智能化葡聚糖纳米药物载体的构建及其在肿瘤诊疗一体化中的应用

Effective drug delivery and evaluate therapy efficiency are important issues for chemotherapy. We design a theranostic system to achieve effective drug delivery and evaluate therapy efficiency. The dextran is modified with urocanic acid and lipoic acid, and then the dye is conjugated to dextran with DEVD as linker. The dextran derivative and Au can self-assemble into nanoparticles, and then drug could be loaded in the nanoparticles. Au could quench the fluorescence of dye and decrease the backgroud of imaging. The nanopartilces could accumulate into tumor through EPR effect and release drug rapidly in the weak acid environment. Then the drug cause the tumor cells apoptosis, and the caspase-3 is actived in apoptosis process and cleaving DEVD specifically. The dye is released and fluorescence recovered for imaging, which could be used to evaluate the chemotherapy efficiency. This project could offer some basic data on architecting the theranostic systems with sensitive polymers.

化疗药物的有效递送及对化疗效果的及时评估是肿瘤化疗的关键问题。针对此问题，本项目拟通过构建一种诊疗一体化纳米药物载体实现化疗药物的有效递送和早期化疗效果检测，提高化疗效果。用尿刊酸、硫辛酸改性葡聚糖，并将染料通过DEVD多肽和葡聚糖偶联，制得两亲性葡聚糖衍生物。利用金-硫键的相互作用和葡聚糖衍生物的两亲性自组装制备纳米载体，负载疏水性的化疗药物，金颗粒可通过FRET效应淬灭染料荧光，降低成像背景。纳米颗粒经ERP效应在肿瘤聚集后，通过尿刊酸的敏感性实现化疗药物的酸触发控释，引发细胞凋亡，实现药物的高效递送；早期治疗效果的检测则通过细胞凋亡过程激活caspase-3酶、切断DEVD片段、消除FRET效应实现。通过该项目的研究，提供一种构建新型智能诊疗一体化纳米载体的方法，实现对化疗药物的高效递送和早期治疗效果的精确检测，并为环境敏感高分子构建高效的诊疗一体化纳米体系提供有价值的基础研究结果。

化疗药物的有效递送及对化疗效果的及时评估是肿瘤化疗的关键问题。该项目拟提供一种构建新型智能诊疗一体化纳米载体的方法，实现对化疗药物的高效递送和早期治疗效果的精确检测。通过三年项目研究，我们成功制备了pH响应性双亲葡聚糖衍生物dextran-g-P(DPA-co-TIBMA)/K(Dabcyl)-DEVDGK(FAM)，并利用该衍生物制备了阿霉素负载纳米颗粒。该载药纳米颗粒可以有效的递送阿霉素和降低阿霉素的毒副作用，并可用于基于caspase-3的化疗效果监控。通过该项目的研究为利用葡聚糖构建诊疗一体化纳米体系提供了一些基础研究结果，为肿瘤的诊疗提供可靠的临床前数据。