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

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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.

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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

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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).

Author information

Author notes

  1. Ibrahim Aljuffali

    Present address: Nanomedicine Research Unit, Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

Authors and Affiliations

  1. Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia, 30602, USA

    Jeong Yeon Kang & Ibrahim Aljuffali

  2. Department of Drug Discovery & Development, Harrison School of Pharmacy, Auburn University, Walker Building, Room 3211-D, Auburn, Alabama, 36849, USA

    Mathew Eggert, Shravanthi Mouli, Xiaoyu Fu, Ben Nie, Amy Sheil, Kendall Waddey, Rajesh Amin & Robert D. Arnold

  3. School of Chemistry & Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, 30332, USA

    Charlie D. Oldham & Sheldon W. May

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  1. Jeong Yeon Kang
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Correspondence to Robert D. Arnold.

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Kang, J.Y., Eggert, M., Mouli, S. et al. Pharmacokinetics, Antitumor and Cardioprotective Effects of Liposome-Encapsulated Phenylaminoethyl Selenide in Human Prostate Cancer Rodent Models. Pharm Res 32, 852–862 (2015). https://doi.org/10.1007/s11095-014-1501-5

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