Enzyme-activatable kidney-targeted dendrimer-drug conjugate for efficient childhood nephrotic syndrome therapy

作者：Danfei Chen, Junjun Xu, Sha Lv, Xiaoqin Jin, Yuyan Chen, Haifang Cai, Qili Wang, Xiaobo Xuan, Guowei Wang, Weidong Fei, Jian Chen · 发表于：Theranostics · 年份：2024 · DOI：10.7150/thno.101606 · 被引用次数：8 · 研究领域：Renal Diseases and Glomerulopathies、Amyloidosis: Diagnosis, Treatment, Outcomes、Pregnancy and Medication Impact

Rationale: 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.Methods: This study found that -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.Results: 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 -glutamyl transfer reactions of glutathione to generate positively charged primary amines.The resulting cationic conjugate rapidly underwent caveola-mediated endocyto...