Copper carbonate nanoparticles as an effective biomineralized carrier to load macromolecular drugs for multimodal therapy |
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| Affiliation: | 1. Changsha Medical University, Academician Workstation, Changsha 410219, China;2. Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China;3. State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Beijing 100850, China;4. Key Laboratory of Biological Nanotechnology of National Health Commission, Changsha 410000, China;1. Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China;2. Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Tarragona 43007, Spain;3. Dipartimento di Farmacia, Università degli Studi “G. D''Annunzio” Chieti-Pescara, Via dei Vestini, Chieti 66100, Italy;4. State key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210023, China;1. CAS Key Laboratory of Design and Assembly of Functional Nanostructures, and Fujian Provincial Key Laboratory of Nanomaterials, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China;2. University of Chinese Academy of Sciences, Beijing 100049, China;3. Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institutes, Chinese Academy of Sciences, Xiamen 361021, China;4. State Key Laboratory of Structure Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China;5. Fujian Science & Technology Innovation Laboratory for Optoelectronic Information of China, Fuzhou 350108, China;1. Key Laboratory of Functional Polymer Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China;2. School of Medicine, Nankai University, Tianjin 300071, China;3. Clinical College of Ophthalmology, Tianjin Medical University, Tianjin 300020, China;4. Tianjin Key Laboratory of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin Eye Hospital, Tianjin 300020, China;5. CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences and National Center for Nanoscience and Technology of China, Beijing 100190, China;1. College of Medical Imaging, Shanxi Medical University, Taiyuan 030001, China;2. College of Public Health, Shanxi Medical University, Taiyuan 030001, China;3. School of Basic Medical Science, Health Science Center, Xi''an Jiaotong University, Xi''an 710061, China;4. School of Public Health, Health Science Center, Xi''an Jiaotong University, Xi''an 710061, China;5. College of Chemistry and Life Science, Sichuan Provincial Key Laboratory for Structural Optimization and Application of Functional Molecules, Chengdu Normal University, Chengdu 611130, China;1. Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, Affiliated Dongguan Hospital, Southern Medical University, Dongguan 523058, China;2. Dongguan Institute of Clinical Cancer Research, Dongguan Key Laboratory of Precision Diagnosis and Treatment for Tumors, Affiliated Dongguan Hospital, Southern Medical University, Dongguan 523058, China;3. Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China;4. Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University (Foshan Maternity & Child Healthcare Hospital), Foshan 528000, China |
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| Abstract: | Macromolecular drugs have attracted great interest as biotherapy to cure previously untreatable diseases. For clinical translation, biomacromolecules encounter several common druggability difficulties, such as in vivo instability and poor penetration to cross physiologic barriers, thus requiring sophisticated systems for drug delivery. Inspired by the natural biomineralization via interaction between inorganic ions and biomacromolecules, herein we rationally screened biocompatible transition metals to biomineralize with carbonate for macromolecules loading. Among the metal ions, Cu2+ was found to be the best candidate, and its superiority over the widely studied Ca2+ minerals was also demonstrated. Capitalized on this finding, copper carbonate nanoparticles were prepared via a simple mixing process to co-load glucose oxidase (GOx) and a HIF-α DNAzyme (DZ), achieving ultra-high loading capacity of 61%. Upon encapsulation into nanoparticles, enzymatic activity of both drugs was passivated to avoid potential side-effects during circulation, while the drugs could be rapidly released within 1 h in response to acidic pH to fully recover their activities. The nanoparticles could accumulate into tumor via intravenous injection, facilitate the cell membrane penetration, and release the payloads of GOx, DZ and Cu2+ inside cells to exert a series of anti-tumor effects. GOx caused tumor starvation by catalytic glucose consumption, and the concomitantly generated H2O2 byproduct boosted the Cu2+-mediated chemodynamic therapy (CDT). Meanwhile, the DZ silenced HIF-α expression to sensitize both starvation therapy and CDT. As a result, a synergistic tumor growth inhibition was achieved. This work provides a simple method to prepare biomineralized nanoparticles, and offers a general approach for macromolecular drugs delivery via Cu2+-based biomineralization. |
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