载IL-12基因/过氧化氢酶靶向M2pep纳米产氧脂质体增强肝癌射频消融术后PD-1抗体疗效

我们已发表论文表明，肝癌射频消融（RFA）术后乏氧增强残癌侵袭和转移力。虽然程序性死亡分子-1（PD-1）抗体能增强肿瘤治疗效果，但由于肿瘤微环境存在乏氧、活性氧（ROS）升高和M2型肿瘤相关巨噬细胞（TAM）浸润等免疫抑制因素，使PD-1抗体临床显效率不足30%。我们预实验也发现，RFA术后残癌区域M2型TAM浸润增多。那么，能否通过改善乏氧和重极化TAM提高PD-1抗体疗效呢？如何避免M2重极化为M1后及乏氧产生的ROS对PD-1抗体的抑制作用呢？为此，我们拟在前期制备纳米靶向脂质体和载基因纳米粒基础上，制备M2pep靶向载IL-12基因/过氧化氢酶纳米粒，利用过氧化氢酶与乏氧产生的ROS作用产生氧气，促进IL-12重极化M2型TAM为M1型，并利用过氧化氢酶持续清除M1型TAM产生的ROS，不断产生氧气，持久改善免疫微环境，增强术后PD-1抗体疗效，为肝癌综合治疗探索新方法。

Our former articles demonstrated that tumor cells in the hypoxic microenvironment after radiofrequency ablation (RFA) showed enhanced invasive and metastatic abilities. Although the programmed death-1 (PD-1) antibody could enhance therapeutic effect against tumor, in the clinical studies, the response rates are no more than 30%, which might due to factors such as the hypoxic tumor environment, high level of ROS and the infiltration of M2-skewed tumor associated macrophage (TAM). Our pilot experiments showed infiltration of M2-skewed TAM increased in the residual tumors. Then, can we improve the therapeutic effect of PD-1 antibody by improving postoperative hypoxia and repolarizing TAM after RFA? How to avoid the inhibitory effect of ROS, which is produced by M1-skewed TAM and the hypoxic tumor environment, on PD-1 antibody? We previously synthesized nano-targeting liposomes and gene delivery nanoparticles, and we propose to synthesize the M2pep targeted nanoparticles encapsulating IL-12 pDNA and catalase in this study. The catalase is utilized to react with the ROS produced by the hypoxic environment, and drive IL-12 pDNA to repolarize M2-skewed TAM to M1-skewed TAM. The catalase could also continuously remove the ROS produced by M1-skewed TAM and produce oxygen, improving the immune microenvironment durably and enhancing the therapeutic effect of the PD-1 antibody. The success of the study can offer prospects of new comprehensive treatment for liver cancer.