Development of liposome-loaded macrophages as tumor-targeted drug delivery carriers: Impact of macrophage phenotypes on their liposome-loading capacity and tumor-homing potential

Macrophages have not only a high phagocytic capacity, but also a tumor-homing ability, and, thus, nanoparticle-loaded macrophages are regarded as an active drug delivery carrier targeting tumors. Macrophages exhibit several phenotypes, such as proinflammatory M1 and anti-inflammatory M2; however, it remains unclear which phenotype possesses superior characteristics as a drug delivery carrier. Therefore, we herein comparatively examined the cellular uptake of doxorubicin (DOX)-encapsulated liposomes (DOX-Lip) and associated cytotoxicity in RAW264.7 murine macrophage-like cells with three different phenotypes: the naïve M0, M1, and tumor-associated macrophage (TAM)-like phenotypes, the latter of which shows similar characteristics to the M2 phenotype. The highest uptake of liposomes was by TAM-like RAW264.7 cells, whereas a significant reduction in cell viability associated with liposome uptake also occurred. M0-type and M1-type RAW264.7 cells showed high cell viability after liposome uptake. M0-type cells exhibited higher tolerance to DOX-Lip uptake than M1-type cells. An in vitro migration assay demonstrated that DOX-Lip-loaded M0-type cells preferentially migrated towards the tumor microenvironment, whereas DOX-Lip-loaded M1-type cells did not. DOX-Lip-loaded M0-type cells also efficiently accumulated in tumor tissue and exhibited significant anti-tumor efficacy in B16/BL6 tumor-bearing mice. These results provide valuable information for the development of a macrophage-based tumor-targeted active drug delivery system.