Adam C Midgley1,2, Yongzhen Wei3, Dashuai Zhu3, Fangli Gao3,2, Hongyu Yan3, Anila Khalique3,2, Wenya Luo3,2, Huan Jiang3, Xiangsheng Liu3,4, Jiasen Guo5, Chuangnian Zhang6, Guowei Feng7, Kai Wang3, Xueyuan Bai8,9, Wen Ning5, Chao Yang4, Qiang Zhao3, Deling Kong1,2,6. 1. Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China midgleyac@nankai.edu.cn kongdeling@nankai.edu.cn. 2. Rongxiang Xu Center for Regenerative Life Science, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China. 3. Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China. 4. Key Laboratory of Molecular Microbiology and Technology, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China. 5. Department of Genetics and Cellular Biology, College of Life Sciences, Nankai University, Tianjin, China. 6. Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. 7. Department of Genitourinary Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China. 8. Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, Beijing, China. 9. State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China.
Abstract
BACKGROUND: Progressive fibrosis is the underlying pathophysiological process of CKD, and targeted prevention or reversal of the profibrotic cell phenotype is an important goal in developing therapeutics for CKD. Nanoparticles offer new ways to deliver antifibrotic therapies to damaged tissues and resident cells to limit manifestation of the profibrotic phenotype. METHODS: We focused on delivering plasmid DNA expressing bone morphogenetic protein 7 (BMP7) or hepatocyte growth factor (HGF)-NK1 (HGF/NK1) by encapsulation within chitosan nanoparticles coated with hyaluronan, to safely administer multifunctional nanoparticles containing the plasmid DNA to the kidneys for localized and sustained expression of antifibrotic factors. We characterized and evaluated nanoparticles in vitro for biocompatibility and antifibrotic function. To assess antifibrotic activity in vivo, we used noninvasive delivery to unilateral ureteral obstruction mouse models of CKD. RESULTS: Synthesis of hyaluronan-coated chitosan nanoparticles containing plasmid DNA expressing either BMP7 or NGF/NKI resulted in consistently sized nanoparticles, which-following endocytosis driven by CD44+ cells-promoted cellular growth and inhibited fibrotic gene expression in vitro. Intravenous tail injection of these nanoparticles resulted in approximately 40%-45% of gene uptake in kidneys in vivo. The nanoparticles attenuated the development of fibrosis and rescued renal function in unilateral ureteral obstruction mouse models of CKD. Gene delivery of BMP7 reversed the progression of fibrosis and regenerated tubules, whereas delivery of HGF/NK1 halted CKD progression by eliminating collagen fiber deposition. CONCLUSIONS: Nanoparticle delivery of HGF/NK1 conveyed potent antifibrotic and proregenerative effects. Overall, this research provided the proof of concept on which to base future investigations for enhanced targeting and transfection of therapeutic genes to kidney tissues, and an avenue toward treatment of CKD.
BACKGROUND: Progressive fibrosis is the underlying pathophysiological process of CKD, and targeted prevention or reversal of the profibrotic cell phenotype is an important goal in developing therapeutics for CKD. Nanoparticles offer new ways to deliver antifibrotic therapies to damaged tissues and resident cells to limit manifestation of the profibrotic phenotype. METHODS: We focused on delivering plasmid DNA expressing bone morphogenetic protein 7 (BMP7) or hepatocyte growth factor (HGF)-NK1 (HGF/NK1) by encapsulation within chitosan nanoparticles coated with hyaluronan, to safely administer multifunctional nanoparticles containing the plasmid DNA to the kidneys for localized and sustained expression of antifibrotic factors. We characterized and evaluated nanoparticles in vitro for biocompatibility and antifibrotic function. To assess antifibrotic activity in vivo, we used noninvasive delivery to unilateral ureteral obstructionmouse models of CKD. RESULTS: Synthesis of hyaluronan-coated chitosan nanoparticles containing plasmid DNA expressing either BMP7 or NGF/NKI resulted in consistently sized nanoparticles, which-following endocytosis driven by CD44+ cells-promoted cellular growth and inhibited fibrotic gene expression in vitro. Intravenous tail injection of these nanoparticles resulted in approximately 40%-45% of gene uptake in kidneys in vivo. The nanoparticles attenuated the development of fibrosis and rescued renal function in unilateral ureteral obstructionmouse models of CKD. Gene delivery of BMP7 reversed the progression of fibrosis and regenerated tubules, whereas delivery of HGF/NK1 halted CKD progression by eliminating collagen fiber deposition. CONCLUSIONS: Nanoparticle delivery of HGF/NK1 conveyed potent antifibrotic and proregenerative effects. Overall, this research provided the proof of concept on which to base future investigations for enhanced targeting and transfection of therapeutic genes to kidney tissues, and an avenue toward treatment of CKD.
Authors: Yafeng Song; Leon Morales; Alock S Malik; Andrew F Mead; Christopher D Greer; Marilyn A Mitchell; Mihail T Petrov; Leonard T Su; Margaret E Choi; Shira T Rosenblum; Xiangping Lu; Daniel J VanBelzen; Ranjith K Krishnankutty; Frederick J Balzer; Emanuele Loro; Robert French; Kathleen J Propert; Shangzhen Zhou; Benjamin W Kozyak; Peter P Nghiem; Tejvir S Khurana; Joe N Kornegay; Hansell H Stedman Journal: Nat Med Date: 2019-10-07 Impact factor: 53.440
Authors: Michael Zeisberg; Cindy Bottiglio; Navin Kumar; Yohei Maeshima; Frank Strutz; Gerhard A Müller; Raghu Kalluri Journal: Am J Physiol Renal Physiol Date: 2003-08-12