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

<b>Rationale:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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). <b>Conclusion:</b> 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.