Controlled-release nanoparticle of toll-like receptors-7/8 agonist enhances immune activation and inhibits gastric cancer in a preclinical mouse model

초록

Background: TLR-7/8 agonists are potent immunostimulators that can promote tumoricidal immune cell activities. However, the systemic side effects of these agents have limited their clinical application. To address this, we developed K-nanoadjuvant, which consists of nanoparticles that encapsulate a TLR-3 agonist and slowly release a TLR-7/8 agonist. We evaluated the efficacy and safety of K-nanoadjuvant in a newly developed preclinical mouse model of gastric cancer that was generated with triple-conditional (Tcon) gastric cancer cells. Methods: The Tcon gastric cancer cell line was derived from the spontaneous gastric cancers that developed in mice whose gastric parietal-cell lineage cells had been genetically engineered to bear activated Kras and lack E-cadherin and p53. Tumors were generated in syngeneic mice by subcutaneous injection of Tcon cells into the flank. The tumors were then injected with K-nanoadjuvant and/or the mice were injected intraperitoneally with the chemotherapeutic agent 5-FU. Tumor size and body weight were monitored to assess efficacy and safety, respectively. Fluorescence-activated cell sorting and immunohistochemistry were conducted on the tumors to assess the intratumoral immune status. Results: K-nanoadjuvant significantly inhibited tumor growth without inducing weight loss or any notable side effects. 5-FU was relatively ineffective and had only a mild additive effect when it was combined with K-nanoadjuvant. Immune profiling showed that K-nanoadjuvant generated a favorable M1/M2 macrophage ratio and increased CD4 and CD8 T cell infiltration, IFN-gamma production, and NK cell recruitment. K-nanoadjuvant treatment alone also effectively reduced lymph node metastasis and suppressed untreated distant Tcon tumors. Conclusion: K-nanoadjuvant, a controlled-release TLR-7/8 drug delivery system, demonstrated significant anti-tumor efficacy and low toxicity in a preclinical mouse model of gastric cancer. Thus, K-nanoadjuvant may have potential as a gastric cancer immunotherapy.

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