Kidney-Targeted Drug Delivery Systems


The kidney has varying physiological and biochemical characteristics compared with other organs that need to be taken into account while designing a drug delivery system. CD Bioparticles offers comprehensive design, synthesis, and evaluation services for kidney-targeted drug delivery systems tailored to the renal cell type and extracellular matrix components of interest to produce highly targeted and high-purity drug delivery systems for customers to achieve the goal of high-level drug concentration at the kidney site, along with minimal systemic exposure.

Introduction to Kidney-Targeted Drug DeliverySystems

The kidneys play a crucial role in maintaining the body's fluid balance, electrolyte balance, and acid-base balance. They also help to remove waste products from the body and regulate blood pressure. Kidney-targeted drugs can help to improve kidney function and prevent or delay the onset of kidney disease. Developing kidney-targeted drugs is important for the treatment of important kidney diseases such as chronic kidney disease, glomerulonephritis, and diabetic nephropathy. These drugs specifically target the underlying mechanisms and pathways that lead to kidney damage or dysfunction. Kidney-targeted drugs can improve kidney function, slow the progression of kidney disease, and reduce the risk of complications such as cardiovascular disease. They can also reduce the need for dialysis or kidney transplant in end-stage kidney disease.

Kidney-specific drug delivery is generally aimed at hitting renal tubules, glomeruli or mesangial cells. The most promising drug delivery systems for kidney targeting are nanocarriers, drug carriers and prodrugs, such as liposomes, biodegradable macromolecules, and dendrimers.

The Specific Features of Kidney-Targeted Drug Delivery Systems:

The kidney has rich blood flow and is a target organ of many hormones and enzymes, suitable for targeted administration.

  • Drug carriers are biodegradable macromolecules, such as proteins, peptide derivatives or Fab fragments of antibodies with a range of molecular weights of < 30,000 kDa. Drugs are chemically conjugated to these carriers. Upon systemic administration, these carriers are filtered at the glomerulus and reabsorbed in the renal tubules, where the carrier is enzymatically cleaved and the drug is locally released.
  • Prodrugs can turn into an active form once they enter the kidney site, such as amino acid conjugates like glutamyl prodrugs exploit the high renal concentration of activating enzymes, such as glutamyl transpeptidase and decarboxylase enzymes, to selectively release active drugs in the kidney.
  • Kidney-targeted nanocarriers' size, shape, surface chemistry, charge, and especially molecular recognition moiety can affect the location, metabolism and clearance.

The Applications of Kidney-Targeted Drug Delivery Systems:

Here we present several developments in nanoparticles designed for kidney targeted delivery or approved by the FDA.

Table 1 Nanomedicines for kidney targeted drug deliver

Target Material Ingredient active References
Glomeruli PEG-modified liposome with desired size (110 nm) and octa-arginine (R8) coating Asiatic acid [1]
Tubules Mesoscale nanoparticles (MNPs) PLGA-PEG p38α MAPK and p65 siRNA [2]
Tubules Ceria nanoparticles modified with triphenylphosphine (TCeria NPs) and coated with ROS-responsive organic polymer Atorvastatin [3]
Tubules DNA-binding protein from
starved cells (Dps)
Dinuclear manganese (Mn) cluster [4]

Table 2 Nanomedicines approved by the FDA

Name Ingredient active Carrier Indication Date of Approval
INFeD® (Sanofi Avertis) Iron dextran (low MW) Iron Chronic kidney failure with iron deficiency FDA (1957)
DexIron®/Dexferrum® (Sanofi Avertis) Iron dextran (high MW) Iron Chronic kidney failure with iron deficiency FDA (1957)
Ferrlecit® (Sanofi Avertis) Sodium ferric gluconate Sodium ferric Chronic kidney failure with iron deficiency FDA (1999)
Venofer® (Luitpold Pharmaceuticals) Iron sucrose Iron oxide Chronic kidney failure with iron deficiency FDA (2000)
Feraheme™ (AMAG pharmaceuticals) Ferumoxytol SPION with polyglucose
sorbitol carboxymethylether
Ferumoxytol-ultrasmall superparamagnetic iron oxide nanopartilces
(SPION)
Chronic kidney failure with iron deficiency FDA (2009)
Renagel® (Sanofi) Polymer-based Nanoparticles sevelamer carbonate Hyperphosphatemia caused by chronic kidney disease (CKD) EMA (2001), FDA (2010)
Rapamune® (Wyeth Pharmaceuticals Inc. (a subsidiary of Pfizer Inc.)) Nanocrystal sirolimus (rapamycin) Prevents rejection of kidney transplants
(immunosuppressant)
FDA (2000)

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Parts of ligand types

Figure 1 Parts of ligand types

  • Design and synthesis: Regarding to the renal cell type and/or extracellular matrix components customers want to target, CD Bioparticles can provide you with one-stop drug delivery system design, synthesis and evaluation services.
  • Ligand conjugation: Modification of drugs, ingredient active or carriers with small-molecule ligand, protein ligand, peptide ligand, aptamer ligand, fluorescence labeling, etc.
  • Antibody conjugation: A variety of antibodies with different antigens can be provided with CD bioparticles to coat kidney-targeted drug delivery systems depending on our antibody platform.
  • Bioparticle characterization: Composition, size, geometry and/or shape, surface charge, surface chemistry, hydrophobicity, roughness, rigidity, etc.
  • Analysis in vitro and in vivo: Drug nephrotoxicity, drug efficacy, immunogenicity, metabolic level, drug aggregation, organ distribution, drug release ability, intrarenal localization studies, etc.

References:
1. He J, Chen H, Zhou W, Chen M, Yao Y, Zhang Z, Tan N: Kidney targeted delivery of asiatic acid using a FITC labeled renal tubular-targeting peptide modified PLGA-PEG system. Int J Pharm 2020, 584:119455.
2. Wang Y, Wu Q, Wang J, Li L, Sun X, Zhang Z, Zhang L: Co-delivery of p38alpha MAPK and p65 siRNA by novel liposomal glomerulus-targeting nano carriers for effective immunoglobulin a nephropathy treatment. J Control Release 2020, 320:457-468.
3. Yu H, Jin F, Liu D, Shu G, Wang X, Qi J, Sun M, Yang P, Jiang S, Ying X et al: ROS-responsive nano-drug delivery system combining mitochondria-targeting ceria nanoparticles with atorvastatin for acute kidney injury. Theranostics 2020, 10(5):2342-2357.
4. Uchida M, Maier B, Waghwani HK, Selivanovitch E, Pay SL, Avera J, Yun E, Sandoval RM, Molitoris BA, Zollman A et al: The archaeal Dps nanocage targets kidney proximal tubules via glomerular filtration. J Clin Invest 2019, 129(9):3941-3951.

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