Nanoparticle-Assisted Transcutaneous Delivery of a Signal Transducer and Activator of Transcription 3-Inhibiting Peptide Ameliorates Psoriasis-like Skin Inflammation
Nanoparticle-Assisted Transcutaneous Delivery of a Signal Transducer and Activator of Transcription 3-Inhibiting Peptide Ameliorates Psoriasis-like Skin Inflammation
复制标题
DOI：
10.1021/acsnano.8b02330
复制
发表时间：
2018-07-01
期刊：
影响因子：
17.1
通讯作者：
Jon, Sangyong
中科院分区：
文献类型：
--
作者：
Kim, Jin Yong;Ahn, Jinhyo;Jon, Sangyong
信号转导子和转录激活子3（STAT 3）在银屑病皮肤炎症中被组成性激活，并在这种自身免疫性疾病的发病机制和进展中起关键作用。尽管已经测试了许多干预STAT 3相关通路的抑制剂，但尚未鉴定出有效的、高度特异性的STAT 3抑制剂。在这里，我们评估了体外和体内的生物活性和治疗效果的高亲和力肽特异性的STAT 3（APTstat 3）后，通过皮内和经皮给药局部治疗。使用银屑病的临床前模型，我们表明皮内注射用9-精氨酸细胞穿透肽（APTstat 3 - 9 R）标记的APTstat 3通过抑制STAT 3磷酸化来减少疾病进展并调节银屑病相关的细胞因子信号传导。此外，通过将APTstat 3 - 9 R与特定脂质制剂复合导致形成盘状脂质纳米颗粒（DLNP），我们能够在经皮给药后实现STAT 3抑制肽的有效皮肤渗透，从而有效抑制银屑病皮肤炎症。总的来说，这些发现表明，DLNP辅助的STAT 3抑制肽的经皮递送可能是治疗银屑病皮肤炎症而不引起不良全身事件的有希望的策略。此外，DLNP系统可用于其他治疗肽的经皮递送。
Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in psoriatic skin inflammation and acts as a key player in the pathogenesis and progression of this autoimmune disease. Although numerous inhibitors that intervene in STAT3-associated pathways have been tested, an effective, highly specific inhibitor of STAT3 has yet to be identified. Here, we evaluated the in vitro and in vivo biological activity and therapeutic efficacy of a high-affinity peptide specific for STAT3 (APTstat3) after topical treatment via intradermal and transcutaneous delivery. Using a preclinical model of psoriasis, we show that intradermal injection of APTstat3 tagged with a 9-arginine cell-penetrating peptide (APTstat3-9R) reduced disease progression and modulated psoriasis-related cytokine signaling through inhibition of STAT3 phosphorylation. Furthermore, by complexing APTstat3-9R with specific lipid formulations led to formation of discoidal lipid nanoparticles (DLNPs), we were able to achieve efficient skin penetration of the STAT3-inhibiting peptide after transcutaneous administration, thereby effectively inhibiting psoriatic skin inflammation. Collectively, these findings suggest that DLNP-assisted transcutaneous delivery of a STAT3-inhibiting peptide could be a promising strategy for treating psoriatic skin inflammation without causing adverse systemic events. Moreover, the DLNP system could be used for transdermal delivery of other therapeutic peptides.