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

One in three Americans is at risk for developing chronic kidney disease (CKD) and end-stage renal disease (ESRD), leading to the need for dialysis or a kidney transplant. Small-molecule drugs have been proposed as therapies to manage kidney diseases, but high dosages are often required to achieve therapeutic efficacy, generating off-target side effects, some of which are lethal. To address these limitations, we developed a novel, kidney-targeting multimodal micelle (KM) system for drug delivery applications. Specifically, we incorporated the kidney-targeting peptide (Lysine-Lysine-Glutamic acid-Glutamic acid-Glutamic acid)3-Lysine) ((KKEEE)3K) into micelles. This peptide binds to megalin, a multi-ligand cell surface receptor present on renal tubule cells. When incubated with human kidney proximal tubule cells, KMs were found to be biocompatible in vitro. In vivo, KMs showed higher accumulation in the kidneys as compared to a non-targeted (NT) control upon intravenous injection in wild-type C57BL/6J mice. Histological evaluation showed no signs of tissue damage, while blood urea nitrogen (BUN) and creatinine levels were within normal ranges, validating the preservation of kidney health upon micelle administration. To our knowledge, this is the first utilization of (KKEEE)3K in a nanoparticle formulation, and our study offers strong evidence that this novel nanoparticle platform can be used as a candidate drug delivery carrier to direct therapeutics to diseased tissue in CKD.

[1]  Liddle's syndrome: Heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel , 1994, Cell.

[2]  Comparisons of the biodistribution and toxicological examinations after repeated intravenous administration of silver and gold nanoparticles in mice , 2017, Scientific Reports.

[3]  R. Day,et al.  Clinical Pharmacokinetics of Metformin , 2011, Clinical pharmacokinetics.

[4]  Christopher Poon,et al.  Self-assembled nanoscale coordination polymers with trigger release properties for effective anticancer therapy , 2014, Nature Communications.

[5]  M. Monsigny,et al.  Sugar-lectin interactions: how does wheat-germ agglutinin bind sialoglycoconjugates? , 1980, European journal of biochemistry.

[6]  E. Van Cutsem,et al.  Reversal of hepatorenal syndrome in four patients by peroral misoprostol (prostaglandin E1 analogue) and albumin administration. , 1990, Journal of hepatology.

[7]  Morris Schambelan,et al.  Liddle's syndrome: heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel , 1994, Cell.

[8]  M. Napimoga,et al.  Establishing Standards for Studying Renal Function in Mice through Measurements of Body Size-Adjusted Creatinine and Urea Levels , 2014, BioMed research international.

[9]  E. J. Chung,et al.  Theranostic Nanoparticles for Tracking and Monitoring Disease State , 2018, SLAS technology.

[10]  Jonathan Wang,et al.  Targeting cell adhesion molecules with nanoparticles using in vivo and flow-based in vitro models of atherosclerosis , 2017, Experimental biology and medicine.

[11]  Ying Cheng,et al.  Development, Optimization, and Characterization of PEGylated Nanoemulsion of Prostaglandin E1 for Long Circulation , 2016, AAPS PharmSciTech.

[12]  G. Germino,et al.  Murine Models of Polycystic Kidney Disease. , 2013, Drug discovery today. Disease mechanisms.

[13]  Matthew Tirrell,et al.  Structural properties of soluble peptide amphiphile micelles , 2011 .

[14]  John P. Johnson,et al.  Resveratrol Inhibits the Epithelial Sodium Channel via Phopshoinositides and AMP-Activated Protein Kinase in Kidney Collecting Duct Cells , 2013, PloS one.

[15]  Xun Sun,et al.  Kidney–targeted drug delivery systems , 2014, Acta pharmaceutica Sinica. B.

[16]  Matthew Tirrell,et al.  In vivo biodistribution and clearance of peptide amphiphile micelles. , 2015, Nanomedicine : nanotechnology, biology, and medicine.

[17]  Matthew Tirrell,et al.  Monocyte‐Targeting Supramolecular Micellar Assemblies: A Molecular Diagnostic Tool for Atherosclerosis , 2015, Advanced healthcare materials.

[18]  M. Caplan,et al.  The cell biology of polycystic kidney disease , 2010, The Journal of cell biology.

[19]  U. Engel,et al.  Lectin staining of renal tubules in normal kidney , 1997, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[20]  P. Choyke,et al.  Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. , 2008, Nanomedicine.

[21]  C. Bailey,et al.  Metformin and the gastrointestinal tract , 2016, Diabetologia.

[22]  Honggang Cui,et al.  Self‐assembly of peptide amphiphiles: From molecules to nanostructures to biomaterials , 2010, Biopolymers.

[23]  E. Bottinger,et al.  Utility of endogenous creatinine clearance as a measure of renal function in mice. , 2004, Kidney international.

[24]  F. Durand,et al.  Hepatorenal syndrome , 1996, Digestive Diseases and Sciences.

