新型靶向αvβ3的近红外CuInS2/ZnS量子点荧光探针对胶质瘤可视化成像的研究

Due to the local invasive character of glioma , it is difficult to define intraoperative tumor margins as judged by subjective experience of the surgeons.Finally,recurrence of glioma frequently occurs due to invading residual cells. Recently, visualization of tumor has great prospects in detecting tumour margins and fluorescence-guided surgery.We have carried out first fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma in our country, and fluorescence-guided surgery increased the extent of tumor resection and improved survival. However, the application of fluorescence-guided surgery has been limited largely due to several of its physicochemical characteristics, such as low permeability for the blood-brain barrier、poor resistance to photobleaching、weak penetration into the tissue and lack of targeting specificity. Based on disadvantages of current fluorescent dyes and cadmium-based quantum dots，we will for the first time research glioma-targeted optical imaging using near-infrared non-cadmium quantum dots as fluorescent probes.we will construct near-infrared non-cadmium CuInS2/ZnS-RGD quantum dots as fluorescent probes for tumor targeting and define characterization、biological safety and pharmacokinetics of the fluorescent probe.In our further researches, we will investigate the characterization of specific visualization and the relationship with the tumor histological boundary. We will also define the role of convection-enhanced delivery on specific visualization of glioma. We will then reveal the molecular mechanisms of visual imaging in vitro、in vivo and tissues of patients with gliomas， The study will lay a good foundation for intraoperative tumor imaging and fluorescence-guided surgery.

因胶质瘤局部侵袭性生长特点，术者凭借主观经验很难准确判定肿瘤的边界，最终因肿瘤细胞残存而复发。近年来，肿瘤可视化成像在判定肿瘤边界、荧光引导手术方面展现出良好的发展前景。本课题组在国内首家开展了5-氨基乙酰丙酸诱导的荧光引导手术，提高了胶质瘤切除率和改善了预后， 但是，由于低的血脑屏障通过率、抗漂白能力差、可见光穿透能力弱及缺少靶向性等问题而限制了其应用。本课题是在目前荧光染料及含镉量子点存在无法规避的瓶颈问题基础上，首次研究无镉、近红外量子点作为荧光探针对胶质瘤的靶向可视化成像。本课题拟构建无镉、近红外CuInS2/ZnS-RGD荧光探针并明确该探针的表征、生物安全性及药代动力学；深入研究该探针靶向可视化成像特点及与肿瘤组织学边界的关系；明确加强对流给药对胶质瘤可视化成像的作用；揭示荧光探针在体外、体内及胶质瘤组织成像的分子机制，本研究将为术中肿瘤成像及荧光引导手术奠定良好的基础。

胶质瘤是中枢神经系统最为常见的原发性脑肿瘤，占原发恶性脑肿瘤的80%,目前最常用的治疗方法是手术治疗。由于胶质瘤的侵袭性，术中普通显微镜很难准确判定肿瘤的实际边界，继而影响肿瘤的切除程度，本课题组在国内率先开展荧光引导技术切除脑胶质瘤，取得了令人鼓舞的治疗效果，但仍存在特异性低、荧光强度不足等缺点。因此，研究高特异性、高组织穿透能力的荧光探针十分重要，该技术可以引导手术精确定位肿瘤与切除肿瘤，必将对胶质瘤治疗具有积极意义。本研究针对临床遇到的难题构建完成近红外线高特异性量子点QDs-RGD，检测该量子点的光谱特性及物理性质，本研究首次将为胶质瘤的荧光引导手术提供新的视角。.接下来，我们进行增强胶质瘤5-ALA荧光成像质量及光动力学治疗的研究，首次研究表明维生素D可以选择性地提高胶质瘤细胞荧光成像质量及改善光动力学治疗效果，这项研究成果有助于术中更加准确客观地判定肿瘤的实际边界，为改善荧光引导手术提供了新的方向，同时，本课题组也应用低剂量的砷剂提高胶质瘤细胞的荧光成像质量及光动力学治疗效果，该研究得到国际学者的认可并发表专栏给予高度评价。