate the plasma and tumor disposition of pegylated liposomal formulations of cisplatin (SPI-077) and CKD-602 (SCKD602). His group has also evaluated the plasma and tumor disposition of docetaxel in tumor models. Dr. Zamboni's lab has an LC-MS/MS assay for docetaxel and paditaxel in plasma, tumor and tissues. As outlined in the Research Design and Methods section, the SPS and analytical assays in Dr. Zamboni's lab will be used to evaluate the PK disposition of nanoparticle formulations of cisplatin and paditaxel as part of Project 3 by Drs. Mumper, DeSimone and Lin. We also plan on applying our extensive experience in designing, performing, and analyzing preclinical PK studies of nano-carrier agents compared with non-nanocarrier agents to the development of nano-carrier formulations of siRNA as part of Project 2 by Drs. Huang, Kim and DeSimone. We are currently developing an assay for siRNA in plasma, tumor, and tissues via liquid chromatography/electrospray ionization high-resolution mass spectrometry (LC/ESI-HRMS) using an LTQ-Orbitrap Mass Spectrometer.

Public Health Relevance

The pharmacokinetic (PK) disposition of nano-carrier agents is dependent upon the carrier and not the parent-drug until the drug Is released from the carrier. The drug that is encapsulated in nanoparticles is an inactive-prodrug and must be released from the carrier to be active. The PK of these agents are complex and detailed studies must be performed to evaluate the encapsulated and released form ofthe drug.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA151652-04
Application #
8540384
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
2013-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$60,807
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Sun, Junjiang; Shao, Wenwei; Chen, Xiaojing et al. (2018) An Observational Study from Long-Term AAV Re-administration in Two Hemophilia Dogs. Mol Ther Methods Clin Dev 10:257-267
Liu, Lina; Wang, Yuhua; Miao, Lei et al. (2018) Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer. Mol Ther 26:45-55
Starling, Brittney R; Kumar, Parag; Lucas, Andrew T et al. (2018) Mononuclear phagocyte system function and nanoparticle pharmacology in obese and normal weight ovarian and endometrial cancer patients. Cancer Chemother Pharmacol :
Chai, Zheng; Zhang, Xintao; Rigsbee, Kelly Michelle et al. (2018) Cryoprecipitate augments the global transduction of the adeno-associated virus serotype 9 after a systemic administration. J Control Release 286:415-424
Wang, Yuhua; Zhang, Lu; Xu, Zhenghong et al. (2018) mRNA Vaccine with Antigen-Specific Checkpoint Blockade Induces an Enhanced Immune Response against Established Melanoma. Mol Ther 26:420-434
Pei, Xiaolei; He, Ting; Hall, Nikita E et al. (2018) AAV8 virions hijack serum proteins to increase hepatocyte binding for transduction enhancement. Virology 518:95-102
Zhang, Xintao; He, Ting; Chai, Zheng et al. (2018) Blood-brain barrier shuttle peptides enhance AAV transduction in the brain after systemic administration. Biomaterials 176:71-83
Chai, Zheng; Sun, Junjiang; Rigsbee, Kelly Michelle et al. (2017) Application of polyploid adeno-associated virus vectors for transduction enhancement and neutralizing antibody evasion. J Control Release 262:348-356
Perry, Jillian L; Reuter, Kevin G; Luft, J Christopher et al. (2017) Mediating Passive Tumor Accumulation through Particle Size, Tumor Type, and Location. Nano Lett 17:2879-2886
Bowerman, Charles J; Byrne, James D; Chu, Kevin S et al. (2017) Docetaxel-Loaded PLGA Nanoparticles Improve Efficacy in Taxane-Resistant Triple-Negative Breast Cancer. Nano Lett 17:242-248

Showing the most recent 10 out of 190 publications