新型超声-光声双模态分子探针用于多重协同增效诊治恶性肿瘤的实验研究

Integration of tumor diagnosis and therapy using ultrasound and microbubbles (MBs) is one of the research focuses in ultrasound medicine. However, the shortage of MBs, including short duration and low drug loading capacity, limited their further applications. On the basis of the previous studies, novel cRGD (targeting to tumor neovasculature) decorated nanobubbles, which encapsulating ICG and PTX, will be designed as an ultrasound-photoacoustic dual-modality molecular probe in this program (cRGD-ICG/PTX-NBs). Taking advantage of the probe, tumor molecular diagnosis will be carried out by molecular ultrasound imaging technology (with low power ultrasound irradiation). Meanwhile, ICG and PTX will be delivered and accumulate in tumor tissue after ultrasound applied, resulting in enhanced photoacoustic imaging effect for drug monitoring. After tumor diagnosis, high power ultrasound will be apply in tumor region to amplify the photothermal effect by disrupting tumor neovasculature. During this procedure, complemented tumor diagnostic effect will be achieved from molecular ultrasound imaging and photoacoustic imaging. At the same time, synergistic therapeutic effect of tumor will be detected from the enhanced photothermal therapy and drug delivery. This program will realize multiple-enhancing effect for tumor diagnosis and therapy by calling into fullplay of ultrasonic technology. This novel ultrasound-photoacoustic dual-modality molecular probe exhibits a great potential to promote the application of ultrasound in tumor theranositc progress.

超声联合多功能微泡（MBs）超声造影剂实现肿瘤诊疗一体化是超声医学基础研究的热点。但MBs本身存在成像时间短、载药效能低的缺陷，肿瘤诊断及治疗效能均较低。本项目拟在前期研究基础上，制备以多肽cRGD（靶向于肿瘤新生血管的整合素）修饰、负载光声对比剂吲哚菁绿（ICG）和抗癌药物紫杉醇（PTX）的纳米微泡（NBs）作为超声-光声双模态分子探针（cRGD-ICG/PTX-NBs）。利用该探针通过超声分子成像技术（低能量超声辐照）对恶性肿瘤进行分子诊断，同时促进ICG、PTX向肿瘤组织递送聚集，增强光声成像的药物示踪效果；随后以超声空化技术（高能量超声辐照）毁损血管，增强光热治疗的效果。在此过程中，超声分子成像与光声成像的肿瘤诊断效能协同互补，光热治疗与药物治疗效能协同增效。本研究通过充分发挥超声的优势来实现肿瘤诊疗的多重协同增效，为推动超声技术在肿瘤诊疗一体化的应用提供有效的临床前实验依据。

针对微泡（micro bubbles，MBs）超声造影剂存在半衰期短、载药效能低的缺陷，导致MBs联合超声在肿瘤诊断和治疗上应用受限的问题。本项目制备了负载吲哚菁绿（Indocyanine green，ICG）并以肿瘤新生血管靶向多肽cRGD修饰的MBs（cRGD-ICG-MBs）。利用诊断超声对肿瘤进行超声分子成像诊断，以光声成像技术对ICG进行肿瘤定位监测；以低频低能量超声击破MBs使ICG在肿瘤释放并聚集；再以低频高能量超声联合微泡毁损肿瘤血管，阻断肿瘤血供；最后以激光辐照肿瘤进行光热治疗。通过低能量超声促进ICG局部聚集和高能量超声阻断血流“热沉效应”，实现肿瘤光热治疗的多次协同增效。此外，本项目还对靶向MBs的制备方法和应用进行系列研究，提出硫醇-马来酰亚胺法制备靶向MBs的新工艺。同时对超声分子成像的定量方法进行改良和验证。本项目的顺利开展，充分以超声、激光技术的优势，弥补MBs自身的不足，使结构简单的靶向载药MBs实现多重协同增效的诊疗一体，为推动超声分子影像及超声诊疗向临床转化提供实验依据。