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.
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.
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