Abstract
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.