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Pharmaceutical Research

, Volume 32, Issue 3, pp 852–862 | Cite as

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

  • Jeong Yeon Kang
  • Mathew Eggert
  • Shravanthi Mouli
  • Ibrahim Aljuffali
  • Xiaoyu Fu
  • Ben Nie
  • Amy Sheil
  • Kendall Waddey
  • Charlie D. Oldham
  • Sheldon W. May
  • Rajesh Amin
  • Robert D. Arnold
Research Paper

Abstract

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.

KEY WORDS

cardiotoxicity doxorubicin liposomes phenylaminoethyl selenide prostate cancer 

Abbreviations

ACN

Acetonitrile

ANP

Atrial natriuretic peptide

AUC

Area under the plasma drug concentration-time curve

Chol

Cholesterol

CL

Total systemic clearance

Cmax

Maximum plasma concentration

CV

Coefficient of variation

DOX

Doxorubicin

DSPC

1,2-distearoyl-sn-glycero-3-phosphatidylcholine

DSPE-PEG

1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]

ESI

Electrospray ionization

FPAESe

4-fluoro-phenyl-2-aminoethyl selenide

H2DCFDA

2′-7′- dichlorodihydrofluorescein diacetate

I.S.

Internal standard

k

Terminal elimination rate

LC

High performance liquid chromatography

Lip-PAESe

SSL-PAESe

LLOQ

Lower limit of quantification

m/z

Mass to charge

MeOH

Methanol

MHC-β

Myosin heavy chain complex beta

MRM

Multiple reaction monitoring

MS

Mass spectrometry

MS/MS

Tandem mass spectrometry

PAESe

Phenyl-2-aminoethyl selenide

PK

Pharmacokinetic

QC

Quality control

qPCR

Quantitative polymerase chain reaction

ROS

Reactive oxygen species

sc

Subcutaneous

SSL

Sterically-stabilized liposomes

SSL-PAESe

Sterically stabilized PAESe liposomes

t1/2

Half-life

V

Apparent volume of distribution

αt1/2

Alpha distribution half-life

βt1/2

Beta elimination half-life

Notes

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).

Supplementary material

11095_2014_1501_MOESM1_ESM.docx (116 kb)
Supplemental data (DOCX 115 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Jeong Yeon Kang
    • 1
  • Mathew Eggert
    • 2
  • Shravanthi Mouli
    • 2
  • Ibrahim Aljuffali
    • 1
    • 4
  • Xiaoyu Fu
    • 2
  • Ben Nie
    • 2
  • Amy Sheil
    • 2
  • Kendall Waddey
    • 2
  • Charlie D. Oldham
    • 3
  • Sheldon W. May
    • 3
  • Rajesh Amin
    • 2
  • Robert D. Arnold
    • 2
  1. 1.Department of Pharmaceutical and Biomedical SciencesCollege of Pharmacy, University of GeorgiaAthensUSA
  2. 2.Department of Drug Discovery & DevelopmentHarrison School of Pharmacy, Auburn UniversityAuburnUSA
  3. 3.School of Chemistry & BiochemistryGeorgia Institute of TechnologyAtlantaUSA
  4. 4.Nanomedicine Research Unit, Department of PharmaceuticsCollege of Pharmacy, King Saud UniversityRiyadhSaudi Arabia

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