Sialic acid conjugate-modified liposomes enable tumor homing of epirubicin via neutrophil/monocyte infiltration for tumor therapy

Neutrophils and monocytes (N/Ms) are potential candidates for the delivery of therapeutic agents to the tumor microenvironment (TME) because of their tumor-accumulating nature. L-selectin and Siglec-1, receptors for sialic acid (SA), are highly expressed in circulating neutrophils and monocytes, respectively, in tumor-bearing mice, and N/Ms are recruited to tumors in response to inflammatory cytokines secreted by the TME, promoting tumor growth and invasion. Therefore, we constructed a drug delivery nano-platform using N/Ms as vehicles. SA-stearic acid conjugate was synthesized and utilized to modify epirubicin-loaded liposomes (EPI-SL) for enhanced endocytosis of liposomes by circulating N/Ms. Cellular uptake studies showed that SA modification improved the accumulation of EPI in N/Ms and did not alter the inherent chemotaxis of N/Ms. In tumor-bearing mice, EPI-SL significantly improved the tumor-targeting efficiency and therapeutic efficacy of EPI compared to other preparations and even eradicated tumors because of the tumor-accumulating and inhibitory effects of N/Ms containing EPI-SL. Our research showed, for the first time, that as an N/M-based drug delivery platform, EPI-SL remedied the limited tumor targeting in the conventional EPR effect-based treatment strategy, contributing to the exploitation of a new drug delivery platform for cancer treatment. STATEMENT OF SIGNIFICANCE: Tumor-associated neutrophils (TANs) and macrophages (TAMs) are closely associated with tumor growth and invasion, and therefore the development of therapeutic strategies targeting TANs and TAMs is crucial for tumor treatment. Given that most TANs and TAMs are derived from peripheral blood neutrophils and monocytes (N/Ms), respectively, we synthesized sialic acid-stearic acid conjugates that specifically bind N/Ms for the surface modification of liposomal epirubicin (EPI-SL). The N/Ms loaded with EPI-SL maintained their inherent chemotaxis toward the tumor. Additionally, EPI-SL significantly improved the survival of tumor-bearing mice and even eradicated tumors. These findings suggested that EPI-SL has substantial potential for clinical application by compensating for the previous low efficacy of ex vivo transformed cell infusion and improving the tumor-targeting efficiency.