LRP1-targeted carbon nanodots for crossing BBB and delivering small molecule or protein drugs into brain

血脑屏障（BBB）严重阻碍了神经胶质瘤和帕金森病（PD）等严重脑部疾病的治疗。克服血脑屏障并将药物靶向患病区域长期以来一直是有效治疗脑部疾病的一个具有挑战性的课题。基于纳米粒子的受体介导的靶向递送被认为是克服血脑屏障的重要策略。在当前的项目中，掺杂碳点（CD）将被开发为基本药物载体，因为先前已证明CD在靶向BBB穿越中作为成像探针的积极特性，其尺寸小（5-20​​ nm）方便，稳定性高，载药量高，并且适合光热治疗。将努力探索最佳CD的简便合成方法。将追求跨 BBB 的主动转胞吞作用的表面修饰。低密度脂蛋白受体相关蛋白 1 (LRP1) 是一种跨膜受体，不仅在 BBB 中高表达，而且在胶质瘤细胞和 PD 黑质 (SN) 黑化神经元中也高表达。在该项目中，基于最近通过噬菌体展示筛选技术获得的LRP1配体肽L57，LRP1结合肽配体将通过一系列技术进一步优化，包括设计代谢稳定的反映（D）肽、环化、甲基化或末端修饰的类似物，所有这些都将通过固相化学包括适当的连接分子来合成。 CD 将与通过亲水性聚乙二醇 (PEG) 连接体连接的 LRP1 配体肽 (LP) 缀合，并装载模型抗肿瘤药物阿霉素 (DOX) 或左旋多巴 (LD) 作为 PD 模型药物。此外，神经胶质细胞系衍生的神经营养因子（GDNF）将通过 CD 的新型脂胶束涂层作为 PD 模型蛋白药物进行测试。 CD-PEG-LP药物递送系统将在体外和体内进行系统评估。两种已建立的脑部疾病动物模型，神经胶质瘤和帕金森病，将用于评估大脑的药物输送机制以及药效学效果。相关结果将极大地促进转细胞 BBB 穿越纳米系统的发展，并为严重脑部疾病提供额外的治疗策略。

The blood-brain barrier (BBB) significantly hinders the treatment of severe brain disorders including glioma and Parkinson’s disease (PD). Overcoming the BBB and targeting drugs to diseased areas has for long been a challenging topic for efficient therapy of brain diseases. Nanoparticle-based receptor-mediated targeting delivery has been considered as an important strategy for overcoming the BBB. In the current project, doped carbon dots (CDs) will be developed as the basic drug carrier, because of previously demonstrated positive characteristics of CDs in targeted BBB crossing, as an imaging probe, their convenient small size of 5-20 nm, high stability and drug loading capacity, and suitability for photothermal therapy. Efforts will be made to explore facile synthesis methods of optimal CDs. Surface modification for active transcytosis across BBB will be pursued. Low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane receptor that is highly expressed not only in the BBB but also in glioma cells and in melanised neurons of the substantia nigra (SN) in PD. In this project, based on a recently described LRP1 ligand peptide L57 obtained by phage display screening technology, LRP1-binding peptide ligands will be further optimized by a series of technologies, including design of metabolically stabilized retro-enantio (D) peptides, cyclized, methylated, or end-modified analogs, which all will be synthesized via solid phase chemistry including appropriate linker molecules. CDs will be conjugated with LRP1 ligand peptides (LP) attached via hydrophilic polyethylene glycol (PEG) linkers and loaded with either the model anti-tumor drug doxorubicin (DOX), or levodopa (LD) as model drug for PD. Additionally, glial cell line-derived neurotrophic factor (GDNF) will be tested as model protein drug for PD by novel lipo-micellar coating of the CDs. The CD-PEG-LP drug delivery systems will be evaluated systematically in vitro and in vivo. Two established brain disorder animal models, glioma and PD, will be used to evaluate the drug delivery mechanisms to the brain and also the pharmacodynamic effect. Relating results will greatly promote the development of transcytotic BBB crossing nanosystems and provide additional therapeutic strategies for severe brain disorders.