Search

Sialic acid derivatives (SA-derivatives) provide a nanomedicine platform for tumor-targeted delivery and treatment, and allow modulation of immunosuppressive tumor microenvironments with excellent therapeutic effects. Further, the multi-reactive groups of sialic acid (SA) contribute to the diversity of SA derivatives, which inevitably has implications for drug delivery systems and tumor therapy. However, relevant research remains lacking at present. Therefore, this study aimed to explore the effects of SA derivatives on SA-mediated drug delivery systems. Four SA-derivatives with different linking bonds (ester and amide bonds), different linking groups (hydroxyl and carboxyl), and different linking objects (cholesterol, octadecanoic acid, and octadecylamine) were synthesized and the respective SA derivative-modified doxorubicin liposomes were prepared. In-depth research was conducted using both cells and animals. We found that an SA-cholesterol conjugate (SA-CH; linking bond, amide bond; linking group, carboxyl; linking object, cholesterol) could improve liposome stability, reduce liposome adsorption to plasma proteins, and enhance the targeting of liposomes for killing tumor-associated macrophages (TAMs). Reduced TAMs in the immunosuppressive tumor microenvironment lead to enhanced tumor infiltration of CD8+ T cells. The results of this experiment provide clarity for research and development on SA-derivatives and a theoretical basis for clinical trials of SA-derivative-modified nanoparticles. [Display omitted] • Sialic acid-derivatives modified liposomes modulated immunosuppressive tumor microenvironment. • Sialic acid-derivatives linking bonds, linking groups, and linking objects influenced sialic acid mediated drug delivery systems. • Sialic acid-cholesterol conjugate could improve the stability of liposomes. • Sialic acid-cholesterol conjugate enhanced the targeting and killing of liposomes to tumor-associated macrophages. • The carboxyl group of sialic acid was not the key to affecting the anti-tumor therapeutic effect of sialic acid modified liposomes. [ABSTRACT FROM AUTHOR]

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]