Preferential siRNA delivery to injured kidneys for combination treatment of acute kidney injury

Acute kidney injury (AKI) is characterized by a sudden loss of renal function and is associated with high morbidity and mortality. Tumor suppressor p53 and chemokine receptor CXCR4 were both implicated in the AKI pathology. Here, we report on the development and evaluation of polymeric CXCR4 antagon...

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Published inJournal of controlled release Vol. 341; pp. 300 - 313
Main Authors Tang, Weimin, Chen, Yi, Jang, Hee-Seong, Hang, Yu, Jogdeo, Chinmay M., Li, Jing, Ding, Ling, Zhang, Chuhan, Yu, Ao, Yu, Fei, Foster, Kirk W., Padanilam, Babu J., Oupický, David
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier B.V 01.01.2022
Subjects
Acute kidney injury
Acute Kidney Injury - complications
Acute Kidney Injury - drug therapy
Cisplatin - therapeutic use
CXCR4
Humans
Kidney - pathology
Kidney - physiology
p53
Polyplexes
Reperfusion Injury - genetics
Reperfusion Injury - therapy
RNA, Small Interfering - genetics
RNA, Small Interfering - therapeutic use
siRNA, nanoparticles
Polyplexes
CXCR4
siRNA, nanoparticles
Acute kidney injury
p53
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Summary:Acute kidney injury (AKI) is characterized by a sudden loss of renal function and is associated with high morbidity and mortality. Tumor suppressor p53 and chemokine receptor CXCR4 were both implicated in the AKI pathology. Here, we report on the development and evaluation of polymeric CXCR4 antagonist (PCX) siRNA carrier for selective delivery to injured kidneys in AKI. Our results show that PCX/siRNA nanoparticles (polyplexes) provide protection against cisplatin injury to tubule cells in vitro when both CXCR4 and p53 are inhibited. The polyplexes selectively accumulate and are retained in the injured kidneys in cisplatin and bilateral ischemia reperfusion injury models of AKI. Treating AKI with the combined CXCR4 inhibition and p53 gene silencing with the PCX/sip53 polyplexes improves kidney function and decreases renal damage. Overall, our results suggest that the PCX/sip53 polyplexes have a significant potential to enhance renal accumulation in AKI and deliver therapeutic siRNA. [Display omitted]
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DO and BP conceived, designed, and supervised the project. WT and YC planned and performed experiments with the help of other authors. HSJ participated in the experimental design and performed IHC staining of kidney samples. CJ, JL, LD, CZ participated in the animal studies. AY, FY helped with polymer synthesis and analysis. KF scored samples for kidney injury. WT analyzed and interpreted the data. DO and WT wrote and reviewed the manuscript with inputs from all authors.
Author Contributions
Present address: Center for Nanomedicine and Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2021.11.029