Gulp1 is associated with the pharmacokinetics of PEGylated liposomal doxorubicin (PLD) in inbred mouse strains

Gina Song; Oscar T Suzuki; Charlene M Santos; Andrew T Lucas; Tim Wiltshire; William C Zamboni

doi:10.1016/j.nano.2016.05.019

Gulp1 is associated with the pharmacokinetics of PEGylated liposomal doxorubicin (PLD) in inbred mouse strains

Nanomedicine. 2016 Oct;12(7):2007-2017. doi: 10.1016/j.nano.2016.05.019. Epub 2016 Jun 9.

Authors

Gina Song¹, Oscar T Suzuki¹, Charlene M Santos², Andrew T Lucas¹, Tim Wiltshire³, William C Zamboni⁴

Affiliations

¹ Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² The Animal Studies Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Carolina Center of Cancer Nanotechnology Excellence, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: [email protected].

PMID: 27288666
DOI: 10.1016/j.nano.2016.05.019

Abstract

Nanoparticles (NP) including liposomes are cleared by phagocytes of the mononuclear phagocyte system. High inter-patient variability in pharmacokinetics of PEGylated liposomal doxorubicin (PLD) has been reported. We hypothesized that genetic factors may be associated with the variable disposition of PLD. We evaluated plasma and tissue disposition of doxorubicin after administration of PLD at 6mg/kg IV ×1 via tail vein in 23 different male inbred mouse strains. An approximately 13-fold difference in plasma clearance of PLD was observed among inbred strains. We identified a correlation between strain-specific differences in PLD clearance and genetic variation within a genomic region encoding GULP1 (PTB domain containing engulfment adapter 1) protein using haplotype associated mapping and the efficient mixed-model association algorithms. Our results also show that Gulp1 expression in adipose tissue was associated with PLD disposition in plasma. Our findings suggest that genetic variants may be associated with inter-individual pharmacokinetic differences in NP clearance.

Keywords: Gulp1; Nanoparticles; PLD; Pharmacogenetics; Pharmacokinetics.

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Doxorubicin*
Humans
Kinetics
Liposomes
Male
Mice
Mice, Inbred Strains
Nanoparticles*
Pharmacogenomic Variants
Polyethylene Glycols

Substances

Adaptor Proteins, Signal Transducing
Liposomes
Polyethylene Glycols
Doxorubicin

Grants and funding

U54 CA151652/CA/NCI NIH HHS/United States