肿瘤微环境包含酸性（内、外环境均酸性）和还原性，本申请通过设计还原敏感型前药，利用酸性敏感的载体递送，达到对肿瘤“胞外响应，胞内触发”式连环靶向。以顺铂为模型药物，将Pt(II)氧化成细胞毒性低的Pt(IV)前药，通过与酸敏感的聚组氨酸结合，并与改性聚谷氨酸配位键合载药，构建肿瘤微环境响应的连环机制递送系统。本课题的连环递送系统由于选择的聚组氨酸的亲脂性及聚谷氨酸的亲水性，在中性条件下以胶束形式存在，带负电性的聚谷氨酸胶束外壳，延长了体内循环时间，在肿瘤组织酸性环境下，胶束伸展为链状高分子复合物，聚组氨酸介导穿透肿瘤细胞膜并引发溶酶体逃逸，Pt(IV)在肿瘤细胞内经还原作用发生构型翻转，由低活性八面体Pt(IV)翻转为高活性平面四边形Pt(II)，继而发挥细胞毒性，实现靶向治疗。本课题将通过多种体内外研究手段，研究该连环递送系统的靶向性和安全性，为进一步研究肿瘤靶向治疗提供基础。

Tumor acidity (tumor intracellular and extracellular acidity) and elevated glutathione levels are characteristic features in the tumor microenvironment. The purpose of this application is to construct an extracellular responsive and intracellular triggered consecutive drug delivery system by designing redox-sensitive prodrug delivered with an acidity-responsive carrier. To construct the tumor microenvironment responsive and consecutive drug delivery system, cisplatin was selected as a model drug. Based on the former research work, Pt (II) was oxidized into less toxic Pt (IV) prodrug, coupled with acidity-sensitive polyhistidine peptides for cell-penetrating functions, and sequently conjugated with modified γ-polyglumatic acid. The nanoconjugates showed a micellar conformation under neutral conditions and the negatively charged polyglumatic acid shell of micelles extended the blood circulation time. Exposed into the tumor extracellular acidity, the micellar conformation disassembled rapidly and stretched into linear polymer compounds. After the transitions of nanoconjugates, polyhistidine induced cell-penetrating uptake and endosomal escape. The configuration reversions of Pt(IV) were demonstrated in the presence of reduction conditions. The low reactive Pt(IV) structure inverted into highly active Pt (II) structure and then exerted cytotoxicity for tumor targeted therapy. In this study, the tumor targeting and safety of the consecutive drug delivery system were examined through cell tests, in vivo antitumor activities and pharmacokinetics studies. We hope that the tumor microenvironment responsive and consecutive drug delivery system can provide the foundation for further research on targeted tumor therapy.