title: Roles of chemokines CCL2 and CCL5 in the pharmacokinetics of PEGylated liposomal doxorubicin in vivo and in patients with recurrent epithelial ovarian cancer.
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.
  
  
  BACKGROUND
  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.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Gina
authors.initials: G
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Teresa K
authors.initials: TK
authors.lastname: Tarrant
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Taylor F
authors.initials: TF
authors.lastname: White
authors.affiliation: Cytokine and Biomarker Analysis Facility, Center for Oral and Systemic Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Barrow
authors.affiliation: 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.
authors.forename: Charlene M
authors.initials: CM
authors.lastname: Santos
authors.affiliation: Department of Medicine, Division of Rheumatology, Allergy, and Immunology, Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Roman G
authors.initials: RG
authors.lastname: Timoshchenko
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Suzan K
authors.initials: SK
authors.lastname: Hanna
authors.affiliation: Virginia G. Piper Cancer Institute, Scottsdale, AZ, USA.
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.affiliation: 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.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bae-Jump
authors.affiliation: 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.
authors.forename: Paola A
authors.initials: PA
authors.lastname: Gehrig
authors.affiliation: 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.
authors.forename: William C
authors.initials: WC
authors.lastname: Zamboni
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D018932:Chemokine CCL2 / Q000097:blood*; D018946:Chemokine CCL5 / Q000097:blood*; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D014018:Tissue Distribution / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: CCL2; CCL5; Macrophages; Nanoparticles; Pharmacokinetics