Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, Av. Eduardo Primo Yúfera 3, Valencia 46012, Spain.
Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, El Sultan Hussein St Azarita, Egypt; John A. Paulson school of engineering and applied sciences and Wyss institute for biologically inspired engineering, Harvard University, 52 Oxford St, Cambridge, MA 02138, USA.
J Control Release. 2020 Feb;318:210-222. doi: 10.1016/j.jconrel.2019.12.016. Epub 2019 Dec 14.
Topical treatment of mild-to-moderate psoriasis with corticosteroids suffers from challenges that include reduced drug bioavailability at the desired site of action. The retention of therapeutics within the epidermis can safely treat skin inflammation, scaling, and erythema associated with psoriasis while avoiding possible side effects associated with systemic treatments. We successfully synthesized and characterized a pH-responsive biodegradable poly-L-glutamic acid (PGA)-fluocinolone acetonide (FLUO) conjugate that allows the controlled release of the FLUO to reduce skin inflammation. Additionally, the application of a hyaluronic acid (HA)-poly-L-glutamate cross polymer (HA-CP) vehicle boosted skin permeation. During in vitro and ex vivo analyses, we discovered that PGA-FLUO inhibited pro-inflammatory cytokine release, suggesting that polypeptidic conjugation fails to affect the anti-inflammatory activity of FLUO. Additionally, ex vivo human skin permeation studies using confocal microscopy revealed the presence of PGA-FLUO within the epidermis, but a minimal presence in the dermis, thereby reducing the likelihood of FLUO entering the systemic circulation. Finally, we demonstrated that PGA-FLUO applied within HA-CP effectively reduced psoriasis-associated phenotypes in an in vivo mouse model of human psoriasis while also lowering levels of pro-inflammatory cytokines in tissue and serum. Overall, our experimental results demonstrate that PGA-FLUO within an HA-CP penetration enhancer represents an effective topical treatment for psoriasis.
局部治疗轻中度银屑病的皮质类固醇存在一些挑战，包括在所需作用部位的药物生物利用度降低。在表皮内保留治疗药物可以安全地治疗与银屑病相关的皮肤炎症、鳞屑和红斑，同时避免与全身治疗相关的潜在副作用。我们成功合成并表征了一种 pH 响应性可生物降解的聚谷氨酸（PGA）-氟轻松醋酸酯（FLUO）缀合物，该缀合物可以控制 FLUO 的释放，以减轻皮肤炎症。此外，透明质酸（HA）-聚谷氨酸交联聚合物（HA-CP）载体的应用增加了皮肤渗透。在体外和离体分析中，我们发现 PGA-FLUO 抑制促炎细胞因子的释放，这表明多肽缀合不会影响 FLUO 的抗炎活性。此外，使用共聚焦显微镜进行的离体人皮肤渗透研究表明 PGA-FLUO 存在于表皮内，但在真皮内存在极少，从而降低了 FLUO 进入全身循环的可能性。最后，我们证明，在 HA-CP 内应用 PGA-FLUO 可有效减轻人银屑病体内模型中的银屑病相关表型，同时降低组织和血清中促炎细胞因子的水平。总的来说，我们的实验结果表明，HA-CP 中的 PGA-FLUO 作为一种有效的局部治疗银屑病的方法具有潜力。
