Folate Conjugated Nanomedicines for Selective Inhibition of mTOR Signaling in Polycystic Kidneys at Clinically Relevant Doses

Authors

Rajasekharreddy Pala, Chapman UniversityFollow
Ayan K. Barui, Chapman University
Ashraf M. Mohieldin, Chapman UniversityFollow
Jing Zhou, Harvard Medical School
Surya M. Nauli, Chapman UniversityFollow

Document Type

Article

Publication Date

9-13-2023

Abstract

Although rapamycin is a very effective drug for rodents with polycystic kidney disease (PKD), it is not encouraging in the clinical trials due to the suboptimal dosages compelled by the off-target side effects. We here report the generation, characterization, specificity, functionality, pharmacokinetic, pharmacodynamic and toxicology profiles of novel polycystic kidney-specific-targeting nanoparticles (NPs). We formulated folate-conjugated PLGA-PEG NPs, which can be loaded with multiple drugs, including rapamycin (an mTOR inhibitor) and antioxidant 4-hydroxy-TEMPO (a nephroprotective agent). The NPs increased the efficacy, potency and tolerability of rapamycin resulting in an increased survival rate and improved kidney function by decreasing side effects and reducing biodistribution to other organs in PKD mice. The daily administration of rapamycin-alone (1 mg/kg/day) could now be achieved with a weekly injection of NPs containing rapamycin (379 μg/kg/week). This polycystic kidney-targeting nanotechnology, for the first time, integrated advances in the use of 1) nanoparticles as a delivery cargo, 2) folate for targeting, 3) near-infrared Cy5-fluorophore for in vitro and in vivo live imaging, 4) rapamycin as a pharmacological therapy, and 5) TEMPO as a combinational therapy. The slow sustained-release of rapamycin by polycystic kidney-targeting NPs demonstrates a new era of nanomedicine in treatment for chronic kidney diseases at clinically relevant doses.

Comments

NOTICE: this is the author’s version of a work that was accepted for publication in Biomaterials. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Biomaterials, volume 302, in 2023. https://doi.org/10.1016/j.biomaterials.2023.122329

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Recommended Citation

Pala R, Barui AK, Mohieldin AM, Zhou J, Nauli SM. Folate conjugated nanomedicines for selective inhibition of mTOR signaling in polycystic kidneys at clinically relevant doses. Biomaterials. 2023;302:122329. https://doi.org/10.1016/j.biomaterials.2023.122329

Copyright

Elsevier

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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.