Targeted delivery of epirubicin to tumor-associated macrophages by sialic acid-cholesterol conjugate modified liposomes with improved antitumor activity

- A new SA derivative, sialic acid-cholesterol conjugate (SA-CH), was synthesized.
- Epirubicin-loaded liposomes decorated with SA-CH (EPI-SAL) were prepared.
- EPI-SAL improved the delivery of EPI to tumor-associated macrophages(TAMs).
- The treatment of EPI-SAL reduced the number of TAMs in tumor-bearing mice, which exhibited an excellent antitumor activity.
- EPI-SAL significantly prolonged the lifespan of tumor-bearing mice with reduced systemic toxicity.

With the knowledge that the receptors of sialic acid are overexpressed on the surface of tumor-associated macrophages (TAMs), which play a crucial role in the tumor's progression and metastasis, a sialic acid-cholesterol conjugate (SA-CH) was synthesized and modified on the surface of epirubicin (EPI)-loaded liposomes (EPI-SAL) to improve the delivery of EPI to the TAMs. The liposomes were developed using remote loading technology via a pH gradient. The liposomes were evaluated for particle size, encapsulation efficiency, in vitro release, stability, in vitro cytotoxicity and pharmacokinetics. And the in vitro and in vivo cellular uptake studies demonstrated EPI-SAL achieved enhanced accumulation of EPI into TAMs. The antitumor studies indicated that EPI-SAL provided the strongest antitumor activity compared with the other formulations (EPI-S, EPI-CL and EPI-PL represent EPI solution, conventional liposomal EPI, PEGylated liposomal EPI, respectively), and the survival percent of tumor-bearing mice was 83.3%. The superior antitumor efficacy was probably attributed to the killing of TAMs by EPI-SAL, and modulating the tumor microenvironment with the depletion of TAMs. These findings suggested that SA-CH decorated EPI-loaded liposomes may present an effective strategy to eradicate TAMs, which may be a promising approach for cancer therapy.

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