Oral delivery of nanomedicine for genetic kidney disease.

Autor:	Huang Y; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA., Wang J; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA., Mancino V; Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.; USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA., Pham J; Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.; USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA., O'Grady C; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA., Li H; Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.; USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA., Jiang K; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA., Chin D; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA., Poon C; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA., Ho PY; Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.; USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA., Gyarmati G; Department of Physiology and Neuroscience, and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033, USA., Peti-Peterdi J; Department of Physiology and Neuroscience, and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033, USA., Hallows KR; Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.; USC/UKRO Kidney Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA., Chung EJ; Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA.; Department of Medicine, Division of Nephrology and Hypertension, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.; Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, USA.; Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.; Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA 90089, USA.; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.; Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
Jazyk:	angličtina
Zdroj:	PNAS nexus [PNAS Nexus] 2024 May 10; Vol. 3 (5), pp. pgae187. Date of Electronic Publication: 2024 May 10 (Print Publication: 2024).
DOI:	10.1093/pnasnexus/pgae187
Abstrakt:	Chronic and genetic kidney diseases such as autosomal dominant polycystic kidney disease (ADPKD) have few therapeutic options, and clinical trials testing small molecule drugs have been unfavorable due to low kidney bioavailability and adverse side effects. Although nanoparticles can be designed to deliver drugs directly to the diseased site, there are no kidney-targeted nanomedicines clinically available, and most FDA-approved nanoparticles are administered intravenously which is not ideal for chronic diseases. To meet these challenges of chronic diseases, we developed a biomaterials-based strategy using chitosan particles (CP) for oral delivery of therapeutic, kidney-targeting peptide amphiphile micelles (KMs). We hypothesized that encapsuling KMs into CP would enhance the bioavailability of KMs upon oral administration given the high stability of chitosan in acidic conditions and mucoadhesive properties enabling absorption within the intestines. To test this, we evaluated the mechanism of KM access to the kidneys via intravital imaging and investigated the KM biodistribution in a porcine model. Next, we loaded KMs carrying the ADPKD drug metformin into CP (KM-CP -met ) and measured in vitro therapeutic effect. Upon oral administration in vivo, KM-CP -met showed significantly greater bioavailability and accumulation in the kidneys as compared to KM only or free drug. As such, KM-CP -met treatment in ADPKD mice ( Pkd1 fl/fl ; Pax8-rtTA ; Tet-O-Cre which develops the disease over 120 days and mimics the slow development of ADPKD) showed enhanced therapeutic efficacy without affecting safety despite repeated treatment. Herein, we demonstrate the potential of KM-CP as a nanomedicine strategy for oral delivery for the long-term treatment of chronic kidney diseases. (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)
Databáze:	MEDLINE
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