[25]  Matthew Tirrell,et al.  Recent Advances in Targeted, Self‐Assembling Nanoparticles to Address Vascular Damage Due to Atherosclerosis , 2015, Advanced healthcare materials.

[26]  S. Tan,et al.  Hepatitis C and kidney disease: An overview and approach to management. , 2015, World journal of hepatology.

[27]  P. Verroust,et al.  Megalin and cubilin--the story of two multipurpose receptors unfolds. , 2002, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[28]  Jonathan Wang,et al.  Peptide and antibody ligands for renal targeting: nanomedicine strategies for kidney disease. , 2017, Biomaterials science.

[29]  Mark E. Davis,et al.  Targeting kidney mesangium by nanoparticles of defined size , 2011, Proceedings of the National Academy of Sciences.

[30]  Xingya Jiang,et al.  Glomerular Barrier Behaves as an Atomically Precise Bandpass Filter in a Sub-nanometre Regime * , 2022, Nanomaterials and Neoplasms.

[31]  P. Choyke,et al.  Improving Conventional Enhanced Permeability and Retention (EPR) Effects; What Is the Appropriate Target? , 2013, Theranostics.

[32]  S. Somlo,et al.  Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis , 2011, Proceedings of the National Academy of Sciences.

[33]  J. Wendon,et al.  Renal dysfunction in chronic liver disease , 2010, Critical care.

[34]  Akihiro Tojo,et al.  Mechanisms of Glomerular Albumin Filtration and Tubular Reabsorption , 2012, International journal of nephrology.

[35]  M. Irazabal,et al.  Experimental therapies and ongoing clinical trials to slow down progression of ADPKD. , 2013, Current hypertension reviews.

[36]  M. Gross,et al.  Protein Mimetic and Anticancer Properties of Monocyte-Targeting Peptide Amphiphile Micelles. , 2017, ACS biomaterials science & engineering.

[37]  M. Arrese,et al.  Bile Acids and Portal Hypertension , 2017, Annals of hepatology.

[38]  B. Kasiske,et al.  Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. , 2015, Kidney international.

[39]  Matthew Tirrell,et al.  Self‐Assembled Peptide Amphiphile Micelles Containing a Cytotoxic T‐Cell Epitope Promote a Protective Immune Response In Vivo , 2012, Advanced materials.

[40]  N. Karabulut,et al.  Abdominal sarcoidosis: cross-sectional imaging findings. , 2015, Diagnostic and interventional radiology.

[41]  R. Kalluri,et al.  Determinants of Vascular Permeability in the Kidney Glomerulus* , 2002, The Journal of Biological Chemistry.

[42]  H. Holthofer.  Lectin binding sites in kidney. A comparative study of 14 animal species. , 1983 .

[43]  Xinxin Ma,et al.  Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials , 2017, BMC Nephrology.

[44]  U. Ravnskov,et al.  Glomerular, tubular and interstitial nephritis associated with non-steroidal antiinflammatory drugs. Evidence of a common mechanism. , 1999, British journal of clinical pharmacology.

[45]  U. Haberkorn,et al.  Renal Targeting: Peptide-Based Drug Delivery to Proximal Tubule Cells. , 2016, Bioconjugate chemistry.

[46]  U. Haberkorn,et al.  Drug Conjugation Affects Pharmacokinetics and Specificity of Kidney-Targeted Peptide Carriers. , 2016, Bioconjugate chemistry.

[47]  E. Douzinas,et al.  Acute renal dysfunction in liver diseases. , 2007, World journal of gastroenterology.

[48]  M. Bekheirnia,et al.  Developments in the management of autosomal dominant polycystic kidney disease , 2008, Therapeutics and clinical risk management.

[49]  A. Saito,et al.  The Endocytic Receptor Megalin and its Associated Proteins in Proximal Tubule Epithelial Cells , 2014, Membranes.

[50]  R. Jin,et al.  Glomerular Barrier Behaves As an Atomically Precise Bandpass Filter in a Sub-nanometer Regime , 2017, Nature nanotechnology.

[51]  D. Samuel,et al.  Changes in renal function in patients with familial amyloid polyneuropathy treated with orthotopic liver transplantation. , 2004, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[52]  Yu Cheng,et al.  Fibrin-binding, peptide amphiphile micelles for targeting glioblastoma☆ , 2013, Biomaterials.

[53]  T. Gonwa,et al.  Kidney disease in the setting of liver failure: core curriculum 2013. , 2013, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[54]  Matthew Tirrell,et al.  Fibrin-Targeting, Peptide Amphiphile Micelles as Contrast Agents for Molecular MRI , 2014 .

[55]  Christopher Poon,et al.  Gadolinium-Functionalized Peptide Amphiphile Micelles for Multimodal Imaging of Atherosclerotic Lesions , 2016, ACS omega.

[56]  Erkki Ruoslahti,et al.  Targeting atherosclerosis by using modular, multifunctional micelles , 2009, Proceedings of the National Academy of Sciences.