Abstract: FR-PO234
Renally Targeted Nanoparticle Drug Therapy for Rhabdomyolysis-Induced AKI
Session Information
- Pharmacology
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics‚ -Dynamics‚ -Genomics)
- 1900 Pharmacology (PharmacoKinetics‚ -Dynamics‚ -Genomics)
Authors
- Hebert, Jessica Faith, Oregon Health & Science University, Portland, Oregon, United States
- Funahashi, Yoshio, Oregon Health & Science University, Portland, Oregon, United States
- Munhall, Adam C., Oregon Health & Science University, Portland, Oregon, United States
- Nickerson, Megan N., Oregon Health & Science University, Portland, Oregon, United States
- Eiwaz, Mahaba B., Oregon Health & Science University, Portland, Oregon, United States
- Kim, Jonghan, University of Massachusetts Lowell, Lowell, Massachusetts, United States
- Choi, Hak soo, Massachusetts General Hospital, Boston, Massachusetts, United States
- Hutchens, Michael, Oregon Health & Science University, Portland, Oregon, United States
Background
Rhabdomyolysis-induced acute kidney injury (RIAKI) results from excess physical training, crush, or drugs. Specific treatment is lacking. The megalin inhibitor cilastatin is effective in rodent RIAKI, however, achieving inhibition of renal megalin with systemically-administered cilastatin requires a high dose; this could cause off-target effects. To improve efficacy and specificity we tested the hypothesis that a kidney-specific nanoparticle complexed to cilastatin (Cil) and the renoprotective agent dexamethasone (Dex) would ameliorate RIAKI in mice.
Methods
The kidney-specific nanoparticle (“H-Dot”) is comprised of a poly-epsilon-lysine backbone with moieties supporting targeting and therapeutic domain complexation chemistry and a fluorescent imaging domain. Cilastatin and dexamethasone were complexed to the H-Dot. Cil/Dex/H-Dot was administered to human kidney cells in vitro. In vivo, pharmacokinetic (PK) parameters were quantified in mice by HPLC. To test efficacy, Cil/Dex/H-Dot or vehicle was administered intravenously to mice subjected to RIAKI.
Results
Synthesized Cil/Dex/H-Dots were pure and contained 2:1:1 Cil:Dex:H-Dot ratio. In vitro studies demonstrated rapid drug release from the nanoparticle at late endosomal pH and endosomal delivery of Cil with nuclear delivery of Dex. Cil/Dex/H-Dots were exclusively renally filtered. PK demonstrated that kidney-specific H-Dot complexation more than doubled Cil/Dex delivery to the kidney. Efficacy studies in RIAKI-exposed mice demonstrated that loss of renal function was ameliorated 24h after induction of RIAKI in mice which received Cil/H-Dot or Cil/Dex/H-Dot treatment (mean±stdev GFR in Sham: 1111±191, Vehicle: 204±46, Cil/H-Dot 1064±453, Cil/Dex/H-Dot 1074±104, n= 3-6/group, p<0.01 by ANOVA with post-hoc Sidak test for both drugs compared to vehicle).
Conclusion
A kidney-specific nanoparticle formulation results in enhanced renal endosomal delivery of complexed drugs, including Cil and Dex. Complexing Cil and Dex to H-Dot nanoparticles ameliorates renal functional loss due to RIAKI in mice. Kidney-specific treatment of RIAKI with Cil/Dex/H-Dot may lead to effective, organ and mechanism-targeted therapy, with potential applications beyond RIAKI.
Funding
- Other NIH Support