Tumor-associated macrophages (TAMs) are increasingly considered a viable target for
tumor imaging and
therapy. Previously, we reported that innovative surface-functionalization of nanoparticles may help target them to TAMs. In this report, using
poly(lactic-co-glycolic) acid (PLGA) nanoparticles incorporated with
doxorubicin (DOX) (DOX-NPs), we studied the effect of surface-modification of the nanoparticles with
mannose and/or
acid-sensitive sheddable
polyethylene glycol (PEG) on the biodistribution of DOX and the uptake of DOX by TAMs in
tumor-bearing mice. We demonstrated that surface-modification of the DOX-NPs with both
mannose and
acid-sensitive sheddable PEG significantly increased the accumulation of DOX in
tumors, enhanced the uptake of the DOX by TAMs, but decreased the distribution of DOX in mononuclear phagocyte system (MPS), such as liver. We also confirmed that the
acid-sensitive sheddable PEGylated,
mannose-modified DOX-nanoparticles (DOX-AS-M-NPs) targeted TAMs because depletion of TAMs in
tumor-bearing mice significantly decreased the accumulation of DOX in
tumor tissues. Furthermore, in a B16-F10
tumor-bearing mouse model, we showed that the DOX-AS-M-NPs were significantly more effective than free DOX in controlling
tumor growth but had only minimum effect on the macrophage population in mouse liver and spleen. The AS-M-NPs are promising in targeting cytotoxic or macrophage-modulating agents into
tumors to improve
tumor therapy.