Efficient and selective kidney targeting by chemically modified carbohydrate conjugates.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-11-12 DOI:10.1016/j.ymthe.2024.10.020
Vikas Kumar, Aniket Wahane, Ming Shen Tham, Stefan Somlo, Anisha Gupta, Raman Bahal
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引用次数: 0

Abstract

We investigated a renal tubule-targeting carbohydrate (RENTAC) that can selectively deliver small-molecule and nucleic acid analogs to the proximal convoluted tubules of the kidney following systemic delivery in mice. We comprehensively evaluated anti-miR-21-peptide nucleic acid-RENTAC, and fluorophore-RENTAC conjugates in cell culture and in vivo. We established that RENTAC conjugates showed megalin- and cubilin-dependent endocytic uptake in the immortalized kidney cell line. In vivo biodistribution studies confirmed the retention of RENTAC conjugates in the kidneys for several days compared with other organs. Immunofluorescence staining confirmed the selective distribution of the RENTAC conjugates in proximal convoluted tubules. We further demonstrated proximal convoluted tubule targeting features of RENTAC conjugates in a folic acid-induced kidney fibrosis mouse model. As a biological readout, we targeted miR-33 using antisense peptide nucleic acid (PNA) 33-RENTAC conjugates in the fibrotic kidney disease model. The targeted delivery of PNA 33-RENTAC resulted in slower fibrosis progression and decreased collagen deposition. We also confirmed that the RENTAC ligand did not exert any adverse reactions. Thus, we established that the RENTAC ligand can be used for broad clinical applications targeting the kidneys selectively.

通过化学修饰的碳水化合物共轭物高效、选择性地靶向肾脏。
我们研究了一种肾小管靶向碳水化合物(RENTAC),它能在小鼠全身给药后将小分子和核酸类似物选择性地输送到肾脏近端曲小管。我们在细胞培养和体内全面评估了抗 miR-21 肽核酸-RENTAC 和荧光团-RENTAC 结合物。我们发现,RENTAC 结合物在永生肾细胞系中显示出巨球蛋白和立方体蛋白依赖性内吞作用。体内生物分布研究证实,与其他器官相比,RENTAC共轭物可在肾脏中保留数天。免疫荧光染色证实了 RENTAC 结合物在近曲小管中的选择性分布。在叶酸诱导的肾脏纤维化小鼠模型中,我们进一步证实了 RENTAC 结合物的近端卷曲小管靶向特性。作为生物学读数,我们在纤维化肾病模型中使用反义肽核酸(PNA)33-RENTAC 结合物靶向 miR-33。PNA 33-RENTAC 的靶向递送减缓了纤维化进程,减少了胶原沉积。我们还证实,RENTAC 配体不会产生任何不良反应。因此,我们确定 RENTAC 配体可广泛应用于选择性靶向肾脏的临床治疗。
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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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