金纳米材料复合微气泡分子探针的构建及用于肿瘤超声/光声成像与治疗的方法研究

The accurately and efficiently targeted delivery of therapeutic/ diagnostic agents into tumor areas in a controllable fashion remains a big challenge. Herein, a novel cancer targeting gold-nanobubbles is elaborately fabricated. Firstly, the gold nanomaterials are optimized to chemically conjugate on the surface of polymer microbubbles. Then, Arginine-Glycine-Aspartic acid (RGD) is precisely conjugated with gold nanomaterials of microbubbles to construct RGD molecularly targeted gold- nanobubble. Based on the study of the molecular probe enhanced ultrasound and photoacoustic imaging, the mechanism of the double mode imaging enhancement of the gold-nanobubbles probe is discussed in depth, and it also provides an effective way to solve the contradiction between the particle size of ultrasound contrast agent and the ability of ultrasonic enhancement. The ability of the probe to bind to the tumor cells and the killing effect of the tumor cells under laser irradiation will also be studied. The experimental study of ultrasound / photoacoustic imaging in tumor bearing animals, as well as targeting and inhibiting tumor effects will be carried out to evaluate the clinical application of the gold-nanobubbles probe.

将多模态造影剂与诊疗一体化分子探针相耦合，可构建出功能强大，综合了多模态成像、分子成像、主动精准靶向与治疗、及各种能量场介导下的生物协同效应等有效手段的探针平台，全方位地为微小肿瘤的诊疗服务。本项目是将纳米尺度的超声造影剂微气泡与金纳米材料结合起来，并在其表面修饰靶向因子RGD，构建出多模态多功能纳米金复合微气泡分子探针。通过研究外源激光响应下探针增强超声和光声成像的情况，深入探讨其双模态成像协同增强机制，同时也为有效解决超声造影剂粒径与超声增强能力之间的矛盾提供了思路；通过细胞实验考察纳米金复合微气泡分子探针靶向结合肿瘤细胞的能力及激光介导下对肿瘤细胞的杀伤作用；通过荷瘤动物体内超声/光声成像实验，及靶向并抑制肿瘤效果实验，综合分析该探针的临床应用前景。

本课题是将纳米尺度的超声造影剂微气泡与金纳米颗粒结合起来，聚焦于建立一个金纳米材料复合微纳气泡的小尺寸、智能化的通用性多功能诊疗平台，这个平台有与其它多种载体材料、靶向分子、治疗药物偶联的潜力，可发展为应用领域广泛的诊疗系统。.首先，从小型化和智能化两个方面对纳米金-气泡复合材料进行设计、制备和优化，得到了初始尺度为纳米量级、可随温度变化进行粒径调控，从而在外源激光介导下具有超声显影增强能力和良好光热效应的诊疗一体化复合材料，这一复合材料的设计也为有效解决超声造影剂粒径与超声增强能力之间的矛盾提供了思路。对复合材料在超声诊断和光热治疗两方面的应用潜力进行了体外评估，此外还将这种金纳米材料复合微纳气泡与水凝胶结合，借助微纳气泡激光/温度控制下的粒径变化特性，实现了对水凝胶结构和浮力的智能调控。发现复合水凝胶可灵敏响应激光/温度信号，内部结构和浮力改变明显。且可通过调节气泡的膜材、金的装载量、气泡的浓度，对水凝胶的智能响应能力进行调控。这为智能调控型水凝胶的研究提供了研究思路和一定的研究基础。