Chen Danfei, Xu Junjun, Lv Sha, Jin Xiaoqin, Chen Yuyan, Cai Haifang, Wang Qili, Xuan Xiaobo, Wang Guowei, Fei Weidong, Chen Jian
Department of Pediatrics, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Zhejiang Chinese Medical University, Hangzhou 310006, China.
Department of Pharmacy, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China.
Theranostics. 2024 Oct 21;14(18):6991-7006. doi: 10.7150/thno.101606. eCollection 2024.
Childhood nephrotic syndrome (NS) is a serious disease affecting the health and quality of life of children, which is characterized by a series of pathophysiological changes due to the increased permeability of the glomerular membrane to plasma proteins. Low renal drug distribution and inefficient cellular uptake, resulting from cellular dysfunctions of filtration and internalization, are the main barriers to drug treatment in childhood NS, leading to deterioration in nephropathy. However, efficient therapeutic methods against childhood NS are still lacking in clinic. This study found that γ-glutamyltransferase (GGT) was highly expressed in the glomeruli of childhood NS in juvenile rats. We proposed GGT as the receptor target of the kidney-targeted drug delivery system, and then designed a GGT enzyme-responsive dendrimer-drug conjugate (GSHPD) as a kidney-targeted drug delivery platform for treating childhood NS. This platform could overcome the physiological and cellular uptake barriers of the kidney through receptor-mediated transcytosis. GSHPD was composed of glutathione-modified polyamidoamine dendrimers and conjugated with triptolide (TP). Once GSHPD was delivered to the glomerulus in nephropathy, the overexpressed GGT in the endothelial cells of the glomerular capillaries activated the γ-glutamyl transfer reactions of glutathione to generate positively charged primary amines. The resulting cationic conjugate rapidly underwent caveola-mediated endocytosis and exocytosis, augmenting its renal accumulation and cellular internalization. Active TP was gradually released by intracellular enzyme hydrolysis, enabling sustained therapeutic effects and resulting in significant recovery of renal physiological function (e.g., lowering the levels of urea nitrogen and serum creatinine, improving the levels of urinary creatinine and creatinine clearance rate, and inhibiting podocyte injury). The conjugate exhibited an excellent kidney-targeted distribution and a potent recovery of renal physiological function in NS of juvenile rats. This study presented a promising and active kidney-targeted drug delivery platform for efficient childhood nephropathy therapy.
儿童肾病综合征（NS）是一种影响儿童健康和生活质量的严重疾病，其特征是由于肾小球膜对血浆蛋白通透性增加而导致一系列病理生理变化。肾小球滤过和内化功能障碍导致肾脏药物分布低和细胞摄取效率低下，是儿童NS药物治疗的主要障碍，导致肾病恶化。然而，临床上仍缺乏针对儿童NS的有效治疗方法。本研究发现，γ-谷氨酰转移酶（GGT）在幼年大鼠儿童NS的肾小球中高表达。我们提出将GGT作为肾靶向药物递送系统的受体靶点，然后设计了一种GGT酶响应性树枝状聚合物-药物偶联物（GSHPD）作为治疗儿童NS的肾靶向药物递送平台。该平台可通过受体介导的转胞吞作用克服肾脏的生理和细胞摄取障碍。GSHPD由谷胱甘肽修饰的聚酰胺胺树枝状聚合物组成，并与雷公藤甲素（TP）偶联。一旦GSHPD被递送至肾病中的肾小球，肾小球毛细血管内皮细胞中过度表达的GGT会激活谷胱甘肽的γ-谷氨酰转移反应，生成带正电荷的伯胺。生成的阳离子偶联物迅速经历小窝介导的内吞作用和胞吐作用，增加其在肾脏的积累和细胞内化。活性TP通过细胞内酶水解逐渐释放，实现持续治疗效果，并导致肾脏生理功能显著恢复（例如，降低尿素氮和血清肌酐水平，提高尿肌酐水平和肌酐清除率，抑制足细胞损伤）。该偶联物在幼年大鼠NS中表现出优异的肾靶向分布和强大的肾脏生理功能恢复能力。本研究提出了一个有前景的、活跃的肾靶向药物递送平台，用于高效治疗儿童肾病。
