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

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 EditorThe 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.

Graphical AbstractNanoparticles (NPs) have immunological properties leading to recognition and internalization of NPs by the mononuclear phagocytic cells, such as macrophages. Evidence exists that these cells play an essential role in the clearance of NP drugs, but its actual contribution to high pharmacokinetic (PK) variability of nanomedicines and related underlying mechanisms remain elusive. In this study, we report that chemokines CCL2 and CCL5 play an important role in the PKs of PEGylated liposomal doxorubicin and the total exposure of plasma CCL2 and CCL5 correlated with plasma exposure of encapsulated liposomal doxorubicin in patients with recurrent epithelial ovarian cancer.Figure optionsDownload high-quality image (204 K)Download as PowerPoint slide