Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing

Piul S. Rabbani; Anna Zhou; Zachary M. Borab; Joseph A. Frezzo; Nikita Srivastava; Haresh T. More; William J. Rifkin; Joshua A. David; Samuel J. Berens; Raymond Chen; Sophia Hameedi; Muhammad H. Junejo; Camille Kim; Rita A. Sartor; Che F. Liu; Pierre B. Saadeh; Jin K. Montclare; Daniel J. Ceradini

doi:10.1016/j.biomaterials.2017.04.001

Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing

Piul S. Rabbani, Anna Zhou, Zachary M. Borab, Joseph A. Frezzo, Nikita Srivastava, Haresh T. More, William J. Rifkin, Joshua A. David, Samuel J. Berens, Raymond Chen, Sophia Hameedi, Muhammad H. Junejo, Camille Kim, Rita A. Sartor, Che F. Liu, Pierre B. Saadeh, Jin K. Montclare, Daniel J. Ceradini

Chemical and Biomolecular Engineering

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

Abstract

Therapeutics utilizing siRNA are currently limited by the availability of safe and effective delivery systems. Cutaneous diseases, specifically ones with significant genetic components are ideal candidates for topical siRNA based therapy but the anatomical structure of skin presents a considerable hurdle. Here, we optimized a novel liposome and protein hybrid nanoparticle delivery system for the topical treatment of diabetic wounds with severe oxidative stress. We utilized a cationic lipid nanoparticle (CLN) composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the edge activator sodium cholate (NaChol), in a 6:1 ratio of DOTAP:NaChol (DNC). Addition of a cationic engineered supercharged coiled-coil protein (CSP) in a 10:1:1 ratio of DNC:CSP:siRNA produced a stable lipoproteoplex (LPP) nanoparticle, with optimal siRNA complexation, minimal cytotoxicity, and increased transfection efficacy. In a humanized murine diabetic wound healing model, our optimized LPP formulation successfully delivered siRNA targeted against Keap1, key repressor of Nrf2 which is a central regulator of redox mechanisms. Application of LPP complexing siKeap1 restored Nrf2 antioxidant function, accelerated diabetic tissue regeneration, and augmented reduction-oxidation homeostasis in the wound environment. Our topical LPP delivery system can readily be translated into clinical use for the treatment of diabetic wounds and can be extended to other cutaneous diseases with genetic components.

Original language	English (US)
Pages (from-to)	1-15
Number of pages	15
Journal	Biomaterials
Volume	132
DOIs	https://doi.org/10.1016/j.biomaterials.2017.04.001
State	Published - Jul 1 2017

Keywords

Diabetic wound
Gene therapy
Keap1
Lipoproteoplex vehicle
Nrf2
siRNA

ASJC Scopus subject areas

Biophysics
Bioengineering
Ceramics and Composites
Biomaterials
Mechanics of Materials

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10.1016/j.biomaterials.2017.04.001

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Rabbani, P. S., Zhou, A., Borab, Z. M., Frezzo, J. A., Srivastava, N., More, H. T., Rifkin, W. J., David, J. A., Berens, S. J., Chen, R., Hameedi, S., Junejo, M. H., Kim, C., Sartor, R. A., Liu, C. F., Saadeh, P. B., Montclare, J. K., & Ceradini, D. J. (2017). Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing. Biomaterials, 132, 1-15. https://doi.org/10.1016/j.biomaterials.2017.04.001

Rabbani, PS, Zhou, A, Borab, ZM, Frezzo, JA, Srivastava, N, More, HT, Rifkin, WJ, David, JA, Berens, SJ, Chen, R, Hameedi, S, Junejo, MH, Kim, C, Sartor, RA, Liu, CF, Saadeh, PB, Montclare, JK & Ceradini, DJ 2017, 'Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing', Biomaterials, vol. 132, pp. 1-15. https://doi.org/10.1016/j.biomaterials.2017.04.001

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title = "Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing",

abstract = "Therapeutics utilizing siRNA are currently limited by the availability of safe and effective delivery systems. Cutaneous diseases, specifically ones with significant genetic components are ideal candidates for topical siRNA based therapy but the anatomical structure of skin presents a considerable hurdle. Here, we optimized a novel liposome and protein hybrid nanoparticle delivery system for the topical treatment of diabetic wounds with severe oxidative stress. We utilized a cationic lipid nanoparticle (CLN) composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the edge activator sodium cholate (NaChol), in a 6:1 ratio of DOTAP:NaChol (DNC). Addition of a cationic engineered supercharged coiled-coil protein (CSP) in a 10:1:1 ratio of DNC:CSP:siRNA produced a stable lipoproteoplex (LPP) nanoparticle, with optimal siRNA complexation, minimal cytotoxicity, and increased transfection efficacy. In a humanized murine diabetic wound healing model, our optimized LPP formulation successfully delivered siRNA targeted against Keap1, key repressor of Nrf2 which is a central regulator of redox mechanisms. Application of LPP complexing siKeap1 restored Nrf2 antioxidant function, accelerated diabetic tissue regeneration, and augmented reduction-oxidation homeostasis in the wound environment. Our topical LPP delivery system can readily be translated into clinical use for the treatment of diabetic wounds and can be extended to other cutaneous diseases with genetic components.",

