Neutrophils as Emerging Immunotherapeutic Targets: Indirect Treatment of Tumors by Regulating the Tumor Immune Environment Based on a Sialic Acid Derivative-Modified Nanocomplex Platform

Abstract

Tumor cells are dependent on their microenvironment; thus, targeting the non-cancerous components of the tumor might lead to the development of new treatment methods. Neutrophils, which are important inflammatory cells in the tumor microenvironment (TME), significantly affect tumor cell proliferation, metastasis, angiogenesis, and immune regulation. Direct tumor targeting method results in a nanoparticle tumor distribution lower than 0.7%; therefore, targeted regulation of tumor associated neutrophil-related pathways is expected to become a new tumor therapeutic approach. Here, a sialic acid and cholesterol derivative (SA-CH) was synthesized and modified on the surface of nanocomposites to express a novel colchicine derivative (SA-EPG-BCS) for targeted immunotherapy. The interaction between the amphiphilic egg phosphatidylglycerol (EPG) structure and a newly synthesized low-toxic colchicine derivative (BCS) enables a high encapsulation rate, which greatly reduces the BCS toxicity. SA-CH modification improves the ability of the preparation to target peripheral blood neutrophils and exhibits effective anti-tumor activity in vitro and in vivo. Immunohistochemical and pathological section analyses further confirmed that SA-EPG-BCS significantly inhibited neutrophil accumulation in the tumor site, without eliciting unwanted effects. Therefore, the neutrophil migration blocking strategy using an SA-modified colchicine derivative nanocomplex, which treats the tumor indirectly by regulating the tumor immune microenvironment, may become a potential approach for cancer immunotherapy.