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Efficient and selective kidney targeting by chemically modified carbohydrate conjugates.

Vikas Kumar1, Aniket Wahane1, Ming Shen Tham2

  • 1Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|November 12, 2024
PubMed
Summary

A novel renal tubule-targeting carbohydrate (RENTAC) selectively delivers therapeutics to kidney proximal tubules. This RENTAC ligand shows potential for broad clinical applications in treating kidney diseases.

Keywords:
RENTACacetylated lactobionic acidantisense oligonucleotidecubilinfibrosiskidney deliverymegalinmiR-33peptide nucleic acidproximal convoluted tubules

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Area of Science:

  • Biomaterials Science
  • Renal Physiology
  • Drug Delivery Systems

Background:

  • Targeted kidney drug delivery remains a challenge.
  • Proximal convoluted tubules are key sites for kidney function and disease.
  • Developing selective renal tubule-targeting agents is crucial for effective kidney disease treatment.

Purpose of the Study:

  • To develop and evaluate a renal tubule-targeting carbohydrate (RENTAC) for selective delivery to kidney proximal convoluted tubules.
  • To assess the efficacy of RENTAC conjugates in delivering therapeutic payloads, such as antisense peptide nucleic acids (PNAs), in a kidney fibrosis model.
  • To confirm the safety and targeting specificity of the RENTAC ligand.

Main Methods:

  • Synthesis and evaluation of RENTAC conjugates with anti-miR-21 and fluorophore payloads.
  • Assessment of RENTAC conjugate uptake in an immortalized kidney cell line, confirming megalin- and cubilin-dependent endocytosis.
  • In vivo biodistribution studies in mice to determine RENTAC conjugate retention and distribution.
  • Immunofluorescence staining to confirm selective localization in proximal convoluted tubules.
  • Evaluation of PNA 33-RENTAC conjugate efficacy in a folic acid-induced kidney fibrosis mouse model.

Main Results:

  • RENTAC conjugates demonstrated megalin- and cubilin-dependent endocytic uptake in kidney cells.
  • In vivo studies showed prolonged RENTAC conjugate retention in kidneys (several days) with selective distribution in proximal convoluted tubules.
  • Targeted delivery of PNA 33-RENTAC conjugates in a fibrotic kidney disease model led to slower fibrosis progression and reduced collagen deposition.
  • The RENTAC ligand did not induce adverse reactions, indicating a favorable safety profile.

Conclusions:

  • The RENTAC ligand enables selective targeting and delivery to kidney proximal convoluted tubules.
  • RENTAC conjugates are effective in delivering therapeutic nucleic acid analogs, as demonstrated by reduced fibrosis progression.
  • The RENTAC ligand holds significant promise for broad clinical applications in targeted kidney therapies.