keywords = "Diabetic wound, Gene therapy, Keap1, Lipoproteoplex vehicle, Nrf2, siRNA",

author = "Rabbani, {Piul S.} and Anna Zhou and Borab, {Zachary M.} and Frezzo, {Joseph A.} and Nikita Srivastava and More, {Haresh T.} and Rifkin, {William J.} and David, {Joshua A.} and Berens, {Samuel J.} and Raymond Chen and Sophia Hameedi and Junejo, {Muhammad H.} and Camille Kim and Sartor, {Rita A.} and Liu, {Che F.} and Saadeh, {Pierre B.} and Montclare, {Jin K.} and Ceradini, {Daniel J.}",

note = "Publisher Copyright: {\textcopyright} 2017",

year = "2017",

month = jul,

day = "1",

doi = "10.1016/j.biomaterials.2017.04.001",

language = "English (US)",

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T1 - Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing

AU - Rabbani, Piul S.

AU - Zhou, Anna

AU - Borab, Zachary M.

AU - Frezzo, Joseph A.

AU - Srivastava, Nikita

AU - More, Haresh T.

AU - Rifkin, William J.

AU - David, Joshua A.

AU - Berens, Samuel J.

AU - Chen, Raymond

AU - Hameedi, Sophia

AU - Junejo, Muhammad H.

AU - Kim, Camille

AU - Sartor, Rita A.

AU - Liu, Che F.

AU - Saadeh, Pierre B.

AU - Montclare, Jin K.

AU - Ceradini, Daniel J.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Therapeutics utilizing siRNA are currently limited by the availability of safe and effective delivery systems. Cutaneous diseases, specifically ones with significant genetic components are ideal candidates for topical siRNA based therapy but the anatomical structure of skin presents a considerable hurdle. Here, we optimized a novel liposome and protein hybrid nanoparticle delivery system for the topical treatment of diabetic wounds with severe oxidative stress. We utilized a cationic lipid nanoparticle (CLN) composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the edge activator sodium cholate (NaChol), in a 6:1 ratio of DOTAP:NaChol (DNC). Addition of a cationic engineered supercharged coiled-coil protein (CSP) in a 10:1:1 ratio of DNC:CSP:siRNA produced a stable lipoproteoplex (LPP) nanoparticle, with optimal siRNA complexation, minimal cytotoxicity, and increased transfection efficacy. In a humanized murine diabetic wound healing model, our optimized LPP formulation successfully delivered siRNA targeted against Keap1, key repressor of Nrf2 which is a central regulator of redox mechanisms. Application of LPP complexing siKeap1 restored Nrf2 antioxidant function, accelerated diabetic tissue regeneration, and augmented reduction-oxidation homeostasis in the wound environment. Our topical LPP delivery system can readily be translated into clinical use for the treatment of diabetic wounds and can be extended to other cutaneous diseases with genetic components.

AB - Therapeutics utilizing siRNA are currently limited by the availability of safe and effective delivery systems. Cutaneous diseases, specifically ones with significant genetic components are ideal candidates for topical siRNA based therapy but the anatomical structure of skin presents a considerable hurdle. Here, we optimized a novel liposome and protein hybrid nanoparticle delivery system for the topical treatment of diabetic wounds with severe oxidative stress. We utilized a cationic lipid nanoparticle (CLN) composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the edge activator sodium cholate (NaChol), in a 6:1 ratio of DOTAP:NaChol (DNC). Addition of a cationic engineered supercharged coiled-coil protein (CSP) in a 10:1:1 ratio of DNC:CSP:siRNA produced a stable lipoproteoplex (LPP) nanoparticle, with optimal siRNA complexation, minimal cytotoxicity, and increased transfection efficacy. In a humanized murine diabetic wound healing model, our optimized LPP formulation successfully delivered siRNA targeted against Keap1, key repressor of Nrf2 which is a central regulator of redox mechanisms. Application of LPP complexing siKeap1 restored Nrf2 antioxidant function, accelerated diabetic tissue regeneration, and augmented reduction-oxidation homeostasis in the wound environment. Our topical LPP delivery system can readily be translated into clinical use for the treatment of diabetic wounds and can be extended to other cutaneous diseases with genetic components.

KW - Diabetic wound

KW - Gene therapy

KW - Keap1

KW - Lipoproteoplex vehicle

KW - Nrf2

KW - siRNA

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DO - 10.1016/j.biomaterials.2017.04.001

M3 - Article

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AN - SCOPUS:85016974030

SN - 0142-9612

VL - 132

SP - 1

EP - 15

JO - Biomaterials

JF - Biomaterials

ER -

Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing

Abstract

Keywords

ASJC Scopus subject areas

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