Kidney-targeted drug delivery via rhein-loaded polyethyleneglycol- co-polycaprolactone- co-polyethylenimine nanoparticles for diabetic nephropathy therapy

Int J Nanomedicine. 2018 Jun 19:13:3507-3527. doi: 10.2147/IJN.S166445. eCollection 2018.

Abstract

Introduction: Diabetic nephropathy (DN) is the primary root of morbidity and mortality in diabetic patients. Unfortunately, currently, no effective therapeutic strategies are available to ameliorate and reverse the progression of DN. Rhein (RH) is an anthraquinone derivative extracted from herbal medicines with various pharmacological effects on DN. However, its clinical administration is limited by its poor solubility, low bioavailability, reduced distribution into the kidney and adverse effects.

Methods and results: To improve the delivery of RH into kidney and the therapeutic effect on DN, we synthesized and utilized polyethyleneglycol-co-polycaprolactone-co-polyethylenimine triblock amphiphilic polymers to prepare RH-loaded polyethyleneglycol-co-polycaprolactone-co-polyethylenimine nanoparticles (PPP-RH-NPs). PPP-RH-NP size was optimized to 75 ± 25 nm for kidney-targeted drug delivery; the positive zeta potential allowed an effective cellular uptake and the polyethylenimine amine groups facilitate the endosomal escape quickly. The distribution and pharmacodynamics of PPP-RH-NPs were studied in a streptozocin-induced DN model, which explicitly demonstrated kidney-targeted distribution and improved the therapeutic effects of RH on DN by ameliorating several pathological indicators.

Conclusion: Therefore, this study not only stimulates further clinical research on RH but also, more importantly, proposes a promising DN therapy consisting of an effective kidney-targeted drug delivery.

Keywords: diabetic nephropathy; in vitro/vivo evaluation; nanoparticles; polyethyleneglycol-co-polycaprolactone-co-polyethylenimine; rhein; targeting drug delivery.

MeSH terms

  • Animals
  • Anthraquinones / pharmacology
  • Anthraquinones / therapeutic use*
  • Blood Glucose / metabolism
  • Cell Death / drug effects
  • Chromatography, Gel
  • Diabetic Nephropathies / blood
  • Diabetic Nephropathies / drug therapy*
  • Disease Models, Animal
  • Drug Delivery Systems*
  • Drug Liberation
  • Endocytosis / drug effects
  • Fasting / blood
  • Hemolysis / drug effects
  • Humans
  • Kidney / drug effects
  • Kidney / pathology*
  • Kinetics
  • Male
  • Mice, Inbred C57BL
  • Nanoparticles / chemistry*
  • Nanoparticles / ultrastructure
  • Particle Size
  • Polyethylene Glycols / chemical synthesis
  • Polyethylene Glycols / chemistry*
  • Polyethyleneimine / analogs & derivatives*
  • Polyethyleneimine / chemical synthesis
  • Polyethyleneimine / chemistry*
  • Rabbits
  • Static Electricity
  • Streptozocin
  • Subcellular Fractions / metabolism

Substances

  • Anthraquinones
  • Blood Glucose
  • poly(ethylene glycol)-co-poly(ethyleneimine)
  • Polyethylene Glycols
  • Streptozocin
  • Polyethyleneimine
  • rhein