超声响应相变型脂质体用于增效乏氧特异性前药治疗肿瘤的实验研究

As one of the reasons leading to treatment failure of solid tumors, hypoxia has already become an important target in cancer therapy. Among these, hypoxia-activated prodrugs: Tirapazamine (TPZ) which display high cytotoxicity under low-oxygen conditions have gained great passions. However, due to the uneven distribution of oxygen and the limited penetration depth of nanoparticles causing by the dense matrix and high interstitial fluid pressure at tumor region, the hypoxia-dependent TPZ alone is usually ineffective. Herein, we intend to design ultrasound-responsive nanoliposomes （LIP-PpIX-TPZ@PFP） encapsulating sonosensitizer (PpIX), perfluoropentane (PFP) and TPZ to address these issues. Under the ultrasound irradiation, each component of LIP-PpIX-TPZ@PFP could play different roles at different regions of tumor: at the oxygen-rich region, sonosensitizer (PpIX) could be activated and depleted oxygen to produce reactive oxygen species, inducing the activation of TPZ; as for the hypoxia region far from vessels, the violent mechanical force caused by vaporization of PFP could directly induce tissue erosion and vascular disruption. The break of tumor microenvironment barriers facilitates TPZ to penetrate into interstitial tissue and attack the hypoxic cells that are distant from the vessels. Additionally, PFP vaporization could enhance ultrasound contrast imaging and thus realize the real-time monitoring of therapeutic process by ultrasound imaging. As a result, the ultrasound mediated synergism of hypoxia-activated prodrugs would provide a new strategy for tumor treatment.

乏氧是造成恶性实体瘤治疗失败的重要原因之一，已经成为肿瘤治疗的热门靶点。其中可在乏氧条件下特异性激活的前药替拉扎明（TPZ），得到了广泛的关注。但是TPZ单用抑瘤效果欠佳，这与肿瘤内氧气分布不均及TPZ渗透深度受限有关。为增效TPZ，本课题设计载有声敏剂（PpIX）、全氟戊烷（PFP）和TPZ的脂质复合体（LIP-PpIX-TPZ@PFP），利用其声响应特性，使其在超声辐照后，各复合物在近血管区域（氧含量较高）及远离血管区域（氧含量较低）均可发挥作用：PpIX可在近血管区域生成活性氧，从而消耗该区域的氧气而激活TPZ；PFP在超声触发下发生液-气相变，产生的机械力破坏肿瘤间质和血管，从而促进TPZ的穿透深度而作用于远离血管的乏氧细胞。PFP气化后显著增强超声信号，使该治疗过程可在超声显影下实施动态监测。综上所述，该声响应体系的开发旨在利用超声的生物学效应增效TPZ，为肿瘤治疗提供新策略。

本研究利用超声的生物学效应用于三阴性乳腺癌的诊疗及预后判断，主要包括一下2个方面：1.本研究成功制备超声响应相变型聚乳酸-羟基乙酸共聚物（PLGA）纳米液滴（PTP@PLGA），该液滴载有声敏剂（PpIX）、全氟戊烷（PFP）和乏氧激活前药替拉扎明（TPZ），利用超声的机械效应及化学声动力效应调控肿瘤微环境增效TPZ。在超声辐照下，PFP相变的空化效应增强超声的机械作用，破坏肿瘤微环境中的纤维基质促进纳米液滴的穿透深度，使TPZ能作用于远离血管的乏氧细胞；同时PpIX介导的声动力效应可消耗近血管区域的氧气，恶化乏氧微环境从而激活TPZ。多种效应协调取得较好的乳腺癌治疗效果。2.本研究通过收集636例三阴性乳腺癌患者的临床及超声图片信息，分析研究超声图片特征与三阴性乳腺癌预后的关系。结果显示，高腋窝淋巴结负荷、无辅助化疗及多个超声恶性特征与三阴性乳腺癌不良预后有关，并成功构建列线图预测模型用于预测1、3、5年的无病生存期。