Design and in vivo characterization of kidney-targeting multimodal micelles for renal drug delivery

Autosomal-dominant polycystic kidney disease (ADPKD) affects up to 12 million individuals and is the fourth most common cause for renal replacement therapy worldwide. There have been many recent advances in the understanding of its molecular genetics and biology, and in the diagnosis and management of its manifestations. Yet, diagnosis, evaluation, prevention, and treatment vary widely and there are no broadly accepted practice guidelines. Barriers to translation of basic science breakthroughs to clinical care exist, with considerable heterogeneity across countries. The Kidney Disease: Improving Global Outcomes Controversies Conference on ADPKD brought together a panel of multidisciplinary clinical expertise and engaged patients to identify areas of consensus, gaps in knowledge, and research and health-care priorities related to diagnosis; monitoring of kidney disease progression; management of hypertension, renal function decline and complications; end-stage renal disease; extrarenal complications; and practical integrated patient support. These are summarized in this review.

The glomerular filtration barrier is known as a “size cut-off” slit to retain nanoparticles or proteins larger than 6~8 nm in the body, and to rapidly excrete the smaller ones through the kidneys. However, in a sub-nm size regime, we found that this barrier behaved as an atomically precise “bandpass” filter to significantly slow down renal clearance of few-atom gold nanoclusters (AuNCs) with the same surface ligands but different sizes (Au18, Au15 and Au10–11). Compared to Au25 (~1.0 nm), just few-atom decreases in the size resulted in 4~9 times reductions in the renal clearance efficiency in the early elimination stage because the smaller AuNCs were more readily trapped by the glomerular glycocalyx than the larger ones. This unique in vivo nano-bio interaction in the sub-nm regime also slows down the extravasation of sub-nm AuNCs from normal blood vessels and enhances their passive targeting to cancerous tissues through enhanced permeability and retention effect. This discovery highlights the size precision in the body’s response to nanoparticles and opens a new pathway to develop nanomedicines for many diseases associated with glycocalyx dysfunction.

Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves both fluid secretion and abnormal proliferation of cyst-lining epithelial cells. The chloride channel of the cystic fibrosis transmembrane conductance regulator (CFTR) participates in secretion of cyst fluid, and the mammalian target of rapamycin (mTOR) pathway may drive proliferation of cyst epithelial cells. CFTR and mTOR are both negatively regulated by AMP-activated protein kinase (AMPK). Metformin, a drug in wide clinical use, is a pharmacological activator of AMPK. We find that metformin stimulates AMPK, resulting in inhibition of both CFTR and the mTOR pathways. Metformin induces significant arrest of cystic growth in both in vitro and ex vivo models of renal cystogenesis. In addition, metformin administration produces a significant decrease in the cystic index in two mouse models of ADPKD. Our results suggest a possible role for AMPK activation in slowing renal cystogenesis as well as the potential for therapeutic application of metformin in the context of ADPKD.