Effervescent cannabidiol solid dispersion-doped dissolving microneedles for boosted melanoma therapy via the “TRPV1-NFATc1-ATF3” pathway and tumor microenvironment engineering

作者：Jiachen Shi, Qiuling Ma, Wenting Su, Congyan Liu, Huangqin Zhang, Yuping Liu, Xiaoqi Li, Xi Jiang, Chang Ge, Fei Kong, Yan Chen, Ding Qu · 发表于：Biomaterials Research · 年份：2023 · DOI：10.1186/s40824-023-00390-x · 被引用次数：15 · 研究领域：Advancements in Transdermal Drug Delivery、Cannabis and Cannabinoid Research、Toxin Mechanisms and Immunotoxins

Abstract Background Conventional dissolving microneedles (DMNs) face significant challenges in anti-melanoma therapy due to the lack of active thrust to achieve efficient transdermal drug delivery and intra-tumoral penetration. Methods In this study, the effervescent cannabidiol solid dispersion-doped dissolving microneedles (Ef/CBD-SD@DMNs) composed of the combined effervescent components (CaCO 3 & NaHCO 3 ) and CBD-based solid dispersion (CBD-SD) were facilely fabricated by the “one-step micro-molding” method for boosted transdermal and tumoral delivery of cannabidiol (CBD). Results Upon pressing into the skin, Ef/CBD-SD@DMNs rapidly produce CO 2 bubbles through proton elimination, significantly enhancing the skin permeation and tumoral penetration of CBD. Once reaching the tumors, Ef/CBD-SD@DMNs can activate transient receptor potential vanilloid 1 (TRPV1) to increase Ca 2+ influx and inhibit the downstream NFATc1-ATF3 signal to induce cell apoptosis. Additionally, Ef/CBD-SD@DMNs raise intra-tumoral pH environment to trigger the engineering of the tumor microenvironment (TME), including the M1 polarization of tumor-associated macrophages (TAMs) and increase of T cells infiltration. The introduction of Ca 2+ can not only amplify the effervescent effect but also provide sufficient Ca 2+ with CBD to potentiate the anti-melanoma efficacy. Such a “one stone, two birds” strategy combines the advantages of effervescent effects on transdermal delivery and TME regulation, creat...