Positive-charge tuned gelatin hydrogel-siSPARC injectable for siRNA anti-scarring therapy in post glaucoma filtration surgery
Abstract Small interfering RNA (siRNA) therapy is a promising epigenetic silencing strategy. However, its widespread adoption has been severely impeded by its ineffective delivery into the cellular environment. Here, a biocompatible injectable gelatin-based hydrogel with positive-charge tuned surfac...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-01-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-020-80542-4 |
| _version_ | 1819202707742785536 |
|---|---|
| author | Yong Yao Chun Zhu Li Yap Li Fong Seet Hiok Hong Chan Li Zhen Toh Stephanie W. L. Chu Ying Shi Lee Tina T. Wong Timothy T. Y. Tan |
| author_facet | Yong Yao Chun Zhu Li Yap Li Fong Seet Hiok Hong Chan Li Zhen Toh Stephanie W. L. Chu Ying Shi Lee Tina T. Wong Timothy T. Y. Tan |
| author_sort | Yong Yao Chun |
| collection | DOAJ |
| description | Abstract Small interfering RNA (siRNA) therapy is a promising epigenetic silencing strategy. However, its widespread adoption has been severely impeded by its ineffective delivery into the cellular environment. Here, a biocompatible injectable gelatin-based hydrogel with positive-charge tuned surface charge is presented as an effective platform for siRNA protection and delivery. We demonstrate a two-step synthesis of a gelatin-tyramine (Gtn-Tyr) hydrogel with simultaneous charge tunability and crosslinking ability. We discuss how different physiochemical properties of the hydrogel interact with siSPARC (siRNA for secreted protein, acidic and rich in cysteine), and study the positive-charge tuned gelatin hydrogel as an effective delivery platform for siSPARC in anti-fibrotic treatment. Through in vitro studies using mouse tenon fibroblasts, the positive-charge tuned Gtn-Tyr hydrogel shows sustained siSPARC cellular internalization and effective SPARC silencing with excellent biocompatibility. Similarly, the same hydrogel platform delivering siSPARC in an in vivo assessment employing a rabbit model shows an effective reduction in subconjunctival scarring in post glaucoma filtration surgery, and is non-cytotoxic compared to a commonly used anti-scarring agent, mitomycin-C. Overall, the current siRNA delivery strategy involving the positive-charge tuned gelatin hydrogel shows effective delivery of gene silencing siSPARC for anti-fibrotic treatment. The current charge tunable hydrogel delivery system is simple to fabricate and highly scalable. We believe this delivery platform has strong translational potential for effective siRNA delivery and epigenetic silencing therapy. |
| first_indexed | 2024-12-23T04:08:18Z |
| format | Article |
| id | doaj.art-6e9d9e1df63743018713f7752bd1781a |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-23T04:08:18Z |
| publishDate | 2021-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-6e9d9e1df63743018713f7752bd1781a2022-12-21T18:00:34ZengNature PortfolioScientific Reports2045-23222021-01-0111111410.1038/s41598-020-80542-4Positive-charge tuned gelatin hydrogel-siSPARC injectable for siRNA anti-scarring therapy in post glaucoma filtration surgeryYong Yao Chun0Zhu Li Yap1Li Fong Seet2Hiok Hong Chan3Li Zhen Toh4Stephanie W. L. Chu5Ying Shi Lee6Tina T. Wong7Timothy T. Y. Tan8School of Chemical and Biomedical Engineering, Nanyang Technological UniversityOcular Therapeutics and Drug Delivery, Singapore Eye Research InstituteOcular Therapeutics and Drug Delivery, Singapore Eye Research InstituteGlaucoma Service, Singapore National Eye CentreOcular Therapeutics and Drug Delivery, Singapore Eye Research InstituteOcular Therapeutics and Drug Delivery, Singapore Eye Research InstituteOcular Therapeutics and Drug Delivery, Singapore Eye Research InstituteOcular Therapeutics and Drug Delivery, Singapore Eye Research InstituteSchool of Chemical and Biomedical Engineering, Nanyang Technological UniversityAbstract Small interfering RNA (siRNA) therapy is a promising epigenetic silencing