耐药肿瘤联合治疗的共递系统存在化药在耐药逆转剂起效前释放而被细胞外排，及肿瘤靶向渗透能力差、耐药逆转不均一的问题。本项目联合具肿瘤归巢及穿透能力的iRGD肽修饰和新型氧化石墨烯矿化策略，构建具肿瘤靶向渗透及胞内触发式序贯异药释放功能的共递系统，实现异药有效共载、肿瘤靶向促渗、耐药逆转先行而化药时控断后，通过调控双药释放动力学达到协同药效最大化。本项目将系统考察载体结构及矿化工艺对纳米形态、药物共载、胞内序贯释药能力的影响，探讨释药机制并尝试建立体内外肿瘤耐药逆转“时控”评价体系。从耐药逆转剂的生效“时间窗”及化药在“时间窗”内释放程度为切入点，观察胞内化药对靶点的聚集度、对耐药肿瘤抑制效果的影响，并通过体系于肿瘤的微分布及治疗时肿瘤不同部位耐药水平的逆转程度等，多层次考察该体系序贯深入、高效均质的耐药逆转效果，为实现针对耐药肿瘤的优化逆转提供一种全新的设计思路和方法。

The combined treatment of drug-resistant tumor with chemotherapeutic drug and drug-resistance gene targeted siRNA is now hindered by a mild tumor-targeted penetration and a poor drug-release control. This means that a uniformed drug-resistance reversal is not achieved. To make matters worse, the chemotherapeutic drug payload is always released before the drug resistance phenotype has been silenced by siRNA. Herein, a graphene-based co-delivery system (IPHG) with iRGD modification and calcium phosphate mineralization strategy was designed with function of tumor homing and penetration, as well as a spatiotemporally controlled sequential drug release. Resultantly, IPHG is to achieve an effective drug co-encapsulation, tumor homing and penetration, and a reasonable dual-drug release kinetics that chemotherapeutic drug is burst released after the drug resistance phenotype has been silenced by siRNA for a maximized synergistic anti-tumor effect. In this project, the effect of carrier structure and mineralization technology on nano-morphology, drug co-loading ability, intracellular controlled sequential drug release kinetics of IPHG will be systematically studied. Besides, an in-vitro and in-vivo evaluation system based on a spatiotemporally controlled manner for drug resistance reversal will be established. It means the aggregation degree of the chemical drug on target sites and its subsequent anti-tumor efficiency under the different chemical drug release rate in the silencing duration of siRNA will be studied deeply. Finally, the drug micro-distribution and the reversal degree of drug resistance in different domains within the same tumor will be detected to demonstrate the effective and homogeneous reversal effect of drug resistance by IPHG.