Target specific systemic delivery of TGF-β siRNA/(PEI-SS)-g-HA complex for the treatment of liver cirrhosis

Kitae Park; Sung Woo Hong; Wonhee Hur; Min Young Lee; Jeong A. Yang; Sung Woo Kim; Seung Kew Yoon; Sei Kwang Hahn

doi:10.1016/j.biomaterials.2011.03.044

Target specific systemic delivery of TGF-β siRNA/(PEI-SS)-g-HA complex for the treatment of liver cirrhosis

Kitae Park
, Sung Woo Hong
, Wonhee Hur
, Min Young Lee
, Jeong A. Yang
, Sung Woo Kim
, Seung Kew Yoon
, Sei Kwang Hahn

Division of Gastroenterology

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

63 Scopus citations

Abstract

A target specific systemic delivery system of siRNA therapeutics was successfully developed using reducible polyethyleneimine grafted hyaluronic acid [(PEI-SS)-g-HA] conjugates. The PEI-SS was synthesized by Michael addition of low molecular weight PEI (MW = 2000) with cystaminebisacrylamide (CBA), and grafted to carboxyl groups of HA via amide bond formation after activation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1-hydroxybenzotriazole monohydrate (HOBt). The confocal microscopic and fluorometric analyses confirmed the effective cellular uptake of siRNA/(PEI-SS)-g-HA complex by HA receptor mediated endocytosis. In vitro gene silencing efficiency was ca. 80% in the presence of 10 vol% serum and ca. 50% in the presence of 50 vol% serum in B16F1 melanoma cells and activated hepatic stellate cells (HSCs). Furthermore, target specific systemic delivery of apolipoprotein B (ApoB) siRNA/(PEI-SS)-g-HA complex resulted in a drastically reduced ApoB mRNA level down to ca. 20% in a dose-dependent manner. Finally, TGF-β siRNA/(PEI-SS)-g-HA complex showed a feasible therapeutic effect on liver cirrhosis with a significantly reduced nodule formation, collagen content, and HSC number. The siRNA/(PEI-SS)-g-HA complex can be exploited for the target specific systemic treatment of various liver diseases.

Original language	English
Pages (from-to)	4951-4958
Number of pages	8
Journal	Biomaterials
Volume	32
Issue number	21
DOIs	https://doi.org/10.1016/j.biomaterials.2011.03.044
State	Published - Jul 2011

Bibliographical note

Funding Information:
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2009-0072986 ). This research was supported by the R&D Program of MKE/KEIT ( 10035159 ). This research was supported by the Converging Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2009-0081871 ).

Keywords

Hyaluronic acid
Liver cirrhosis
Polyethyleneimine
SiRNA
Targeted systemic delivery

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10.1016/j.biomaterials.2011.03.044

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@article{55a9717ec8714803ab5cd1ada52f91ad,

title = "Target specific systemic delivery of TGF-β siRNA/(PEI-SS)-g-HA complex for the treatment of liver cirrhosis",

abstract = "A target specific systemic delivery system of siRNA therapeutics was successfully developed using reducible polyethyleneimine grafted hyaluronic acid [(PEI-SS)-g-HA] conjugates. The PEI-SS was synthesized by Michael addition of low molecular weight PEI (MW = 2000) with cystaminebisacrylamide (CBA), and grafted to carboxyl groups of HA via amide bond formation after activation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1-hydroxybenzotriazole monohydrate (HOBt). The confocal microscopic and fluorometric analyses confirmed the effective cellular uptake of siRNA/(PEI-SS)-g-HA complex by HA receptor mediated endocytosis. In vitro gene silencing efficiency was ca. 80\% in the presence of 10 vol\% serum and ca. 50\% in the presence of 50 vol\% serum in B16F1 melanoma cells and activated hepatic stellate cells (HSCs). Furthermore, target specific systemic delivery of apolipoprotein B (ApoB) siRNA/(PEI-SS)-g-HA complex resulted in a drastically reduced ApoB mRNA level down to ca. 20\% in a dose-dependent manner. Finally, TGF-β siRNA/(PEI-SS)-g-HA complex showed a feasible therapeutic effect on liver cirrhosis with a significantly reduced nodule formation, collagen content, and HSC number. The siRNA/(PEI-SS)-g-HA complex can be exploited for the target specific systemic treatment of various liver diseases.",

keywords = "Hyaluronic acid, Liver cirrhosis, Polyethyleneimine, SiRNA, Targeted systemic delivery",

author = "Kitae Park and Hong, \{Sung Woo\} and Wonhee Hur and Lee, \{Min Young\} and Yang, \{Jeong A.\} and Kim, \{Sung Woo\} and Yoon, \{Seung Kew\} and Hahn, \{Sei Kwang\}",

note = "Funding Information: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2009-0072986 ). This research was supported by the R\&D Program of MKE/KEIT ( 10035159 ). This research was supported by the Converging Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2009-0081871 ).",

year = "2011",

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doi = "10.1016/j.biomaterials.2011.03.044",

language = "English",

volume = "32",

pages = "4951--4958",

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T1 - Target specific systemic delivery of TGF-β siRNA/(PEI-SS)-g-HA complex for the treatment of liver cirrhosis

