Effect of surface mannosylation on the cytotoxicity and cellular uptake of stearoyl gemcitabine-incorporated, acid-sensitive micelles.

Elevated expression of C-type like receptors (CLRs) by tumor cells and tumor-associated macrophages (TAMs) present a unique target for the delivery of anticancer agents. Stearoyl gemcitabine (GemC18)-incorporated, acid-sensitive micelles (G-AS-M) prepared with a stearoyl polyethylene glycol (PEG2000) hydrazone were surface-mannosylated in this study for potential targeted killing of tumor cells and TAMs. The surface mannosylated micelles (i.e. G-MAS-M) were significantly more cytotoxic than the G-AS-M micelles to macrophages and tumor cells that express CLRs. Surprisingly, the uptake of GemC18 in the mannosylated G-MAS-M micelles by the macrophages and tumor cells was lower than that of GemC18 in the G-AS-M micelles. The lack of correlation between the cytoxicity and cellular uptake of GemC18 in the micelles was likely caused by a reduction in the sensitivity of the hydrazone bond linking the PEG2000 to the mannosylated G-MAS-M micelles to hydrolysis, resulting in more stable micelles.