The Development of Liposomal and Nanoparticle Anticancer Agents: Methods to Evaluate the Encapsulated and Released Drug in Plasma and Tumor and Phenotypic Probes for Pharmacokinetic (PK) and Pharmacodynamic (PD) Disposition.

Keywords:
Liposomes, Nanoparticles, Pharmacokinetic, Encapsulated and Released Drug, Sample Processing Methods, Phenotypic Probes, Reticuloendothelial System

Abstract:
Introduction: We developed sample processing and analytical methods to measure inactive-encapsulated and active-released drug in plasma and tumors and developed phenotypic probes for the PK and PD disposition of liposomal and nanoparticle anticancer agents. Methods: Plasma samples were processed to measure encapsulated, released, and sum total (encapsulated + released) drug. Encapsulated and released drug in plasma are separated using solid phase separation (SPS). Microdialysis methodology was used to evaluate the tumor disposition of encapsulated and released drugs. Reticuloendothelial system (RES) in tumors was measured by immunohistochemistry. Results: Results are from liposomal camptothecins and taxanes. Using SPS, we are able to measure encapsulated, released, and sum total drug in plasma. In plasma, the recovery of encapsulated and released drug was 99.9 ± 0.1% and 98.9 ± 0.5%, respectively. In plasma, the ratio of encapsulated + released drug to sum total drug was 0.97 ± 0.04. Relative-recovery of released drug in tumor ECF was 39.1 ± 15.5%. The exposure of encapsulated and released drug in tumor was correlated with RES staining. We are evaluating phenotypic probes for the PK and PD of carrier anticancer agents in patients using factors in the blood and non-invasive imaging of the probe in tumor and tissues.

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Nanotech 2007 Conference Program Abstract