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

• Applicant: Professor Dr. Ernst Wagner
• Subject Area: Pharmacy ; Biomaterials
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 410149116

• Final Report Year: 2023

Final Report Abstract

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 NSFC – DFG Joint Sino-German Research Project, the Chinese project partners developed new carbon dots (CDs) as drug carriers, which demonstrated positive characteristics in targeted BBB crossing, as an imaging probe, their convenient small size of 5-20 nm, high stability and suitability for photothermal therapy. Surface modification for active transcytosis across BBB were pursued. Transferrin receptor (TfR) is a transmembrane receptor highly expressed in the BBB and in glioma cells. Low-density lipoprotein receptor-related protein 1 (LRP1) is another transmembrane receptor that is highly expressed not only in the BBB but also in glioma cells and in melanized neurons of the substantia nigra (SN) in PD. The German project partner successfully evaluated a recently described retro-enantio ligand peptide reTfR for TfR mediated delivery of nanoparticles. A recently described ligand peptide L57 and its novel retro-enantio version reL57 was applied for LRP1 targeting. CDs obtained from the Chinese project partners were surface-modified with PEG and receptor ligands using a novel caging technology. LRP1 receptor-targeted uptake of CDs was successfully demonstrated in cell culture and reagents were provided to the Chinese project partners for further testing. Material shipments and synchronization of joint work packages were highly challenging in COVID times due to quarantines and differing lock-down periods.

Publications

• Biodegradable Mesoporous Silica Achieved via Carbon Nanodots-Incorporated Framework Swelling for Debris-Mediated Photothermal Synergistic Immunotherapy. Nano Letters, 19(12), 8409-8417.
  Qian, Min; Chen, Leilei; Du, Yilin; Jiang, Huiling; Huo, Taotao; Yang, Yafeng; Guo, Wei; Wang, Yi & Huang, Rongqin
  
• Non‐viral nucleic acid delivery to the central nervous system and brain tumors. The Journal of Gene Medicine, 21(7).
  Wang, Shanshan & Huang, Rongqin
  
• Multifunctional mesoporous black phosphorus-based nanosheet for enhanced tumor-targeted combined therapy with biodegradation-mediated metastasis inhibition. Biomaterials, 236, 119770.
  Chen, Leilei; Qian, Min; Jiang, Huiling; Zhou, Yiwei; Du, Yilin; Yang, Yafeng; Huo, Taotao; Huang, Rongqin & Wang, Yi
  
• Multimodal theranostics augmented by transmembrane polymer-sealed nano-enzymatic porous MoS2 nanoflowers. International Journal of Pharmaceutics, 586, 119606.
  Jiang, Huiling; Du, Yilin; Chen, Leilei; Qian, Min; Yang, Yafeng; Huo, Taotao; Yan, Xueying; Ye, Tao; Han, Bing; Wang, Yi & Huang, Rongqin
  
• Polymer-Based Tumor-targeted Nanosystems. New Nanomaterials and Techniques for Tumor-targeted Systems, 371-411. Springer Singapore.
  Benli-Hoppe, Teoman & Wagner, Ernst
  
• Versatile hollow COF nanospheres via manipulating transferrin corona for precise glioma-targeted drug delivery. Biomaterials, 260, 120305.
  Huo, Taotao; Yang, Yafeng; Qian, Min; Jiang, Huiling; Du, Yilin; Zhang, Xiaoyi; Xie, Yibo & Huang, Rongqin
  
• Carriers for Nucleic Acid Delivery to the Brain. Nanoparticles for Brain Drug Delivery, 289-316. Jenny Stanford Publishing.
  Reinhard, Sören & Wagner, Ernst
  
• Sugar-originated carbon nanodots selectively damage the tumor and enhance the sensitivity of chemotherapy. Nano Today, 38, 101200.
  Wang, Yi; Huo, Taotao; Jiang, Huiling; Xie, Yibo; Zhang, Xiaoyi; Nie, Huifang; Yang, Yafeng; Qian, Min; Li, Wenshuai; Hao, Tingting; Guo, Wei; Qin, Yanhui; Shi, Jinlong; Shi, Wei & Huang, Rongqin
  
• Transferrin Receptor Targeted Polyplexes Completely Comprised of Sequence‐Defined Components. Macromolecular Rapid Communications, 43(12).
  Benli‐Hoppe, Teoman; Göl, Öztürk Şurhan; Öztürk, Özgür; Berger, Simone; Wagner, Ernst & Yazdi, Mina
  
• Ultra-small MoS2 nanodots-incorporated mesoporous silica nanospheres for pH-sensitive drug delivery and CT imaging. Journal of Materials Science & Technology, 63, 91-96.
  Chen, Leilei; Xu, Jun; Wang, Yi & Huang, Rongqin
  
• Dual EGFR- and TfR-targeted gene transfer for sodium iodide symporter gene therapy of glioblastoma. Molecular Therapy - Oncolytics, 27, 272-287.
  Spellerberg, Rebekka; Benli-Hoppe, Teoman; Kitzberger, Carolin; Hageneier, Mara; Schwenk, Nathalie; Öztürk, Özgür; Steiger, Katja; Multhoff, Gabriele; Eiber, Matthias; Schilling, Franz; Weber, Wolfgang A.; Kälin, Roland E.; Glass, Rainer; Nelson, Peter J.; Wagner, Ernst & Spitzweg, Christine
  
• Mitochondrial Dysfunction and Antioxidation Dyshomeostasis-Enhanced Tumor Starvation Synergistic Chemotherapy Achieved using a Metal–Organic Framework-Based Nano-Enzyme Reactor. ACS Applied Materials & Interfaces, 14(3), 3675-3684.
  Huo, Taotao; Leilei, chen NA; Nie, Huifang; Li, Wenshuai; Lin, Chenteng; Akhtar, Muhammad & Huang, Rongqin
  
• Tumor-Targeted Fluorescence Imaging and Mechanisms of Tumor Cell-Derived Carbon Nanodots. Pharmaceutics, 14(1), 193.
  Huo, Taotao; Li, Wenshuai; Liang, Dong & Huang, Rongqin
  
• Tumor‐Selective Biodegradation‐Regulated Photothermal H2S Donor for Redox Dyshomeostasis‐ and Glycolysis Disorder‐Enhanced Theranostics. Small, 18(8).
  Wang, Yi; Qian, Min; Du, Yilin; Zhou, Jianglu; Huo, Taotao; Guo, Wei; Akhtar, Muhammad & Huang, Rongqin