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

血脑屏障(BBB)严重阻碍了包括胶质瘤和帕金森病(PD)在内的严重脑部疾病的治疗。长期以来，克服血脑屏障并将药物靶向疾病区域一直是脑部疾病有效治疗的一个具有挑战性的课题。基于纳米颗粒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。在本项目中，掺杂碳点(CDS)将被开发为基本的药物载体，因为CDS在靶向BBB交叉中表现出积极的特性，作为一种成像探针，其方便的小尺寸为5-20 nm，高的稳定性和载药量，以及适合于光热治疗。将努力探索优化的硫化镉的简便合成方法。积极的跨血脑屏障的细胞穿透的表面修饰将被寻求。低密度脂蛋白受体相关蛋白1(LRP1)是一种跨膜受体，不仅在血脑屏障中高表达，而且在PD的胶质瘤细胞和黑质黑质黑化神经元中也有高表达。在本项目中，基于最近通过噬菌体展示技术获得的LRP1配体多肽L57，将通过一系列技术进一步优化LRP1结合多肽配体，包括设计代谢稳定的逆转(D)多肽，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合成，包括适当的连接体分子。CDS将与LRP1配体多肽(LP)通过亲水性聚乙二醇链联结在一起，并负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，胶质细胞源性神经营养因子(GDNF)将作为治疗帕金森病的模型蛋白药物，通过新型的CDS脂胶束涂层进行测试。CD-PEG-LP给药系统将在体内外进行系统的评价。两个已建立的脑功能障碍动物模型，胶质瘤和帕金森病，将被用来评估药物对大脑的传递机制和药效学效应。相关结果将极大地促进跨细胞血脑屏障交叉纳米系统的发展，并为严重的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.