新型自给氧基声动力治疗(SDT)增效剂用于改善胰腺癌乏氧环境以及SDT增效治疗机制研究

Abstract: Pancreatic cancer is one of those highly lethal, hard to tackle tumors with low survival rate, and conventional therapeutic protocols (surgery, chemotherapy, radiotherapy) inevitably encounter significant risks. Therefore, sonodynamic therapy (SDT) that features high efficiency and safety can act as a potential candidate that holds great promise in addressing the side-effects that these conventional methods cause. However, the hypoxia milieu severely limit the delivery and operation of SDT agents. To address this obstacle, fluorocarbon chains-modified hollow mesoporous silica nanoparticles (FHMSNs) that were successfully developed in previous work. In particular, they can be used to load sonosensitizers featuring NIR-infrared fluorescence imaging and perfluorohexane (PFH) capable of dissolving oxygen, respectively, ultimately constructing novel SDT enhancement agents, which holds the great promise to increase the probability of SDT and ultrasound/fluorescence imaging for pancreatic cancer. Confocal microscopy, flow cytometry, dissolved oxygen analyzer, electron spin resonance (ESR) analyzer, etc., will be employed to exploit ultrasound-excited PFH cavitation and quantify and comprehend the relation between dissolved O2, reactive oxygen species (ROS), cavitation dose and SDT outcomes for pancreatic cancer. ICP-AES, ultrasound contrast imaging and animal fluorescence imaging will be used to quantify the retention of SDT enhancement agents in pancreatic cancer and investigate how ultrasound and artificial cavitation nuclei break the limit of stroma barrier and how this self-produced oxygen supply ameliorates the hypoxia milieu and realize ultrasound/fluorescence dual-mode imaging. Furthermore, the principle of SDT will be evaluated and investigated via profile monitoring of tumor growth, pathological examination, molecular characterization, paving a new route to SDT for pancreatic cancer.

胰腺癌是一种恶性度高、易转移、生存率低的肿瘤，传统的手术、化疗等均存在极大的风险，高效、安全的SDT成为极具潜力的治疗手段，但胰腺癌乏氧环境极大地限制了SDT输运以及治疗。为克服这一限制，本项目以前期制得的氟碳改性的中空介孔氧化硅纳米颗粒为载体，分别担载具有近红外荧光成像功能的声敏剂和溶氧功能的液态全氟己烷（PFH），构建新型的SDT增效剂，有望为胰腺癌的SDT和超声/荧光双模式诊断提供可能。通过共聚焦、电子自旋共振（ESR）等手段考察超声激励PFH空化剂量、溶氧量、活性氧与SDT关系。通过ICP-AES、小动物荧光成像等评价SDT增效剂在胰腺癌中富集并研究超声联合人造空化核突破胰腺癌基质的机制；同时研究该自给氧方式在改善胰腺癌乏氧环境上的机制和实现超声/荧光双模式成像。进一步利用肿瘤生长曲线、分子生物学等手段研究胰腺癌SDT机制，为临床胰腺癌SDT诊断治疗研究提供新思路。

大多数实体瘤内部都存在乏氧，而乏氧与肿瘤的发生、发展、转移密切相关；更重要的是通过增加耐受性、减少活性氧（ROS）产率来影响ROS基抗肿瘤策略（如声动力治疗、光动力治疗）的疗效。因此，本项目的研究内容就是构建可减轻乏氧微环境的技术和材料，并研究其改善乏氧、增强ROS产率以及提高胰腺癌抗肿瘤疗效的机制。据此，我们合成了氟碳链改性的中空介孔氧化硅载体，并利用其介孔孔道以及氟碳链分别担载声敏剂和吸附氧气，得到一种自给氧声动力系统。在超声辐照下，该系统可连续释放氧气，逆转乏氧胰腺癌微环境，提供充足的原料产生ROS，同时解除乏氧诱导的治疗耐受性。此外，连续释放O2气泡产生空化效应也可增强ROS产量，进一步放大胰腺癌的声动力疗效；同时空化效应也可增强渗透性，促进更多颗粒进入到肿瘤内部，增强疗效。这些作用的累加，使得治疗剂在肿瘤中富集量提高7倍以上，治疗效果提高10倍以上。在此基础上，我们担载了一种NO供体，除了之前的改善肿瘤乏氧微环境以及提高ROS产率外，还可以产生NO，进一步提高协同抗肿瘤疗效，例如，将光动力抗乏氧乳腺癌治疗效果提高15倍以上。此外，我们在肿瘤靶向超声造影成像的基础研究、临床研究以及肿瘤特异性靶标检测方面也做出了一些成绩，除了提高信噪比、精准定位出肿瘤外，还可实现肿瘤病理可视化检测。这些成果的取得提高肿瘤精准治疗效率、安全性和有效性方面提供新的技术手段和理论基础。