Modified chitosan for effective renal delivery of siRNA to treat acute kidney injury

Weimin Tang; Sudipta Panja; Chinmay M. Jogdeo; Siyuan Tang; Ling Ding; Ao Yu; Kirk W. Foster; Del L. Dsouza; Yashpal S. Chhonker; Heather Jensen-Smith; Hee Seong Jang; Erika I. Boesen; Daryl J. Murry; Babu Padanilam; David Oupický

doi:10.1016/j.biomaterials.2022.121562

Modified chitosan for effective renal delivery of siRNA to treat acute kidney injury

Weimin Tang, Sudipta Panja, Chinmay M. Jogdeo, Siyuan Tang, Ling Ding, Ao Yu, Kirk W. Foster, Del L. Dsouza, Yashpal S. Chhonker, Heather Jensen-Smith, Hee Seong Jang, Erika I. Boesen, Daryl J. Murry, Babu Padanilam, David Oupický

Research output: Contribution to journal › Article › peer-review

Abstract

Acute kidney injury (AKI) is characterized by a sudden decrease in renal function and impacts growing number of people worldwide. RNA interference (RNAi) showed potential to treat diseases with no or limited conventional therapies, including AKI. Suitable carriers are needed to protect and selectively deliver RNAi to target cells to fully explore this therapeutic modality. Here, we report on the synthesis of chitosan modified with α-cyclam-p-toluic acid (C-CS) as a novel siRNA carrier for targeted delivery to injured kidneys. We demonstrate that conjugation of the α-cyclam-p-toluic acid to chitosan imparts the C-CS polymer with targeting and antagonistic properties to cells overexpressing chemokine receptor CXCR4. In contrast, the parent α-cyclam-p-toluic acid showed no such properties. Self-assembled C-CS/siRNA nanoparticles rapidly accumulate in the injured kidneys and show long retention in renal tubules. Apoptosis and metabolic and inflammatory pathways induced by p53 are important pathological mechanisms in the development of AKI. Nanoparticles with siRNA against p53 (sip53) were formulated and intravenously injected for attenuation of IRI-AKI. Due to the favorable accumulation in injured kidneys, the treatment with C-CS/sip53 decreased renal injury, extent of renal apoptosis, macrophage and neutrophil infiltration, and improved renal function. Overall, our study suggests that C-CS/siRNA nanoparticles have the potential to effectively accumulate and deliver therapeutic siRNAs to injured kidneys through CXCR4 binding, providing a novel way for AKI therapy.

Original language	English (US)
Article number	121562
Journal	Biomaterials
Volume	285
DOIs	https://doi.org/10.1016/j.biomaterials.2022.121562
State	Published - Jun 2022
Externally published	Yes

Keywords

Acute kidney injury
CXCR4
Chitosan
Ischemia-reperfusion injury
Polyplexes
p53

ASJC Scopus subject areas

Mechanics of Materials
Ceramics and Composites
Bioengineering
Biophysics
Biomaterials

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10.1016/j.biomaterials.2022.121562

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Tang, W., Panja, S., Jogdeo, C. M., Tang, S., Ding, L., Yu, A., Foster, K. W., Dsouza, D. L., Chhonker, Y. S., Jensen-Smith, H., Jang, H. S., Boesen, E. I., Murry, D. J., Padanilam, B., & Oupický, D. (2022). Modified chitosan for effective renal delivery of siRNA to treat acute kidney injury. Biomaterials, 285, Article 121562. https://doi.org/10.1016/j.biomaterials.2022.121562

@article{100029393309430aa223c048fc486102,

title = "Modified chitosan for effective renal delivery of siRNA to treat acute kidney injury",

abstract = "Acute kidney injury (AKI) is characterized by a sudden decrease in renal function and impacts growing number of people worldwide. RNA interference (RNAi) showed potential to treat diseases with no or limited conventional therapies, including AKI. Suitable carriers are needed to protect and selectively deliver RNAi to target cells to fully explore this therapeutic modality. Here, we report on the synthesis of chitosan modified with α-cyclam-p-toluic acid (C-CS) as a novel siRNA carrier for targeted delivery to injured kidneys. We demonstrate that conjugation of the α-cyclam-p-toluic acid to chitosan imparts the C-CS polymer with targeting and antagonistic properties to cells overexpressing chemokine receptor CXCR4. In contrast, the parent α-cyclam-p-toluic acid showed no such properties. Self-assembled C-CS/siRNA nanoparticles rapidly accumulate in the injured kidneys and show long retention in renal tubules. Apoptosis and metabolic and inflammatory pathways induced by p53 are important pathological mechanisms in the development of AKI. Nanoparticles with siRNA against p53 (sip53) were formulated and intravenously injected for attenuation of IRI-AKI. Due to the favorable accumulation in injured kidneys, the treatment with C-CS/sip53 decreased renal injury, extent of renal apoptosis, macrophage and neutrophil infiltration, and improved renal function. Overall, our study suggests that C-CS/siRNA nanoparticles have the potential to effectively accumulate and deliver therapeutic siRNAs to injured kidneys through CXCR4 binding, providing a novel way for AKI therapy.",

