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Therapeutic RNAi robed with ionic liquid moieties as a simple, scalable prodrug platform for treating skin disease.

ABSTRACT: The high prevalence of skin diseases and their visible symptoms result in major physical, emotional, and economic burden for which few solutions exist. To address this unmet medical need, topical delivery of RNAi such as siRNA holds many advantages including direct access to the diseased site, potent knockdown of disease symptoms, and limited off-target effects. Unfortunately, delivering drugs into skin is extremely difficult. To address these concerns, we present RNAi robed with ionic liquid moieties. Specifically, we show that robed-siRNAs can be synthesized by a simple two-step process from bulk materials. Robing affords tuneability of properties necessary for dermal drug delivery including octanol-water partitioning, skin transport, and cell internalization. The efficacy and safety of robed-siRNA for treating skin disease was confirmed by its ability to limit breakdown of elastin, a major cause of premature aging, following UVB exposure to human reconstructed skin tissue. Together, the data strongly support that therapeutic RNAi robed with ionic liquid moieties are a simple, scalable prodrug platform for treating skin disease.

SUBMITTER: Zakrewsky M

PROVIDER: S-EPMC5289309 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Therapeutic RNAi robed with ionic liquid moieties as a simple, scalable prodrug platform for treating skin disease.

Zakrewsky Michael M Mitragotri Samir S

Journal of controlled release : official journal of the Controlled Release Society 20160906

The high prevalence of skin diseases and their visible symptoms result in major physical, emotional, and economic burden for which few solutions exist. To address this unmet medical need, topical delivery of RNAi such as siRNA holds many advantages including direct access to the diseased site, potent knockdown of disease symptoms, and limited off-target effects. Unfortunately, delivering drugs into skin is extremely difficult. To address these concerns, we present RNAi robed with ionic liquid mo ...[more]

PMID: 27612407

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Project description:BackgroundThere is a need to replace petroleum-derived with sustainable feedstocks for chemical production. Certain biomass feedstocks can meet this need as abundant, diverse, and renewable resources. Specific ionic liquids (ILs) can play a role in this process as promising candidates for chemical pretreatment and deconstruction of plant-based biomass feedstocks as they efficiently release carbohydrates which can be fermented. However, the most efficient pretreatment ILs are highly toxic to biological systems, such as microbial fermentations, and hinder subsequent bioprocessing of fermentative sugars obtained from IL-treated biomass.MethodsTo generate strains capable of tolerating residual ILs present in treated feedstocks, a tolerance adaptive laboratory evolution (TALE) approach was developed and utilized to improve growth of two different Escherichia coli strains, DH1 and K-12 MG1655, in the presence of two different ionic liquids, 1-ethyl-3-methylimidazolium acetate ([C2C1Im][OAc]) and 1-butyl-3-methylimidazolium chloride ([C4C1Im]Cl). For multiple parallel replicate populations of E. coli, cells were repeatedly passed to select for improved fitness over the course of approximately 40 days. Clonal isolates were screened and the best performing isolates were subjected to whole genome sequencing.ResultsThe most prevalent mutations in tolerant clones occurred in transport processes related to the functions of mdtJI, a multidrug efflux pump, and yhdP, an uncharacterized transporter. Additional mutations were enriched in processes such as transcriptional regulation and nucleotide biosynthesis. Finally, the best-performing strains were compared to previously characterized tolerant strains and showed superior performance in tolerance of different IL and media combinations (i.e., cross tolerance) with robust growth at 8.5% (w/v) and detectable growth up to 11.9% (w/v) [C2C1Im][OAc].ConclusionThe generated strains thus represent the best performing platform strains available for bioproduction utilizing IL-treated renewable substrates, and the TALE method was highly successful in overcoming the general issue of substrate toxicity and has great promise for use in tolerance engineering.

Dataset Information

Therapeutic RNAi robed with ionic liquid moieties as a simple, scalable prodrug platform for treating skin disease.

Publications

Therapeutic RNAi robed with ionic liquid moieties as a simple, scalable prodrug platform for treating skin disease.

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