Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder CO 80303, United States.
Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder CO 80303, United States; Department of Advanced Organ Bioengineering and Therapeutics, Section: Engineered Therapeutics, University of Twente, Enschede, the Netherlands.
Acta Biomater. 2022 Sep 15;150:211-220. doi: 10.1016/j.actbio.2022.07.053. Epub 2022 Aug 1.
Both innate and adaptive immune systems play a crucial role in the pathology of skin diseases. To control these cells, there is a need for transdermal drug delivery systems that can target multiple cell populations at independently tunable rates. Herein, we describe a tissue-adhesive hydrogel system that contains particles capable of regulating the release of small molecule drugs at defined rates. Resiquimod (a macrophage-targeting drug) and palbociclib (a T cell-targeting drug) are encapsulated within two types of silicone particles embedded within the hydrogel. We demonstrate that drug release is mediated by the crosslink density of the particles, which is decoupled from the bulk properties of the hydrogel. We show that this system can be used to sustainably polarize macrophages toward an anti-tumor phenotype in vitro and ex vivo, and that the hydrogels can remain attached to skin explants for several days without generating toxicity. The hydrogel system is compatible with standard dermatological procedures and allows transdermal passage of drugs. The multimodal, tunable nature of this system has implications in treating a variety of skin disorders, managing infections, and delivering vaccines. STATEMENT OF SIGNIFICANCE: We describe a tissue-adhesive hydrogel that can regulate the release of drugs in a manner that is decoupled from its bulk properties. The mechanism of drug release is mediated by embedded microparticles with well-defined crosslink densities. The significance of this system is that, by encapsulating different drugs into the particles, it is possible to achieve multimodal drug release. We demonstrate this capability by releasing two immunomodulatory drugs at disparate rates. A drug that targets innate immune cells is released quickly, and a drug that targets adaptive immune cells is released slowly. This programmable system offers a direct means by which cellular responses can be enhanced through independent targeting for a variety of transdermal applications, including cancer treatment and vaccine delivery.
先天免疫系统和适应性免疫系统在皮肤病的病理中都起着至关重要的作用。为了控制这些细胞，我们需要一种透皮药物输送系统，该系统能够以独立可调的速率靶向多个细胞群体。在此，我们描述了一种组织黏附水凝胶系统，该系统包含能够以定义的速率调节小分子药物释放的颗粒。瑞喹莫德（一种靶向巨噬细胞的药物）和帕博西尼（一种靶向 T 细胞的药物）被包裹在两种类型的硅酮颗粒内，这些颗粒嵌入水凝胶中。我们证明药物释放是由颗粒的交联密度介导的，这与水凝胶的整体性质是解耦的。我们表明，该系统可用于体外和离体持续将巨噬细胞极化到抗肿瘤表型，并且水凝胶可以在不产生毒性的情况下附着在皮肤外植体上数天。水凝胶系统与标准皮肤科程序兼容，并允许药物经皮传递。该系统的多模式、可调谐性质在治疗各种皮肤疾病、管理感染和输送疫苗方面具有重要意义。
