Therapeutic inhibition of spleen tyrosine kinase in inflammatory macrophages using PLGA nanoparticles for the treatment of non-alcoholic steatohepatitis

D.W. Kurniawan, Arun Kumar Jajoriya, Garima Dhawan, Divya Mishra, Josepmaria Argemi, Raḿon Bataller, G. Storm, Durga Prasad Mishra, J. Prakash, Ruchi Bansal (Corresponding Author)

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Abstract

Non-alcoholic steatohepatitis (NASH) is the leading cause of cirrhosis worldwide and the most rapidly growing indication for liver transplantation. Macrophages are the important cellular component in the inflammatory milieu in NASH. Inflammatory and pro-fibrotic mediators produced by macrophages causes significant tissue injury in many inflammatory diseases. Therefore, inhibition of the inflammatory macrophages would be a promising approach to attenuate NASH. In this study, we studied the implication of SYK pathway in NASH, and investigated PLGA nanoparticles-based delivery of SYK pathway inhibitor as an effective and promising therapeutic approach for the treatment of NASH. We found positive correlation between SYK expression with the pathogenesis of NASH and alcoholic hepatitis in patients. Importantly, SYK expression was significantly induced in M1-differentiated inflammatory macrophages. To inhibit SYK pathway specifically, we used a small-molecule inhibitor R406 that blocks Fc-receptor signaling pathway and reduces immune complex-mediated inflammation. R406 dose-dependently inhibited nitric-oxide release and M1-specific markers in M1-differentiated macrophages. Thereafter, we synthesized PLGA nanoparticles to deliver R406 to increase the drug pharmacokinetics for the efficient treatment of NASH. We investigated the therapeutic efficacy of R406-PLGA in-vitro in differentiated macrophages, and in-vivo in Methionine-Choline-deficient (MCD)-diet induced NASH mouse model. R406-PLGA inhibited M1-specific differentiation markers in RAW and bone-marrow-derived macrophages. In-vivo, R406 and more strongly R406-PLGA ameliorated fibrosis, inflammation and steatosis in mice. R406 and more significantly R406-PLGA reduced ALT, AST, cholesterol and triglyceride plasma levels. These results suggest that delivery of SYK inhibitor using PLGA nanoparticles can be a potential therapeutic approach for the treatment of Non-alcoholic steatohepatitis.
Original languageEnglish
Pages (from-to)227-238
Number of pages12
JournalJournal of controlled release
Volume288
DOIs
Publication statusPublished - 28 Oct 2018

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Fatty Liver
Nanoparticles
Macrophages
Therapeutics
Fibrosis
Alcoholic Hepatitis
Inflammation
Syk Kinase
polylactic acid-polyglycolic acid copolymer
Fc Receptors
Differentiation Antigens
Choline
Antigen-Antibody Complex
Methionine
Liver Transplantation
Nitric Oxide
Triglycerides
Pharmacokinetics
Cholesterol
Diet

Keywords

  • UT-Hybrid-D

Cite this

Kurniawan, D.W. ; Jajoriya, Arun Kumar ; Dhawan, Garima ; Mishra, Divya ; Argemi, Josepmaria ; Bataller, Raḿon ; Storm, G. ; Mishra, Durga Prasad ; Prakash, J. ; Bansal, Ruchi. / Therapeutic inhibition of spleen tyrosine kinase in inflammatory macrophages using PLGA nanoparticles for the treatment of non-alcoholic steatohepatitis. In: Journal of controlled release. 2018 ; Vol. 288. pp. 227-238.
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abstract = "Non-alcoholic steatohepatitis (NASH) is the leading cause of cirrhosis worldwide and the most rapidly growing indication for liver transplantation. Macrophages are the important cellular component in the inflammatory milieu in NASH. Inflammatory and pro-fibrotic mediators produced by macrophages causes significant tissue injury in many inflammatory diseases. Therefore, inhibition of the inflammatory macrophages would be a promising approach to attenuate NASH. In this study, we studied the implication of SYK pathway in NASH, and investigated PLGA nanoparticles-based delivery of SYK pathway inhibitor as an effective and promising therapeutic approach for the treatment of NASH. We found positive correlation between SYK expression with the pathogenesis of NASH and alcoholic hepatitis in patients. Importantly, SYK expression was significantly induced in M1-differentiated inflammatory macrophages. To inhibit SYK pathway specifically, we used a small-molecule inhibitor R406 that blocks Fc-receptor signaling pathway and reduces immune complex-mediated inflammation. R406 dose-dependently inhibited nitric-oxide release and M1-specific markers in M1-differentiated macrophages. Thereafter, we synthesized PLGA nanoparticles to deliver R406 to increase the drug pharmacokinetics for the efficient treatment of NASH. We investigated the therapeutic efficacy of R406-PLGA in-vitro in differentiated macrophages, and in-vivo in Methionine-Choline-deficient (MCD)-diet induced NASH mouse model. R406-PLGA inhibited M1-specific differentiation markers in RAW and bone-marrow-derived macrophages. In-vivo, R406 and more strongly R406-PLGA ameliorated fibrosis, inflammation and steatosis in mice. R406 and more significantly R406-PLGA reduced ALT, AST, cholesterol and triglyceride plasma levels. These results suggest that delivery of SYK inhibitor using PLGA nanoparticles can be a potential therapeutic approach for the treatment of Non-alcoholic steatohepatitis.",
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Therapeutic inhibition of spleen tyrosine kinase in inflammatory macrophages using PLGA nanoparticles for the treatment of non-alcoholic steatohepatitis. / Kurniawan, D.W.; Jajoriya, Arun Kumar; Dhawan, Garima; Mishra, Divya; Argemi, Josepmaria; Bataller, Raḿon; Storm, G.; Mishra, Durga Prasad; Prakash, J. ; Bansal, Ruchi (Corresponding Author).