keywords = "Acute kidney injury, CXCR4, Chitosan, Ischemia-reperfusion injury, Polyplexes, p53",

author = "Weimin Tang and Sudipta Panja and Jogdeo, {Chinmay M.} and Siyuan Tang and Ling Ding and Ao Yu and Foster, {Kirk W.} and Dsouza, {Del L.} and Chhonker, {Yashpal S.} and Heather Jensen-Smith and Jang, {Hee Seong} and Boesen, {Erika I.} and Murry, {Daryl J.} and Babu Padanilam and David Oupick{\'y}",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",

year = "2022",

month = jun,

doi = "10.1016/j.biomaterials.2022.121562",

language = "English (US)",

volume = "285",

journal = "Biomaterials",

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TY - JOUR

T1 - Modified chitosan for effective renal delivery of siRNA to treat acute kidney injury

AU - Tang, Weimin

AU - Panja, Sudipta

AU - Jogdeo, Chinmay M.

AU - Tang, Siyuan

AU - Ding, Ling

AU - Yu, Ao

AU - Foster, Kirk W.

AU - Dsouza, Del L.

AU - Chhonker, Yashpal S.

AU - Jensen-Smith, Heather

AU - Jang, Hee Seong

AU - Boesen, Erika I.

AU - Murry, Daryl J.

AU - Padanilam, Babu

AU - Oupický, David

PY - 2022/6

Y1 - 2022/6

N2 - Acute kidney injury (AKI) is characterized by a sudden decrease in renal function and impacts growing number of people worldwide. RNA interference (RNAi) showed potential to treat diseases with no or limited conventional therapies, including AKI. Suitable carriers are needed to protect and selectively deliver RNAi to target cells to fully explore this therapeutic modality. Here, we report on the synthesis of chitosan modified with α-cyclam-p-toluic acid (C-CS) as a novel siRNA carrier for targeted delivery to injured kidneys. We demonstrate that conjugation of the α-cyclam-p-toluic acid to chitosan imparts the C-CS polymer with targeting and antagonistic properties to cells overexpressing chemokine receptor CXCR4. In contrast, the parent α-cyclam-p-toluic acid showed no such properties. Self-assembled C-CS/siRNA nanoparticles rapidly accumulate in the injured kidneys and show long retention in renal tubules. Apoptosis and metabolic and inflammatory pathways induced by p53 are important pathological mechanisms in the development of AKI. Nanoparticles with siRNA against p53 (sip53) were formulated and intravenously injected for attenuation of IRI-AKI. Due to the favorable accumulation in injured kidneys, the treatment with C-CS/sip53 decreased renal injury, extent of renal apoptosis, macrophage and neutrophil infiltration, and improved renal function. Overall, our study suggests that C-CS/siRNA nanoparticles have the potential to effectively accumulate and deliver therapeutic siRNAs to injured kidneys through CXCR4 binding, providing a novel way for AKI therapy.

AB - Acute kidney injury (AKI) is characterized by a sudden decrease in renal function and impacts growing number of people worldwide. RNA interference (RNAi) showed potential to treat diseases with no or limited conventional therapies, including AKI. Suitable carriers are needed to protect and selectively deliver RNAi to target cells to fully explore this therapeutic modality. Here, we report on the synthesis of chitosan modified with α-cyclam-p-toluic acid (C-CS) as a novel siRNA carrier for targeted delivery to injured kidneys. We demonstrate that conjugation of the α-cyclam-p-toluic acid to chitosan imparts the C-CS polymer with targeting and antagonistic properties to cells overexpressing chemokine receptor CXCR4. In contrast, the parent α-cyclam-p-toluic acid showed no such properties. Self-assembled C-CS/siRNA nanoparticles rapidly accumulate in the injured kidneys and show long retention in renal tubules. Apoptosis and metabolic and inflammatory pathways induced by p53 are important pathological mechanisms in the development of AKI. Nanoparticles with siRNA against p53 (sip53) were formulated and intravenously injected for attenuation of IRI-AKI. Due to the favorable accumulation in injured kidneys, the treatment with C-CS/sip53 decreased renal injury, extent of renal apoptosis, macrophage and neutrophil infiltration, and improved renal function. Overall, our study suggests that C-CS/siRNA nanoparticles have the potential to effectively accumulate and deliver therapeutic siRNAs to injured kidneys through CXCR4 binding, providing a novel way for AKI therapy.

KW - Acute kidney injury

KW - CXCR4

KW - Chitosan

KW - Ischemia-reperfusion injury

KW - Polyplexes

KW - p53

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U2 - 10.1016/j.biomaterials.2022.121562

DO - 10.1016/j.biomaterials.2022.121562

M3 - Article

C2 - 35552115

AN - SCOPUS:85129713064

SN - 0142-9612

VL - 285

JO - Biomaterials

JF - Biomaterials

M1 - 121562

ER -

Modified chitosan for effective renal delivery of siRNA to treat acute kidney injury

Abstract

Keywords

ASJC Scopus subject areas

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