J. A. Lubin1, R. R. Zhang1,2,3, J. P. Weichert2,4, J. S. Kuo1,3,4,5 1University Of Wisconsin,Department Of Neurological Surgery,Madison, WI, USA 2University Of Wisconsin,Department Of Radiology,Madison, WI, USA 3University Of Wisconsin,Department Of Cellular And Molecular Biology,Madison, WI, USA 4University Of Wisconsin,Carbone Cancer Center,Madison, WI, USA 5University Of Wisconsin,Department Of Human Oncology,Madison, WI, USA
Introduction: Alkylphosphocholine (APC) analogs are lipophilic small molecules that selectively target a broad spectrum of human cancers. Radioactive iodine-labeled (CLR1404) or fluorescent APC analogs (CLR1501, CLR1502) are progressing to clinical trials for cancer imaging and therapeutic applications. Pharmacologic strategies to shift the serum partitioning of APC agents from the protein-bound layer (predominantly albumin) to the plasma lipoprotein layer may optimize pharmacokinetics, thus improving timing of APC administration with imaging or surgery. Intralipid, an FDA approved essential fat formulation composed primarily of triglycerides that yields free fatty acids following lipolysis, may decrease the amount of albumin-bound APC analogs through competitive binding of fatty acids. This study assesses whether Intralipid increases the lipoprotein concentration in human plasma to modify plasma:albumin partitioning of APC analogs.
Methods: Fresh unfrozen human plasma samples were incubated with APC analogs (125I-CLR1404, CLR1501, CLR1502) and Intralipid and compared to control samples that contained plasma and APC analogs without Intralipid. To measure the drug partitioning in each layer following ultracentrifugation, assays for the percent activity or fluorescence corresponding to labeled APC were performed.
Results: Addition of Intralipid increased APC partitioning to the plasma lipoprotein layer from 0.64% to 3.78%, 7.33% to 14.40%, and 6.15% to 11.26% for 125I-CLR1404, CLR1501, and CLR1502 respectively. Concomitantly, the albumin-binding percentage decreased from 98.07% to 94.48%, 85.93% to 79.32%, and 90.34% to 84.64% with the use of Intralipid (p<0.05).
Conclusion: These data suggest that the APC partitioning to the lipoprotein fraction increases at the expense of partitioning to the albumin-bound fraction. Because lipoprotein-bound drugs have increased bioavailability following high-fat diets, the use of pharmacologic interventions such as Intralipid administration may reduce time required between administration and cancer imaging and/or surgery applications by promoting tumor cell APC uptake. Further optimization of APC pharmacokinetics and pharmacodynamics profiling is in progress.
