Bioreducible zinc(II)–dipicolylamine functionalized hyaluronic acid mediates safe siRNA delivery and effective glioblastoma RNAi therapy

Meng Zheng, Zhipeng Yang, Shizhu Chen, Haigang Wu, Yang Liu, Amanda Wright, Jeng-Wei Lu, Xue Xia, Albert Lee, Jinchao Zhang, Huijun Yin, Yingze Wang, Weimin Ruan, Xing-Jie Liang

Research output: Contribution to journalArticleResearchpeer-review

Abstract

RNA interference (RNAi) is an emerging therapeutic modality for tumors. However, lack of a safe and efficient small interfering RNA (siRNA) delivery system limits its clinical application. Here, we report a bioreducible and less-cationic siRNA delivery carrier by conjugating Zn(II)–dipicolylamine complexes (Zn–DPA) onto hyaluronic acid (HA) via a redox-sensitive disulfide (-SS-) linker. Such polymer conjugates can formulate stable siRNA nanomedicines via coordination between zinc ions of DPA and the anionic phosphate of siRNA. After the conjugates are taken up by cells, intracellular reduction stimulus subsequently triggers the release of siRNAs and elucidates the desired RNAi effect. Our studies showed the formulated siRNA nanomedicines can be efficiently delivered into tumor cells/tissues and mediates less cytotoxicities both in vitro and in vivo. More importantly, when applied in a xenograft glioblastoma tumor model, this siRNA nanomedicine demonstrated significantly enhanced antitumor ability comparing to naked siRNA. This work demonstrates that such bioreducible Zn–DPA-functionalized HA conjugates without using cationic material as a siRNA carrier represents a promising direction for RNAi-based cancer therapy.
LanguageEnglish
Pages362-369
Number of pages8
JournalACS Applied Bio Materials
Volume2
Issue number1
DOIs
Publication statusPublished - 22 Jan 2019

Fingerprint

Hyaluronic Acid
Glioblastoma
RNA Interference
Small Interfering RNA
Nanomedicine
Therapeutics
Neoplasms
zinc(II) dipicolylamine
Heterografts
Disulfides
Oxidation-Reduction
Zinc
Polymers
Phosphates
Ions

Keywords

  • bioreducible
  • gene therapy
  • glioblastoma
  • siRNA delivery
  • zin(II)-dipicolylamine

Cite this

Zheng, Meng ; Yang, Zhipeng ; Chen, Shizhu ; Wu, Haigang ; Liu, Yang ; Wright, Amanda ; Lu, Jeng-Wei ; Xia, Xue ; Lee, Albert ; Zhang, Jinchao ; Yin, Huijun ; Wang, Yingze ; Ruan, Weimin ; Liang, Xing-Jie. / Bioreducible zinc(II)–dipicolylamine functionalized hyaluronic acid mediates safe siRNA delivery and effective glioblastoma RNAi therapy. In: ACS Applied Bio Materials. 2019 ; Vol. 2, No. 1. pp. 362-369.
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abstract = "RNA interference (RNAi) is an emerging therapeutic modality for tumors. However, lack of a safe and efficient small interfering RNA (siRNA) delivery system limits its clinical application. Here, we report a bioreducible and less-cationic siRNA delivery carrier by conjugating Zn(II)–dipicolylamine complexes (Zn–DPA) onto hyaluronic acid (HA) via a redox-sensitive disulfide (-SS-) linker. Such polymer conjugates can formulate stable siRNA nanomedicines via coordination between zinc ions of DPA and the anionic phosphate of siRNA. After the conjugates are taken up by cells, intracellular reduction stimulus subsequently triggers the release of siRNAs and elucidates the desired RNAi effect. Our studies showed the formulated siRNA nanomedicines can be efficiently delivered into tumor cells/tissues and mediates less cytotoxicities both in vitro and in vivo. More importantly, when applied in a xenograft glioblastoma tumor model, this siRNA nanomedicine demonstrated significantly enhanced antitumor ability comparing to naked siRNA. This work demonstrates that such bioreducible Zn–DPA-functionalized HA conjugates without using cationic material as a siRNA carrier represents a promising direction for RNAi-based cancer therapy.",
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author = "Meng Zheng and Zhipeng Yang and Shizhu Chen and Haigang Wu and Yang Liu and Amanda Wright and Jeng-Wei Lu and Xue Xia and Albert Lee and Jinchao Zhang and Huijun Yin and Yingze Wang and Weimin Ruan and Xing-Jie Liang",
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Zheng, M, Yang, Z, Chen, S, Wu, H, Liu, Y, Wright, A, Lu, J-W, Xia, X, Lee, A, Zhang, J, Yin, H, Wang, Y, Ruan, W & Liang, X-J 2019, 'Bioreducible zinc(II)–dipicolylamine functionalized hyaluronic acid mediates safe siRNA delivery and effective glioblastoma RNAi therapy' ACS Applied Bio Materials, vol. 2, no. 1, pp. 362-369. https://doi.org/10.1021/acsabm.8b00622

