Previously, it was shown that a novel 4-(N)-stearoyl
gemcitabine nanoparticle formulation was more effective than
gemcitabine hydrochloride in controlling the growth of model mouse or human
tumors pre-established in mice. In the present study, the feasibility of targeting the stearoyl
gemcitabine nanoparticles (GemC18-NPs) into
tumor cells that over-express
epidermal growth factor receptor (EGFR) to more effectively control
tumor growth was evaluated. EGFR is over-expressed in a variety of
tumor cells, and
EGF is a known natural
ligand of EGFR. Recombinant murine
EGF was conjugated onto the GemC18-NPs. The ability of the
EGF to target the GemC18-NPs to human breast
adenocarcinoma cells that expressed different levels of EGFR was evaluated in vitro and in vivo. In culture, the extent to which the
EGF-conjugated GemC18-NPs were taken up by
tumor cells was correlated to the EGFR density on the
tumor cells, whereas the uptake of untargeted GemC18-NPs exhibited no difference among those same cell lines. The relative cytotoxicity of the
EGF-conjugated GemC18-NPs to
tumor cells in culture was correlated to EGFR expression as well. In vivo, EGFR-over-expressing MDA-MB-468
tumors in mice treated with the
EGF-conjugated GemC18-NPs grew significantly slower than in mice treated with untargeted GemC18-NPs, likely due to that the EGF-GemC18-NPs were more anti-proliferative, anti-angiogenic, and pro-apoptotic. Fluorescence intensity data from ex vivo imaging showed that the
EGF on the nanoparticles helped increase the accumulation of the GemC18-NPs into MDA-MB-468
tumors pre-established in mice by more than 2-fold as compared to the un-targeted GemC18-NPs. In conclusion, active targeting of the GemC18-NPs into EGFR-over-expressed
tumors can further enhance their anti-
tumor activity.