Dataset Information

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 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.

SUBMITTER: Chun YY

PROVIDER: S-EPMC7809290 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Positive-charge tuned gelatin hydrogel-siSPARC injectable for siRNA anti-scarring therapy in post glaucoma filtration surgery.

Chun Yong Yao YY Yap Zhu Li ZL Seet Li Fong LF Chan Hiok Hong HH Toh Li Zhen LZ Chu Stephanie W L SWL Lee Ying Shi YS Wong Tina T TT Tan Timothy T Y TTY

Scientific reports 20210114 1

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 crosslinki ...[more]

PMID: 33446775

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Project description:PURPOSE: To investigate the efficacy and safety of cationic nano-copolymers CS-g-(PEI-b-mPEG) mediated I?B kinase beta (IKK?) targeting siRNA in modulating wound healing in a monkey model of glaucoma filtration surgery. METHODS: The IKK? targeting siRNAs were chemically synthesized and screened in cultured monkey Tenon's fibroblasts in vitro. Fourteen monkeys underwent trabeculectomy and were randomly allocated to one of three treatment regimens: subconjunctival injection of either CS-g-(PEI-b-mPEG)/IKK?-siRNA (six eyes, 50nM, at the time of surgery and 7 days post surgery) or phosphate buffered saline (four eyes), or treated with mitomycin C (MMC; four eyes, 0.2 mg/ml). Bleb survival and characteristics, and intraocular pressure, were evaluated over a 60-day period. Histology of the surgical eyes was performed to evaluate ocular scarring and fibrosis in each group. RESULTS: Subconjunctival injection of CS-g-(PEI-b-mPEG)/IKK?-siRNA was well tolerated in this model. Both siRNA and MMC significantly prolonged bleb survival compared with the PBS group (the medians for survival days were 45.5, 60, and 29.5 in the siRNA, MMC, and PBS groups, respectively, p<0.01). Higher blebs were observed in the siRNA group than in the PBS group (p<0.01), while the MMC group showed the highest blebs among three groups (p<0.01). The surgical eyes in both the siRNA and MMC groups had significantly larger bleb area compared with the PBS group (p<0.01), but there was no significant difference between the siRNA and MMC groups (p=0.214). There were no significant differences in IOP readings among the three groups on the designated days after surgery (all p>0.05). The histologic examination demonstrated that the eyes treated with siRNA showed a marked reduction in subconjunctival scar tissue compared with the eyes in the PBS group. The conjunctival epithelium appeared healthy without the acellularity that was present in the MMC group. CONCLUSIONS: Subconjunctival injection of cationic nano-copolymers mediated IKK? targeting siRNA is associated with improved surgical outcome in a monkey model of trabeculectomy. This novel approach may potentially be a more controlled alternative as an anti-scarring agent in glaucoma filtration surgery.

Dataset Information

Positive-charge tuned gelatin hydrogel-siSPARC injectable for siRNA anti-scarring therapy in post glaucoma filtration surgery.

Publications

Positive-charge tuned gelatin hydrogel-siSPARC injectable for siRNA anti-scarring therapy in post glaucoma filtration surgery.

Similar Datasets

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