strategy. However, its widespread adoption has been severely impeded by its ineffective delivery into the cellular environment. Here, a biocompatible injectable gelatin-based hydrogel with positive-charge tuned surface charge is presented as an effective platform for siRNA protection and delivery. We demonstrate a two-step synthesis of a gelatin-tyramine (Gtn-Tyr) hydrogel with simultaneous charge tunability and crosslinking ability. We discuss how different physiochemical properties of the hydrogel interact with siSPARC (siRNA for secreted protein, acidic and rich in cysteine), and study the positive-charge tuned gelatin hydrogel as an effective delivery platform for siSPARC in anti-fibrotic treatment. Through in vitro studies using mouse tenon fibroblasts, the positive-charge tuned Gtn-Tyr hydrogel shows sustained siSPARC cellular internalization and effective SPARC silencing with excellent biocompatibility. Similarly, the same hydrogel platform delivering siSPARC in an in vivo assessment employing a rabbit model shows an effective reduction in subconjunctival scarring in post glaucoma filtration surgery, and is non-cytotoxic compared to a commonly used anti-scarring agent, mitomycin-C. Overall, the current siRNA delivery strategy involving the positive-charge tuned gelatin hydrogel shows effective delivery of gene silencing siSPARC for anti-fibrotic treatment. The current charge tunable hydrogel delivery system is simple to fabricate and highly scalable. We believe this delivery platform has strong translational potential for effective siRNA delivery and epigenetic silencing therapy.https://doi.org/10.1038/s41598-020-80542-4 |
| spellingShingle | Yong Yao Chun Zhu Li Yap Li Fong Seet Hiok Hong Chan Li Zhen Toh Stephanie W. L. Chu Ying Shi Lee Tina T. Wong Timothy T. Y. Tan Positive-charge tuned gelatin hydrogel-siSPARC injectable for siRNA anti-scarring therapy in post glaucoma filtration surgery Scientific Reports |
| title | Positive-charge tuned gelatin hydrogel-siSPARC injectable for siRNA anti-scarring therapy in post glaucoma filtration surgery |
| title_full | Positive-charge tuned gelatin hydrogel-siSPARC injectable for siRNA anti-scarring therapy in post glaucoma filtration surgery |
| title_fullStr | Positive-charge tuned gelatin hydrogel-siSPARC injectable for siRNA anti-scarring therapy in post glaucoma filtration surgery |
| title_full_unstemmed | Positive-charge tuned gelatin hydrogel-siSPARC injectable for siRNA anti-scarring therapy in post glaucoma filtration surgery |
| title_short | Positive-charge tuned gelatin hydrogel-siSPARC injectable for siRNA anti-scarring therapy in post glaucoma filtration surgery |
| title_sort | positive charge tuned gelatin hydrogel sisparc injectable for sirna anti scarring therapy in post glaucoma filtration surgery |
| url | https://doi.org/10.1038/s41598-020-80542-4 |
| work_keys_str_mv | AT yongyaochun positivechargetunedgelatinhydrogelsisparcinjectableforsirnaantiscarringtherapyinpostglaucomafiltrationsurgery AT zhuliyap positivechargetunedgelatinhydrogelsisparcinjectableforsirnaantiscarringtherapyinpostglaucomafiltrationsurgery AT lifongseet positivechargetunedgelatinhydrogelsisparcinjectableforsirnaantiscarringtherapyinpostglaucomafiltrationsurgery AT hiokhongchan positivechargetunedgelatinhydrogelsisparcinjectableforsirnaantiscarringtherapyinpostglaucomafiltrationsurgery AT lizhentoh positivechargetunedgelatinhydrogelsisparcinjectableforsirnaantiscarringtherapyinpostglaucomafiltrationsurgery AT stephaniewlchu positivechargetunedgelatinhydrogelsisparcinjectableforsirnaantiscarringtherapyinpostglaucomafiltrationsurgery AT yingshilee positivechargetunedgelatinhydrogelsisparcinjectableforsirnaantiscarringtherapyinpostglaucomafiltrationsurgery AT tinatwong positivechargetunedgelatinhydrogelsisparcinjectableforsirnaantiscarringtherapyinpostglaucomafiltrationsurgery AT timothytytan positivechargetunedgelatinhydrogelsisparcinjectableforsirnaantiscarringtherapyinpostglaucomafiltrationsurgery |