炎症介导肿瘤靶向的荷载脂质体的中性粒细胞递药系统

According to the inflammation immune feature of the tumor microenvironment, a novel self-targeting anticancer drug delivery system is developed based on neutrophils carrier for drug-loaded liposomes mediated by the amplified tumor inflammation reaction. Thermotherapy of PEGylated gold nanorods (PEG-AuNRs) via passive targeting to tumor sites can activate and amplify controllably tumor chemokines as tumor targeting signals. These signals have the strong effect on recruiting intravenously administrated drug-loaded neutrophils, followed by high accumulation of neutrophils into both outer and inner space of the tumor. Neutrophils disintegrate at the tumor inflammation microenvironment through Etosis, a specific pathway, and release drug-loaded liposomes for antitumor treatment. For the proof of neutrophils as a feasible, efficient and safe drug targeting carrier, numerous researches are being performed including the preparation, physiological activity, inflammation tropism, in vitro and in vivo stability of neutrophils loading drug-encapsulated liposomes, and controllable amplification of tumor inflammation reaction by thermotherapy of AuNRs. The design of such immunocytes self-targeting carrier guided by amplified tumor inflammation signals may overcome the barriers in anticancer drug delivery such as low drug concentration and permeation at tumor site, and has the important academic significance and application value.

根据肿瘤微环境的炎性免疫特征，本课题设计以中性粒细胞为载体、荷载含药脂质体并由放大的肿瘤炎症反应介导的新型自主靶向系统。利用PEG化金纳米棒被动靶向肿瘤部位，发生热疗作用，刺激肿瘤微环境释放中性粒细胞相关的趋化因子，可控放大肿瘤的靶向信号，对载药中性粒细胞产生强烈的招募反应，使之在血管注射后浓集至肿瘤及其深层，在肿瘤炎症微环境中以其独特的Etosis途径自然解体而释放出载药脂质体，产生治疗作用。本课题研究中性粒细胞包载含药脂质体及其包载后细胞的生理活性、炎症趋向性、体内外稳定性以及金纳米棒热疗对肿瘤炎症反应的可控放大作用等，阐明中性粒细胞作为药物靶向载体的可行性、有效性和安全性。本课题提出的肿瘤炎症信号引导及增强的免疫细胞载体自主靶向的创新思路，对解决肿瘤组织药物浓度低、不易到达肿瘤组织深部等药物递送关键问题具有重要的学术意义和应用价值。

根据肿瘤微环境的炎性特征，本项目设计和构建了以中性粒细胞（neutrophils，NEs）为载体、荷载紫杉醇阳离子寡肽脂质体，由放大的肿瘤炎症信号介导的新型自主靶向递药系统。利用被动靶向至肿瘤部位的PEG化金纳米棒受近红外光照射产生的热疗作用，刺激肿瘤微环境释放NEs相关的趋化因子，可控放大肿瘤的炎症靶向信号，大量招募载药NEs使其富集于肿瘤组织并穿透至肿瘤深层，随后NEs以其独特的形成天网（Etosis）的途径释放出载药脂质体，产生治疗作用。.本项目系统研究了NEs递药系统的构建、载药后NEs的生理活性、脂质体在NEs中的稳定性以及NEs递药系统在转运过程中的稳定性；热疗试剂的制备、表征和在荷瘤小鼠体内的分布；热疗条件对体内炎症信号的影响；载药NEs在热疗荷瘤小鼠肿瘤部位的渗透和释放、热疗荷瘤小鼠体内的靶向性、组织分布和体内抗肿瘤活性。研究表明：本项目构建的载药NEs递送系统能快速响应热疗放大的肿瘤部位炎症信号，被招募富集于肿瘤组织及肿瘤深层，释放荷载的紫杉醇脂质体，提高药物的肿瘤靶向性。.本项目在完成原有计划的同时，进一步拓宽研究，将载药NEs用于小鼠原位脑胶质瘤的术后治疗。脑胶质瘤具有浸润性生长的特点，手术只能切除大部分肿瘤，残留的肿瘤细胞极易造成术后复发。应用载药NEs治疗后发现该递药系统能响应小鼠原位脑胶质瘤术后的炎症信号，穿过血脑屏障，富集到肿瘤术后残留部位，有效抑制脑瘤的复发和浸润性生长，为脑胶质瘤的治疗提供了新思路。.本项目的研究成果共发表论文19篇，其中SCI收录13篇，2篇IF>10，3篇5<IF<10，包括Angew Chem Int Edit（IF 11.336，被选为VIP论文和封面故事），J Am Chem Soc（IF 13.038），Biomaterials（IF 8.557），J Control Release（IF 7.441）， ACS Appl Mater Inter（IF 7.145）。获得授权专利3项，申请发明专利3项（已公开，含国际公开专利1项）。参加国内会议11次，国际会议4次，特邀报告1次，口头报告4次。培养博士生3名，硕士生5名，均获得学位。项目负责人获得江苏省333人才工程第2层次的培养。此外，基于NEs递药系统用于脑胶质瘤术后治疗的研究论文已投稿于Nature Nanothchnology, 并已三次修回。

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