2. Academic Validation
  3. In Vitro Delivery of mTOR inhibitors by Kidney-Targeted Micelles for Autosomal Dominant Polycystic Kidney Disease

In Vitro Delivery of mTOR inhibitors by Kidney-Targeted Micelles for Autosomal Dominant Polycystic Kidney Disease

  • SLAS Technol. 2023 Feb 17;S2472-6303(23)00011-0. doi: 10.1016/j.slast.2023.02.001.
Alysia Cox 1,  Madelynn Tung 1,  Hui Li 2,  Kenneth R Hallows 2,  Eun Ji Chung 3
Affiliations

Affiliations

  • 1 Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA.
  • 2 Department of Medicine, Division of Nephrology and Hypertension, and USC/UKRO Kidney Research Center, University of Southern California, Los Angeles, CA, USA.
  • 3 Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA; Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA; Department of Medicine, Division of Nephrology and Hypertension, and USC/UKRO Kidney Research Center, University of Southern California, Los Angeles, CA, USA; Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, University of Southern California, Los Angeles, CA, USA. Electronic address: [email protected].
PMID: 36804177 DOI: 10.1016/j.slast.2023.02.001
Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and is characterized by the formation of renal cysts and the eventual development of end-stage kidney disease. One approach to treating ADPKD is through inhibition of the mammalian target of rapamycin (mTOR) pathway, which has been implicated in cell overproliferation, contributing to renal cyst expansion. However, mTOR inhibitors, including rapamycin, everolimus, and RapaLink-1, have off-target side effects including immunosuppression. Thus, we hypothesized that the encapsulation of mTOR inhibitors in drug delivery carriers that target the kidneys would provide a strategy that would enable therapeutic efficacy while minimizing off-target accumulation and associated toxicity. Toward eventual in vivo application, we synthesized cortical collecting duct (CCD) targeted peptide amphiphile micelle (PAM) nanoparticles and show high drug encapsulation efficiency (>92.6 %). In vitro analysis indicated that drug encapsulation into PAMs enhanced the anti-proliferative effect of all three drugs in human CCD cells. Analysis of in vitro biomarkers of the mTOR pathway via western blotting confirmed that PAM encapsulation of mTOR inhibitors did not reduce their efficacy. These results indicate that PAM encapsulation is a promising way to deliver mTOR inhibitors to CCD cells and potentially treat ADPKD. Future studies will evaluate the therapeutic effect of PAM-drug formulations and ability to prevent off-target side effects associated with mTOR inhibitors in mouse models of ADPKD.

Keywords

ADPKD; MTOR; Micelles; Rapalogs; Targeted.

Figures
Products