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Schematic diagram showing the binding of SA-ODA and GM1 co-modified liposome to Siglec-1 receptor on the surface of TAMs. GM1, monosialotetrahexosylganglioside; SA-ODA, sialic acid-octadecylamine; TAMs, tumor-associated macrophage. [Display omitted] Although anti-tumor strategies targeting tumor-associated immune cells were being rapidly developed, the preparations were usually limited in targeting efficiency. To overcome this barrier, this study reported a novel sialic acid-octadecylamine (SA-ODA) and monosialotetrahexosylganglioside (GM1) co-modified epirubicin liposomes (5-5-SAGL- EPI), which improved tumor-targeting ability through the active targeting of tumor-associated macrophages (TAMs) by SA-ODA and the long circulation of GM1. Thus, we evaluated 5-5-SAGL- EPI in vitro and in vivo. Analysis of cellular uptake by RAW264.7 cells using flow cytometry and confocal microscopy showed a higher rate of cellular uptake for 5-5-SAGL- EPI than for the common liposomes (CL- EPI). In pharmacokinetic studies using Wistar rats, compared to CL- EPI , 5-5-SAGL- EPI showed a higher circulation time in vivo. Tissue distribution studies in Kunming mice bearing S180 tumors revealed increased distribution of 5-5-SAGL- EPI in tumor tissues compared with liposomes modified with single ligands (SA-ODA [5-SAL- EPI ] or GM1 [5-GL- EPI ]). In vivo anti-tumor experiments using the S180 tumor-bearing mice revealed a high tumor inhibition rate and low toxicity for 5-5-SAGL- EPI. Moreover, freeze-dried 5-5-SAGL- EPI had good storage stability, and the anti-tumor effect was comparable to that before freeze-drying. Overall, 5-5-SAGL- EPI exhibited excellent anti-tumor effects before and after lyophilization. [ABSTRACT FROM AUTHOR]