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

• Published in: Nanomedicine Vol. 11; no. 7; pp. 1797 - 1807
• Main Authors: Song, Gina, PhD, Tarrant, Teresa K., MD, White, Taylor F., PharmD, Barrow, David A., PhD, Santos, Charlene M., RLATG, Timoshchenko, Roman G., BS, Hanna, Suzan K., BS, Ramanathan, Ramesh K., MD, Lee, Craig R., PhD, Bae-Jump, Victoria L., MD, Gehrig, Paola A., MD, Zamboni, William C., PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2015
• Subjects: Animals; Carcinoma, Ovarian Epithelial; CCL2; CCL5; Chemokine CCL2 - blood; Chemokine CCL5 - blood; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Drug Delivery Systems; Female; Humans; Internal Medicine; Macrophages; Mice; Nanoparticles; 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; Pharmacokinetics; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - chemistry; Tissue Distribution - drug effects; Xenograft Model Antitumor Assays; Nanoparticles; CCL2; Macrophages; Pharmacokinetics; CCL5
• ISSN: 1549-9634; 1549-9642
• 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.