β-Cyclodextrin nanosponges for the ocular delivery of therapeutic Micro-RNA in a Mouse model of retinitis Pigmentosa: A proof of concept study

IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Ilaria Piano , Beatrice Polini , Francesca Corsi , Sara Carpi , Giovanni Petrarolo , Luca Quattrini , Ilaria D’Agostino , Maria Cristina Gamberini , Cecilia Baraldi , Grazia Chiellini , Paola Nieri , Concettina La Motta , Claudia Gargini
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Abstract

The exploitation of micro-RNA (miR) sequences as therapeutics has become highly attractive for the treatment of several diseases, including those still lacking effective cures such as retinitis pigmentosa (RP). Interestingly, miR-155-5p plays a role in photo-oxidative inflammation in wild-type mice and is up-regulated in rd10 mice showing peak rod degeneration, suggesting its inhibition by the corresponding anti-miR as a viable therapeutic strategy for RP. However, biomedical application of (anti-)miRs is limited by their oligonucleotide nature, suffering from low solubility and bioavailability along with a very low half-life in vivo due to enzymatic degradation. Thereby, the need for suitable delivery systems led to the development of various nanocarriers, including oligosaccharide-based polymers. In this context, we designed and prepared an innovative nanosponge (NS) with a β-cyclodextrin (β-CD) motif payload with a bridge-like molecule, the amphipathic adamantane derivative (ADM), able to establish strong interactions with both NS and the therapeutic miR, thereby delivering and eventually releasing it close to the active site. Through an in vivo study, we both validated the NS system as a useful tool for miR topical administration by eye drop formulation and the functional activity of anti-miR-155-5p in RP.

Abstract Image

β-环糊精纳米海绵在色素性视网膜炎小鼠模型中用于眼部递送治疗性微rna:概念验证研究。
利用微rna (miR)序列作为治疗手段已经成为治疗多种疾病的高度吸引力,包括那些仍然缺乏有效治疗方法的疾病,如视网膜色素变性(RP)。有趣的是,miR-155-5p在野生型小鼠的光氧化炎症中发挥作用,并在出现杆状物峰值变性的rd10小鼠中上调,表明相应的抗mir抑制其作为RP的可行治疗策略。然而,(抗)miRs的生物医学应用受到其寡核苷酸性质的限制,具有低溶解度和生物利用度以及由于酶降解而在体内的半衰期很低。因此,对合适的递送系统的需求导致了各种纳米载体的发展,包括低聚糖基聚合物。在此背景下,我们设计并制备了一种创新的纳米海绵(NS),其内含β-环糊精(β-CD)基元和桥状分子,两亲性金刚烷衍生物(ADM),能够与NS和治疗性miR建立强相互作用,从而在活性位点附近传递并最终释放。通过体内研究,我们都验证了NS系统作为眼药水配方局部给药miR的有用工具,以及anti-miR-155-5p在RP中的功能活性。
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来源期刊
CiteScore
8.80
自引率
4.10%
发文量
211
审稿时长
36 days
期刊介绍: The European Journal of Pharmaceutics and Biopharmaceutics provides a medium for the publication of novel, innovative and hypothesis-driven research from the areas of Pharmaceutics and Biopharmaceutics. Topics covered include for example: Design and development of drug delivery systems for pharmaceuticals and biopharmaceuticals (small molecules, proteins, nucleic acids) Aspects of manufacturing process design Biomedical aspects of drug product design Strategies and formulations for controlled drug transport across biological barriers Physicochemical aspects of drug product development Novel excipients for drug product design Drug delivery and controlled release systems for systemic and local applications Nanomaterials for therapeutic and diagnostic purposes Advanced therapy medicinal products Medical devices supporting a distinct pharmacological effect.
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