Bioreducible zinc(II)–dipicolylamine functionalized hyaluronic acid mediates safe siRNA delivery and effective glioblastoma RNAi therapy. / Zheng, Meng; Yang, Zhipeng; Chen, Shizhu; Wu, Haigang; Liu, Yang; Wright, Amanda; Lu, Jeng-Wei; Xia, Xue; Lee, Albert; Zhang, Jinchao; Yin, Huijun; Wang, Yingze; Ruan, Weimin; Liang, Xing-Jie.

In: ACS Applied Bio Materials, Vol. 2, No. 1, 22.01.2019, p. 362-369.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Bioreducible zinc(II)–dipicolylamine functionalized hyaluronic acid mediates safe siRNA delivery and effective glioblastoma RNAi therapy

AU - Zheng,Meng

AU - Yang,Zhipeng

AU - Chen,Shizhu

AU - Wu,Haigang

AU - Liu,Yang

AU - Wright,Amanda

AU - Lu,Jeng-Wei

AU - Xia,Xue

AU - Lee,Albert

AU - Zhang,Jinchao

AU - Yin,Huijun

AU - Wang,Yingze

AU - Ruan,Weimin

AU - Liang,Xing-Jie

PY - 2019/1/22

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N2 - RNA interference (RNAi) is an emerging therapeutic modality for tumors. However, lack of a safe and efficient small interfering RNA (siRNA) delivery system limits its clinical application. Here, we report a bioreducible and less-cationic siRNA delivery carrier by conjugating Zn(II)–dipicolylamine complexes (Zn–DPA) onto hyaluronic acid (HA) via a redox-sensitive disulfide (-SS-) linker. Such polymer conjugates can formulate stable siRNA nanomedicines via coordination between zinc ions of DPA and the anionic phosphate of siRNA. After the conjugates are taken up by cells, intracellular reduction stimulus subsequently triggers the release of siRNAs and elucidates the desired RNAi effect. Our studies showed the formulated siRNA nanomedicines can be efficiently delivered into tumor cells/tissues and mediates less cytotoxicities both in vitro and in vivo. More importantly, when applied in a xenograft glioblastoma tumor model, this siRNA nanomedicine demonstrated significantly enhanced antitumor ability comparing to naked siRNA. This work demonstrates that such bioreducible Zn–DPA-functionalized HA conjugates without using cationic material as a siRNA carrier represents a promising direction for RNAi-based cancer therapy.

AB - RNA interference (RNAi) is an emerging therapeutic modality for tumors. However, lack of a safe and efficient small interfering RNA (siRNA) delivery system limits its clinical application. Here, we report a bioreducible and less-cationic siRNA delivery carrier by conjugating Zn(II)–dipicolylamine complexes (Zn–DPA) onto hyaluronic acid (HA) via a redox-sensitive disulfide (-SS-) linker. Such polymer conjugates can formulate stable siRNA nanomedicines via coordination between zinc ions of DPA and the anionic phosphate of siRNA. After the conjugates are taken up by cells, intracellular reduction stimulus subsequently triggers the release of siRNAs and elucidates the desired RNAi effect. Our studies showed the formulated siRNA nanomedicines can be efficiently delivered into tumor cells/tissues and mediates less cytotoxicities both in vitro and in vivo. More importantly, when applied in a xenograft glioblastoma tumor model, this siRNA nanomedicine demonstrated significantly enhanced antitumor ability comparing to naked siRNA. This work demonstrates that such bioreducible Zn–DPA-functionalized HA conjugates without using cationic material as a siRNA carrier represents a promising direction for RNAi-based cancer therapy.

KW - bioreducible

KW - gene therapy

KW - glioblastoma

KW - siRNA delivery

KW - zin(II)-dipicolylamine

U2 - 10.1021/acsabm.8b00622

DO - 10.1021/acsabm.8b00622

M3 - Article

VL - 2

SP - 362

EP - 369

JO - ACS Applied Bio Materials

T2 - ACS Applied Bio Materials

JF - ACS Applied Bio Materials

SN - 2576-6422

IS - 1

ER -