AU - Park, Kitae

AU - Hong, Sung Woo

AU - Hur, Wonhee

AU - Lee, Min Young

AU - Yang, Jeong A.

AU - Kim, Sung Woo

AU - Yoon, Seung Kew

AU - Hahn, Sei Kwang

N1 - Funding Information: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2009-0072986 ). This research was supported by the R&D Program of MKE/KEIT ( 10035159 ). This research was supported by the Converging Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2009-0081871 ).

PY - 2011/7

Y1 - 2011/7

N2 - A target specific systemic delivery system of siRNA therapeutics was successfully developed using reducible polyethyleneimine grafted hyaluronic acid [(PEI-SS)-g-HA] conjugates. The PEI-SS was synthesized by Michael addition of low molecular weight PEI (MW = 2000) with cystaminebisacrylamide (CBA), and grafted to carboxyl groups of HA via amide bond formation after activation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1-hydroxybenzotriazole monohydrate (HOBt). The confocal microscopic and fluorometric analyses confirmed the effective cellular uptake of siRNA/(PEI-SS)-g-HA complex by HA receptor mediated endocytosis. In vitro gene silencing efficiency was ca. 80% in the presence of 10 vol% serum and ca. 50% in the presence of 50 vol% serum in B16F1 melanoma cells and activated hepatic stellate cells (HSCs). Furthermore, target specific systemic delivery of apolipoprotein B (ApoB) siRNA/(PEI-SS)-g-HA complex resulted in a drastically reduced ApoB mRNA level down to ca. 20% in a dose-dependent manner. Finally, TGF-β siRNA/(PEI-SS)-g-HA complex showed a feasible therapeutic effect on liver cirrhosis with a significantly reduced nodule formation, collagen content, and HSC number. The siRNA/(PEI-SS)-g-HA complex can be exploited for the target specific systemic treatment of various liver diseases.

AB - A target specific systemic delivery system of siRNA therapeutics was successfully developed using reducible polyethyleneimine grafted hyaluronic acid [(PEI-SS)-g-HA] conjugates. The PEI-SS was synthesized by Michael addition of low molecular weight PEI (MW = 2000) with cystaminebisacrylamide (CBA), and grafted to carboxyl groups of HA via amide bond formation after activation with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1-hydroxybenzotriazole monohydrate (HOBt). The confocal microscopic and fluorometric analyses confirmed the effective cellular uptake of siRNA/(PEI-SS)-g-HA complex by HA receptor mediated endocytosis. In vitro gene silencing efficiency was ca. 80% in the presence of 10 vol% serum and ca. 50% in the presence of 50 vol% serum in B16F1 melanoma cells and activated hepatic stellate cells (HSCs). Furthermore, target specific systemic delivery of apolipoprotein B (ApoB) siRNA/(PEI-SS)-g-HA complex resulted in a drastically reduced ApoB mRNA level down to ca. 20% in a dose-dependent manner. Finally, TGF-β siRNA/(PEI-SS)-g-HA complex showed a feasible therapeutic effect on liver cirrhosis with a significantly reduced nodule formation, collagen content, and HSC number. The siRNA/(PEI-SS)-g-HA complex can be exploited for the target specific systemic treatment of various liver diseases.

KW - Hyaluronic acid

KW - Liver cirrhosis

KW - Polyethyleneimine

KW - SiRNA

KW - Targeted systemic delivery

UR - https://www.scopus.com/pages/publications/79955780014

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DO - 10.1016/j.biomaterials.2011.03.044

M3 - Article

C2 - 21481451

AN - SCOPUS:79955780014

SN - 0142-9612

VL - 32

SP - 4951

EP - 4958

JO - Biomaterials

JF - Biomaterials

IS - 21

ER -

Target specific systemic delivery of TGF-β siRNA/(PEI-SS)-g-HA complex for the treatment of liver cirrhosis

Abstract

Bibliographical note

Keywords

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