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

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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.