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. [Display omitted] •Mannosylated, acid-sensitive polymeric micelles that contain stearoyl gemcitabine were prepared and characterized.•The mannosylated micelles were more cytotoxic to tumor cells and macrophages that overexpress C-type like receptors (CLR), but not to tumor cells that do not (over)express CLR.•The cytotoxicity values of the micelles did not correlate with the extent to which the stearoyl gemcitabine in the micelles was taken up by the tumor cells or macrophages.•The release of the stearoyl gemcitabine from the mannosylated micelles was slower than from the unmannosylated ones.