Are third-generation active-targeting nanoformulations definitely the best? In vitro and in vivo comparisons of pixantrone-loaded liposomes modified with different sialic acid derivatives.

Treatment with sialic acid-octadecylamine (SA-ODA)-modified pixantrone (Pix) liposomes results in favorable antitumor effects by targeting tumor-associated macrophages (TAMs). To explore the influence of different types of SA decorations on antitumor efficiency, we synthesized a PEGylated SA derivative, SA-PEG-DSPE, and combined it with SA-ODA to construct three representative types of SA-modified liposomes (SA-ODA-modified Pix liposomes, SA-ODA-modified Pix liposomes with different PEG densities, and SA-PEG-DSPE-modified Pix liposomes, named Pix-SACL, Pix-SPL-0.2/0.5/2.0/5.0, and Pix-SAPL, respectively). All the Pix liposomes were nanoscale formulations, having diameters between 100 and 150 nm, high encapsulation efficiencies (> 90%), and slow drug release properties. The in vivo blood circulation time of the PEGylated formulations (Pix-SPL-0.2/0.5/2.0/5.0 and Pix-SAPL) showed an upward trend with increasing PEG density, but there was no significant difference between adjacent groups. All PEGylated formulations displayed increased tumor accumulation when compared with Pix-SACL, but there was no significant difference among them. However, the antitumor activity of SA-modified liposomes was not positively correlated with circulation time or tumor accumulation in S180-bearing mice. Pix-SPL-0.2 displayed the strongest antitumor effect and lowest toxicity among the formulations tested in this study. With Pix-SPL-0.2 treatment, 66.7% of the mice demonstrated tumor shedding and wound healing.