CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 506007, India.
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307, United States.
ACS Appl Mater Interfaces. 2022 Apr 6;14(13):14859-14870. doi: 10.1021/acsami.1c19180. Epub 2022 Mar 29.
Long-term application of topical therapeutics for psoriasis has a plethora of side effects. Additionally, skin-permeating agents used in their formulations for deeper dermal delivery damage the skin. To address these limitations, we developed novel lithocholic acid analogues that could form lipid nanoparticles (nano-LCs) spontaneously in the aqueous milieu, permeate through the skin, penetrate the deeper dermal layers, and exert anti-inflammatory effects against psoriasis-like chronic skin inflammations. Prior findings demonstrated that lithocholic acid acts as a vitamin D receptor agonist without affecting the Ca metabolism and also as an antagonist for ephrin type-A receptor 2 (EphA2). Taking cues from the previous findings, lithocholic acid derivatives with twin alkyl chains (LC6, LC8, LC10, and LC-12) were synthesized, nanoparticles (nano-LCs) were prepared, and they were evaluated for their skin permeability and anti-inflammatory properties. Among these nano-LCs, nano-LC10 demonstrated superior anti-inflammatory properties and inhibition of keratinocyte proliferation in various cell-based evaluations. Furthermore, the therapeutic efficiency of nano-LC10 was evaluated in an imiquimod-induced psoriasis-like mouse model and demonstrated comparable efficiency with the standard topical formulation, Sorvate, in reducing skin inflammations. Nano-LC10 also reduced systemic inflammation, organ toxicity, and also proinflammatory serum cytokine levels. Overall, nano-lithocholic lipidoid (nano-LC10) can be a potential novel class of therapeutics for topical application in treating psoriasis.
长期应用局部治疗药物治疗银屑病会产生大量的副作用。此外，其配方中用于深层真皮递送的透皮剂会破坏皮肤。为了解决这些局限性，我们开发了新型胆酸类似物，它们可以在水性环境中自发形成脂质纳米颗粒（纳米-LC），渗透皮肤，穿透更深的真皮层，并发挥抗炎作用，对抗类似银屑病的慢性皮肤炎症。先前的研究结果表明，胆酸作为维生素 D 受体激动剂起作用，而不会影响钙代谢，并且作为 EphA2 型受体的拮抗剂。从前人的研究中得到启发，我们合成了带有双烷基链的胆酸衍生物（LC6、LC8、LC10 和 LC-12），制备了纳米颗粒（纳米-LC），并评估了它们的皮肤渗透性和抗炎特性。在这些纳米-LC 中，纳米-LC10 在各种基于细胞的评估中表现出优异的抗炎特性和对角质形成细胞增殖的抑制作用。此外，我们还在咪喹莫特诱导的银屑病样小鼠模型中评估了纳米-LC10 的治疗效果，结果表明其在减轻皮肤炎症方面与标准局部制剂 Sorvate 相当。纳米-LC10 还降低了全身炎症、器官毒性和促炎血清细胞因子水平。总的来说，纳米胆酸类脂（nano-LC10）可以成为一种新型的潜在治疗药物，用于治疗银屑病的局部应用。
