PEG-酚-Fe伪装的细菌外膜囊泡用于多效协同抗肿瘤治疗

Tumor microenvironment is a new point cut and applying nanomaterials delivery drug to modulate tumor microenvironment is a new strategy for tumor therapy, but it is still less than expected due to the drawbacks from the complex process, load single antigen, inactivation and separate component effect. This study applies the natural nanostructure and biomimetic bacterial immune system of bacterial outer membrane vesicles （OMV） to constitute PEG-phenolic-Fe-OMV（PFO） for tumor therapy, which is achieved via a network to camouflage OMV by complexation reaction between PEG-phenolic and Fe ion. Such a feature-packed PFO not only can shield the system toxicity of OMV, also show the behavior of long-circulating; It can accumulate to tumor site by EPR effect and disaggregate in weak acidic environment releasing OMV and ferric ions; More H2O2 will be promoted in the process of OMV modulating tumor microenvironment, which will catalyze the released ferric ions turning H2O2 into highly toxic HO• by Fenton reaction to kill tumor cells for versatile synergic tumor therapy. This strategy will provide the theoretical foundation and essential reference for nanocarrier as biomedical materials applying to tumor therapy.

肿瘤微环境是肿瘤治疗的全新切入点，而利用纳米材料递送药物调控肿瘤微环境又为肿瘤治疗提供了新的思路，但在应用中仍存在制备工艺复杂、装载抗原单一、药物活性下降及各组分作用独立等问题。本项目提出利用细菌外膜囊泡（OMV）的天然纳米结构并仿生细菌免疫原性，通过PEG-酚与Fe离子络合形成的网络结构伪装OMV，构造PEG-酚-Fe-OMV（PFO）纳米体系用于肿瘤治疗。该体系中的PEG-酚-Fe网络结构不仅可以屏蔽OMV的系统毒性，而且可实现纳米粒子在机体内长循环；PFO通过EPR效应富集于肿瘤部位并在该微酸环境中解聚释放OMV及Fe离子；OMV在调控肿瘤微环境过程中同时促使H2O2含量升高，从而促进释放的Fe离子发生芬顿反应，还原H2O2生成HO·杀伤肿瘤细胞，实现该纳米体系多效协同抑制肿瘤生长的作用。本项目为探索纳米载体自身作为医学材料，科学、合理的应用于肿瘤治疗提供理论依据和重要参考。

本项通过PEG-酚-Fe包覆细菌外膜囊泡OMV，已经制备出多效协同的纳米抗肿瘤体系PEG-酚-Fe-OMV（PFO）。制备的PEG-酚-Fe-OMV（PFO）体系实现利用PEG-酚-Fe网状结构伪装OMV，减少OMV在机体内的毒副作用并在PEG作用下长循环；利用EPR效应富集于肿瘤部位并解聚释放OMV及Fe粒子；利用OMV调控肿瘤微环境，促使微环境H2O2含量提高，进一步促进Fe离子还原H2O2生成HO·杀伤肿瘤细胞，达到多效协同破坏肿瘤微环境并消除肿瘤。PFO体系尾静脉给药于4T1荷瘤小鼠后，可有效富集于肿瘤部位，各组分协同作用，抑制肿瘤生长，延长生存期。