2. Academic Validation
  3. Investigation of Basolateral Targeting Micelles for Drug Delivery Applications in Polycystic Kidney Disease

Investigation of Basolateral Targeting Micelles for Drug Delivery Applications in Polycystic Kidney Disease

  • Biomacromolecules. 2024 May 13;25(5):2749-2761. doi: 10.1021/acs.biomac.3c01397.
Yi Huang 1,  Ali Osouli 1,  Jessica Pham 2 3,  Valeria Mancino 2 3,  Colette O'Grady 1,  Taranatee Khan 1,  Baishali Chaudhuri 1,  Nuria M Pastor-Soler 2 3,  Kenneth R Hallows 2 3,  Eun Ji Chung 1 2 4 5 6 7 8
Affiliations

Affiliations

  • 1 Department of Biomedical Engineering, University of Southern California, Los Angeles, California 90089, United States.
  • 2 Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States.
  • 3 USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States.
  • 4 Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, United States.
  • 5 Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States.
  • 6 Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, California 90089, United States.
  • 7 Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90033, United States.
  • 8 Bridge Institute, University of Southern California, Los Angeles, California 90089, United States.
PMID: 38652072 DOI: 10.1021/acs.biomac.3c01397
Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a complex disorder characterized by uncontrolled renal cyst growth, leading to kidney function decline. The multifaceted nature of ADPKD suggests that single-pathway interventions using individual small molecule drugs may not be optimally effective. As such, a strategy encompassing combination therapy that addresses multiple ADPKD-associated signaling pathways could offer synergistic therapeutic results. However, severe off-targeting side effects of small molecule drugs pose a major hurdle to their clinical transition. To address this, we identified four drug candidates from ADPKD clinical trials, bardoxolone methyl (Bar), octreotide (Oct), salsalate (Sal), and pravastatin (Pra), and incorporated them into peptide amphiphile micelles containing the RGD peptide (GRGDSP), which binds to the basolateral surface of renal tubules via Integrin receptors on the extracellular matrix. We hypothesized that encapsulating drug combinations into RGD micelles would enable targeting to the basolateral side of renal tubules, which is the site of disease, via renal secretion, leading to superior therapeutic benefits compared to free drugs. To test this, we first evaluated the synergistic effect of drug combinations using the 20% inhibitory concentration for each drug (IC20) on renal proximal tubule cells derived from PKD1flox/-:TSLargeT mice. Next, we synthesized and characterized the RGD micelles encapsulated with drug combinations and measured their in vitro therapeutic effects via a 3D PKD growth model. Upon both IV and IP injections in vivo, RGD micelles showed a significantly higher accumulation in the kidneys compared to NT micelles, and the renal access of RGD micelles was significantly reduced after the inhibition of renal secretion. Specifically, both Bar+Oct and Bar+Sal in the RGD micelle treatment showed enhanced therapeutic efficacy in ADPKD mice (PKD1fl/fl;Pax8-rtTA;Tet-O-Cre) with a significantly lower KW/BW ratio and cyst index as compared to PBS and free drug-treated controls, while Other combinations did not show a significant difference. Hence, we demonstrate that renal targeting through basolateral targeting micelles enhances the therapeutic potential of combination therapy in genetic kidney disease.

Figures
Products