In: Journal of controlled release, Vol. 288, 28.10.2018, p. 227-238.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Therapeutic inhibition of spleen tyrosine kinase in inflammatory macrophages using PLGA nanoparticles for the treatment of non-alcoholic steatohepatitis

AU - Kurniawan, D.W.

AU - Jajoriya, Arun Kumar

AU - Dhawan, Garima

AU - Mishra, Divya

AU - Argemi, Josepmaria

AU - Bataller, Raḿon

AU - Storm, G.

AU - Mishra, Durga Prasad

AU - Prakash, J.

AU - Bansal, Ruchi

N1 - Elsevier deal

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N2 - Non-alcoholic steatohepatitis (NASH) is the leading cause of cirrhosis worldwide and the most rapidly growing indication for liver transplantation. Macrophages are the important cellular component in the inflammatory milieu in NASH. Inflammatory and pro-fibrotic mediators produced by macrophages causes significant tissue injury in many inflammatory diseases. Therefore, inhibition of the inflammatory macrophages would be a promising approach to attenuate NASH. In this study, we studied the implication of SYK pathway in NASH, and investigated PLGA nanoparticles-based delivery of SYK pathway inhibitor as an effective and promising therapeutic approach for the treatment of NASH. We found positive correlation between SYK expression with the pathogenesis of NASH and alcoholic hepatitis in patients. Importantly, SYK expression was significantly induced in M1-differentiated inflammatory macrophages. To inhibit SYK pathway specifically, we used a small-molecule inhibitor R406 that blocks Fc-receptor signaling pathway and reduces immune complex-mediated inflammation. R406 dose-dependently inhibited nitric-oxide release and M1-specific markers in M1-differentiated macrophages. Thereafter, we synthesized PLGA nanoparticles to deliver R406 to increase the drug pharmacokinetics for the efficient treatment of NASH. We investigated the therapeutic efficacy of R406-PLGA in-vitro in differentiated macrophages, and in-vivo in Methionine-Choline-deficient (MCD)-diet induced NASH mouse model. R406-PLGA inhibited M1-specific differentiation markers in RAW and bone-marrow-derived macrophages. In-vivo, R406 and more strongly R406-PLGA ameliorated fibrosis, inflammation and steatosis in mice. R406 and more significantly R406-PLGA reduced ALT, AST, cholesterol and triglyceride plasma levels. These results suggest that delivery of SYK inhibitor using PLGA nanoparticles can be a potential therapeutic approach for the treatment of Non-alcoholic steatohepatitis.

AB - Non-alcoholic steatohepatitis (NASH) is the leading cause of cirrhosis worldwide and the most rapidly growing indication for liver transplantation. Macrophages are the important cellular component in the inflammatory milieu in NASH. Inflammatory and pro-fibrotic mediators produced by macrophages causes significant tissue injury in many inflammatory diseases. Therefore, inhibition of the inflammatory macrophages would be a promising approach to attenuate NASH. In this study, we studied the implication of SYK pathway in NASH, and investigated PLGA nanoparticles-based delivery of SYK pathway inhibitor as an effective and promising therapeutic approach for the treatment of NASH. We found positive correlation between SYK expression with the pathogenesis of NASH and alcoholic hepatitis in patients. Importantly, SYK expression was significantly induced in M1-differentiated inflammatory macrophages. To inhibit SYK pathway specifically, we used a small-molecule inhibitor R406 that blocks Fc-receptor signaling pathway and reduces immune complex-mediated inflammation. R406 dose-dependently inhibited nitric-oxide release and M1-specific markers in M1-differentiated macrophages. Thereafter, we synthesized PLGA nanoparticles to deliver R406 to increase the drug pharmacokinetics for the efficient treatment of NASH. We investigated the therapeutic efficacy of R406-PLGA in-vitro in differentiated macrophages, and in-vivo in Methionine-Choline-deficient (MCD)-diet induced NASH mouse model. R406-PLGA inhibited M1-specific differentiation markers in RAW and bone-marrow-derived macrophages. In-vivo, R406 and more strongly R406-PLGA ameliorated fibrosis, inflammation and steatosis in mice. R406 and more significantly R406-PLGA reduced ALT, AST, cholesterol and triglyceride plasma levels. These results suggest that delivery of SYK inhibitor using PLGA nanoparticles can be a potential therapeutic approach for the treatment of Non-alcoholic steatohepatitis.

KW - UT-Hybrid-D

U2 - 10.1016/j.jconrel.2018.09.004

DO - 10.1016/j.jconrel.2018.09.004

M3 - Article

VL - 288

SP - 227

EP - 238

JO - Journal of controlled release

JF - Journal of controlled release

SN - 0168-3659

ER -