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Pharmacokinetics, antitumor and cardioprotective effects of liposome-encapsulated phenylaminoethyl selenide in human prostate cancer rodent models.

ABSTRACT: 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.

SUBMITTER: Kang JY

PROVIDER: S-EPMC4329269 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Project description:Background and purposeSystemic glucocorticoid therapy may effectively attenuate lung inflammation but also induce severe side-effects. Delivery of glucocorticoids by liposomes could therefore be beneficial. We investigated if liposome-encapsulated dexamethasone inhibited ventilator-induced lung inflammation. Furthermore, we evaluated whether targeting of cellular Fcγ-receptors (FcγRs) by conjugating immunoglobulin G (IgG) to liposomes, would improve the efficacy of dexamethasone-liposomes in attenuating granulocyte infiltration, one of the hallmarks of lung inflammation.Experimental approachMice were anaesthetized, tracheotomized and mechanically ventilated for 5 h with either 'low' tidal volumes ∼7.5 mL·kg(-1) (LV(T) ) or 'high' tidal volumes ∼15 mL·kg(-1) (HV(T) ). At initiation of ventilation, we intravenously administered dexamethasone encapsulated in liposomes (Dex-liposomes), dexamethasone encapsulated in IgG-modified liposomes (IgG-Dex-liposomes) or free dexamethasone. Non-ventilated mice served as controls.Key resultsDex-liposomes attenuated granulocyte infiltration and IL-6 mRNA expression after LV(T) -ventilation, but not after HV(T) -ventilation. Dex-liposomes also down-regulated mRNA expression of IL-1β and KC, but not of CCL2 (MCP-1) in lungs of LV(T) and HV(T) -ventilated mice. Importantly, IgG-Dex-liposomes inhibited granulocyte influx caused by either LV(T) or HV(T) -ventilation. IgG-Dex-liposomes diminished IL-1β and KC mRNA expression in both ventilation groups, and IL-6 and CCL2 mRNA expression in the LV(T) -ventilated group. Free dexamethasone prevented granulocyte influx and inflammatory mediator expression induced by LV(T) or HV(T) -ventilation.Conclusions and implicationsFcγR-targeted IgG-Dex-liposomes are pharmacologically more effective than Dex-liposomes particularly in inhibiting pulmonary granulocyte infiltration. IgG-Dex-liposomes inhibited most parameters of ventilator-induced lung inflammation as effectively as free dexamethasone, with the advantage that liposome-encapsulated dexamethasone will be released locally in the lung thereby preventing systemic side-effects.

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Pharmacokinetics, antitumor and cardioprotective effects of liposome-encapsulated phenylaminoethyl selenide in human prostate cancer rodent models.

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