Pharmacokinetics, Antitumor and Cardioprotective Effects of Liposome-Encapsulated Phenylaminoethyl Selenide in Human Prostate Cancer Rodent Models

• Published in: Pharmaceutical research 2015-03, Vol.32 (3), p.852-862
• Main Authors: Kang, Jeong Yeon, Eggert, Mathew, Mouli, Shravanthi, Aljuffali, Ibrahim, Fu, Xiaoyu, Nie, Ben, Sheil, Amy, Waddey, Kendall, Oldham, Charlie D., May, Sheldon W., Amin, Rajesh, Arnold, Robert D.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antioxidants - administration & dosage; Antioxidants - chemistry; Antioxidants - pharmacokinetics; Area Under Curve; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Cardiomegaly - chemically induced; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomegaly - prevention & control; Cardiovascular system; Cell Line, Tumor; Chemistry, Pharmaceutical; Chemotherapy; Chromatography, Liquid; Disease Models, Animal; Dose-Response Relationship, Drug; Doxorubicin; Ethylamines - administration & dosage; Ethylamines - chemistry; Ethylamines - pharmacokinetics; Gene Expression Regulation - drug effects; Half-Life; Humans; Injections, Intravenous; Liposomes; Male; Mass Spectrometry; Medical Law; Metabolic Clearance Rate; Mice, Nude; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Organoselenium Compounds - administration & dosage; Organoselenium Compounds - chemistry; Organoselenium Compounds - pharmacokinetics; Oxidative Stress - drug effects; Pharmaceutical sciences; Pharmacology/Toxicology; Pharmacy; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Rats, Inbred F344; Reactive Oxygen Species - metabolism; Research Paper; Rodents; Technology, Pharmaceutical - methods; Toxicity; Tumor Burden - drug effects; Xenograft Model Antitumor Assays
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-014-1501-5

Purpose 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). Methods 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) . Results 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. Conclusions Treatment with free and SSL-PAESe exhibited antitumor activity in a prostate xenograft model and mitigated DOX-mediated cardiotoxicity.