CTX修饰树状大分子构建胶质瘤靶向递药系统及分子影像研究

Chlorotoxin (CTX), a small peptide refined from the venom of the scorpion Leiurus quinquestriatus, has been identified as a targeting ligand to specifically bind to glioma, therefore, CTX-conjugated nanoparticles hold great potential for imaging and therapy of gliomas. In our previous work, 131I-labeled CTX-modified dendrimer nanoparticles (131I-PAMAM-CTX) had been developed for targeted glioma SPECT imaging and radiotherapy. The results of SPECT imaging experiments revealed that the 131I-PAMAM-CTX could observably accumulate in the tumor. The growth of tumor was inhibited and the lifetime of the tumor-bearing mice could be greatly prolonged after the treatment with 131I-PAMAM-CTX. However, the resolution and antitumor effect of 131I are limited. Subsequently, we designed 99mTc-labeled multifunctional dendrimers for targeted SPECT imaging of tumors, built the orthotopic brain tumor xenografts in rats and proved that 99mTc-PAMAM-CTX can pass the BBB and accumulate in tumors. Moreover, we also synthesized doxorubicin (DOX) encapsulated dendrimers for targeted anticancer drug delivery to tumors. In this project, based on our previous studies, we propose to develop CTX and DOX loaded multifunctional dendrimers for glioma targeted drug delivery, and evaluate the specific therapeutic efficacy to cancer cells in vitro and a subcutaneous tumor model in vivo. The multifunctional dendrimers can be further labeled with 99mTc to enable the visualization of targeted drug delivery, which will provide a novel strategy for therapy monitoring of gliomas.

氯毒素CTX是从以色列金蝎毒液中提纯的小分子多肽，能够通过血脑屏障与胶质瘤细胞结合，因此CTX修饰的纳米材料具有显示和治疗胶质瘤的潜力。申请人前期完成了131I标记CTX修饰的树状大分子靶向显像和治疗胶质瘤研究，显像结果表明皮下胶质瘤组织中放射性明显浓聚，体内靶向性良好；治疗实验表明皮下胶质瘤的生长明显被抑制，有效延长荷瘤鼠生存期。然而131I核素显像分辨率不足，治疗效果欠佳。随后申请人发现99mTc标记的树状大分子可实现肿瘤SPECT显像，并建立颅内原位胶质瘤大鼠模型，初步证实CTX修饰的树状大分子能够通过血脑屏障显示胶质瘤位置；树状大分子内部包裹阿霉素可构建肿瘤靶向递药系统，增强肿瘤治疗效果。因此本项目拟以树状大分子为载体，表面修饰CTX，内部包裹阿霉素，标记99mTc后构建一种新型多功能纳米探针，研究其在胶质瘤可视化靶向递药中的价值，为胶质瘤疗效监测提供新方法。

脑胶质瘤是目前颅内发病率和死亡率最高的原发性肿瘤，由于具有侵袭性强和浸润性生长的特点，常常导致肿瘤与周围正常组织分界不清，而常规的CT和MRI技术等不能准确评估肿瘤范围，造成手术治疗效果不佳，术后极易复发。此外，由于血脑屏障的存在，绝大部分抗肿瘤药物难以到达颅内病灶，因此脑胶质瘤的治疗一直是临床难点。氯毒素(CTX)是从蝎毒中分离的小分子多肽，可以通过血脑屏障特异性与胶质瘤细胞，已作为靶向多肽构建多种体系用于胶质瘤显像和治疗。本项目以CTX多肽为胶质瘤靶向分子，修饰在聚乙烯亚胺（PEI）树状大分子表面，并在PEI内部包裹化疗药物DOX，表面标记放射性核素99mTc，构建一种新型分子探针mPEI-CTX-99mTc/DOX，能够通过血脑屏障靶向胶质瘤细胞，实现药物递送和SPECT显像。制备的mPEI-CTX/DOX靶向递药系统以pH敏感的方式释放DOX，在体外细胞实验和皮下胶质瘤模型中均展示良好的靶向性和治疗效果。由于CTX独特的生物学特性，mPEI-CTX/DOX靶向递药系统能够穿过血脑屏障并在脑肿瘤区域积聚，并经99mTc放射标记后可通过SPECT实时观察到肿瘤的积聚。这种基于PEI树状大分子构建的体系不仅展示了一种潜在的药物策略，通过靶向多肽修饰来克服血脑屏障的困难，而且还提供了一种有潜力的方法来发展其它影像引导的药物传递系统，用于不同类型的癌症。此外，本项目在小分子多肽构建核医学分子探针方面开了一些研究，初步发现99mTc标记LyP-1多肽和PTP多肽在肿瘤SPECT显像方面具有潜力，研究团队后续将重点围着这两个小分子多肽，在取得相应的临床前评估后，开展进一步临床试验，争取实现临床转化。受本项目资助，项目成员发表相关SCI论文11篇，中文论著3篇，培养博士生2名，硕士生1名。

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