Pharmacokinetics, Antitumor and Cardioprotective Effects of Liposome-Encapsulated Phenylaminoethyl Selenide in Human Prostate Cancer Rodent Models
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Cardiotoxicity associated with the use of doxorubicin (DOX), and other chemotherapeutics, limits their clinical potential. This study determined the pharmacokinetics and antitumor and cardioprotective activity of free and liposome encapsulated phenyl-2-aminoethyl-selenide (PAESe).
The pharmacokinetics of free PAESe and PAESe encapsulated in liposomes (SSL-PAESe) were determined in rats using liquid chromatography tandem mass-spectrometry. The antitumor and cardioprotective effects were determined in a mouse xenograft model of human prostate (PC-3) cancer and cardiomyocytes (H9C2).
The encapsulation of PAESe in liposomes increased the circulation half-life and area under the drug concentration time profile, and decreased total systemic clearance significantly compared to free PAESe. Free- and SSL-PAESe improved survival, decreased weight-loss and prevented cardiac hypertrophy significantly in tumor bearing and healthy mice following treatment with DOX at 5 and 12.5 mg/kg. In vitro studies revealed PAESe treatment altered formation of reactive oxygen species (ROS), cardiac hypertrophy and gene expression, i.e., atrial natriuretic peptide and myosin heavy chain complex beta, in H9C2 cells.
Treatment with free and SSL-PAESe exhibited antitumor activity in a prostate xenograft model and mitigated DOX-mediated cardiotoxicity.
KEY WORDScardiotoxicity doxorubicin liposomes phenylaminoethyl selenide prostate cancer
Atrial natriuretic peptide
Area under the plasma drug concentration-time curve
Total systemic clearance
Maximum plasma concentration
Coefficient of variation
2′-7′- dichlorodihydrofluorescein diacetate
Terminal elimination rate
High performance liquid chromatography
Lower limit of quantification
Mass to charge
Myosin heavy chain complex beta
Multiple reaction monitoring
Tandem mass spectrometry
Quantitative polymerase chain reaction
Reactive oxygen species
Sterically stabilized PAESe liposomes
Apparent volume of distribution
Alpha distribution half-life
Beta elimination half-life
Acknowledgments and Disclosures
This research was funded in part by NIH 1R01 1EB016100-01 and 1R21 EB008153 (RDA), Auburn University Internal Grants Program, Georgia Cancer Coalition Distinguished Scholar Grant (RDA) and University of Georgia-Georgia Tech Seed Grant (SWM/RDA).
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