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

https://doi.org/10.1016/j.nano.2016.09.015Get rights and content

Abstract

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 Abstract

Prior 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.

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Section snippets

Mice

All mice were handled in accordance with the Guide for the Care and Use of Laboratory Animals (Institute for Laboratory Animal Research, 2011), and studies were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of North Carolina at Chapel Hill (Chapel Hill, NC). Mice (female CB-17 SCID, 5-6 weeks of age, and specific pathogen free) were obtained from Taconic Farms (Albany, NY) and were allowed to acclimate to the animal facilities at the University of North

Macrophages in tumors and tissues in human cancer flank xenograft models

To evaluate the presence of macrophages in the primary MPS organs (i.e. liver and spleen) and in tumors, tissues from mice bearing flank xenografts were processed and stained for F4/80. Characterization was carried out in different cell lines in each of three cancer types: ovarian (SKOV-3, ES-2, CaOV-3, and OVCAR-3), breast (MCF-7, MDA-MS231, SUM149, and BT474), and endometrial (KLE, RL95–2, HEC1A, AN3CA, and SPEC2) cancers.

Significant differences in macrophage exposure within the liver were

Discussion

Tumor-associated macrophages (TAMs) are major leukocytes recruited into murine and human tumors by chemo-attractants and educated by the tumor microenvironment to promote tumor progression.24, 25 Macrophages have proven to be involved in phagocytosis and clearance of NP15, 26, 27 as well as to promote delivery of NP into tumors.28 One of the clinical complications in treating cancers is the heterogeneity in tumor cells and/or the tumor microenvironment within and between tumor types.14, 29

Author contributions

Conception & design: Song, Santos, and Zamboni.

Development of methodology: Song, Santos, and Zamboni.

Acquisition of data: White, Herity, and Santos.

Analysis and interpretation of data: Lucas and Deal.

Writing, review and/or revision of the manuscript: Lucas, Deal, and Zamboni.

Administrative, technical, or material support: Zamboni.

Study supervision: Song and Zamboni.

Acknowledgments

The authors would like to thank the North Carolina Translational and Clinical Sciences Institute (NC TraCS) for its support, NC TraCS Biostatistics Core for its review and consultation on study design, the UNC Lineberger Comprehensive Cancer Center's Mouse Phase I Unit (MP1U) for provision and housing of mouse models, and the UNC Animal Studies Cores for their assistance with the PK and efficacy studies. The authors thank Certara, as a member of the Pharsight Academic Center of Excellence

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  • Cited by (0)

    Financial support: This study was supported by the National Institutes of Health Clinical and Translational Science Award (Award Number UL1RR025747) from the National Center for Research Resources, by the Carolina Center for Cancer Nanotechnology Excellence (CCCNE; 1 U54 CA151652) from the NCI, and by the UNC Lineberger Comprehensive Cancer Center (LCCC) Cancer Center Support Grant (P30 CA016086) from the NCI. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

    Conflicts of interest: Authors have no conflicts to disclose.

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