Profiling the relationship between tumor-associated macrophages and pharmacokinetics of liposomal agents in preclinical murine models

The mononuclear phagocyte system (MPS) has previously been shown to significantly affect the clearance, tumor delivery, and efficacy of nanoparticles (NPs). This study profiled MPS cell infiltration in murine preclinical tumor models and evaluated how these differences may affect tumor disposition of PEGylated liposomal doxorubicin (PLD) in models sensitive and resistant to PLD. Significant differences in MPS presence existed between tumor types (e.g. ovarian versus endometrial), cell lines within the same tumor type, and location of tumor implantation (i.e. flank versus orthotopic xenografts). Further, the differences in MPS presence of SKOV-3 ovarian and HEC1A endometrial orthotopic cancer models may account for the 2.6-fold greater PLD tumor exposure in SKOV-3, despite similar plasma, liver and spleen exposures. These findings suggest that profiling the presence of MPS cells within and between tumor types is important in tumor model selection and in tumor types and patients likely to respond to NP treatment.

Graphical AbstractPrior studies suggest that the mononuclear phagocyte system (MPS) significantly affects the clearance, tumor delivery, and efficacy of nanoparticles (NPs). Thus, we profiled MPS cell infiltration in a series of preclinical tumor models using immunohistochemistry and evaluated how these differences may alter tumor pharmacokinetics and efficacy of PEGylated liposomal doxorubicin (PLD) in models that are sensitive and resistant to PLD. Our findings suggest that it is critical to profile the tumor microenvironment within and between tumor types to select models that are likely to respond to NP treatment.198