Roles of chemokines CCL2 and CCL5 in the pharmacokinetics of PEGylated liposomal doxorubicin in vivo and in patients with recurrent epithelial ovarian cancer

Gina Song; Teresa K Tarrant; Taylor F White; David A Barrow; Charlene M Santos; Roman G Timoshchenko; Suzan K Hanna; Ramesh K Ramanathan; Craig R Lee; Victoria L Bae-Jump; Paola A Gehrig; William C Zamboni

doi:10.1016/j.nano.2015.05.007

Roles of chemokines CCL2 and CCL5 in the pharmacokinetics of PEGylated liposomal doxorubicin in vivo and in patients with recurrent epithelial ovarian cancer

Nanomedicine. 2015 Oct;11(7):1797-807. doi: 10.1016/j.nano.2015.05.007. Epub 2015 Jun 17.

Authors

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 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, Division of Rheumatology, Allergy, and Immunology, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Cytokine and Biomarker Analysis Facility, Center for Oral and Systemic Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; The Animal Studies Core, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Department of Medicine, Division of Rheumatology, Allergy, and Immunology, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Virginia G. Piper Cancer Institute, Scottsdale, AZ, USA.
⁷ 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.
⁸ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Obstetrics and Gynecology, Division of Gynecology Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹ 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: zamboni@email.unc.edu.

PMID: 26093057
DOI: 10.1016/j.nano.2015.05.007

Abstract

Nanoparticles (NPs) are cleared by monocytes and macrophages. Chemokines CCL2 and CCL5 are key mediators for recruitment of these immune cells into tumors and tissues. The purpose of this study was to investigate effects of CCL2 and CCL5 on the pharmacokinetics (PKs) of NPs. Mice deficient in CCL2 or CCL5 demonstrated altered clearance and tissue distribution of polyethylene glycol tagged liposomal doxorubicin (PLD) compared to control mice. The PK studies using mice bearing SKOV3 ovarian cancer xenografts revealed that the presence of tumor cells and higher expression of chemokines were significantly associated with greater clearance of PLD compared to non-tumor bearing mice. Plasma exposure of encapsulated liposomal doxorubicin positively correlated with the total exposure of plasma CCL2 and CCL5 in patients with recurrent epithelial ovarian cancer treated with PLD. These data emphasize that the interplay between PLD and chemokines may have an important role in optimizing PLD therapy.

From the clinical editor: The use of nanoparticles as drug delivery carriers is gaining widespread acceptance in the clinical setting. However, the underlying pharmacokinetics of these novel drugs has not really been elucidated. In this interesting article, the authors carried out experiments using mice deficient in CCL2 or CCL5 to study the clearance of liposomal system. They showed the important role the immune system played and would enable better designs of future drug delivery systems.

Keywords: CCL2; CCL5; Macrophages; Nanoparticles; Pharmacokinetics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Ovarian Epithelial
Chemokine CCL2 / blood*
Chemokine CCL5 / blood*
Doxorubicin / administration & dosage
Doxorubicin / analogs & derivatives*
Drug Delivery Systems
Female
Humans
Mice
Nanoparticles / administration & dosage
Nanoparticles / chemistry
Neoplasm Recurrence, Local / drug therapy*
Neoplasm Recurrence, Local / genetics
Neoplasm Recurrence, Local / pathology
Neoplasms, Glandular and Epithelial / blood
Neoplasms, Glandular and Epithelial / drug therapy*
Neoplasms, Glandular and Epithelial / pathology
Ovarian Neoplasms / blood
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / pathology
Polyethylene Glycols / administration & dosage
Polyethylene Glycols / chemistry
Tissue Distribution / drug effects
Xenograft Model Antitumor Assays

Substances

CCL2 protein, human
Chemokine CCL2
Chemokine CCL5
liposomal doxorubicin
Polyethylene Glycols
Doxorubicin

Abstract

Publication types

MeSH terms

Substances

Grants and funding