Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.
Hunan Chidren's Hospital, Changsha, Hunan, 410007, China.
J Control Release. 2021 Feb 10;330:119-131. doi: 10.1016/j.jconrel.2020.10.069. Epub 2020 Dec 15.
Methotrexate (MTX) has been used as an anchor drug for the treatment of rheumatoid arthritis (RA), while the patients with chronic MTX administration suffer from severe side-effects. To this end, targeted delivery of MTX by nanomedicine has attracted great interest. In this work, we aimed to employ metal-organic frameworks (MOFs) as nanocarrier to deliver MTX by virtue of its facile and green preparation and exceptionally high drug loading. While MTX could be easily and effectively loaded via different MOF construction strategies, such as direct coordination, physical encapsulation, and covalent conjugation, we found that most of the MTX loading MOFs showed premature and burst drug release, attributable to the unstable coordination between MTX and metals. To address this issue, we rationally designed the MOFs by conjugating MTX with tannic acid (TA) at 2:1 M ratio and then coordinating with ferric ion (Fe), followed by surface modification of hyaluronic acid (HA). The resulting MOFs achieved ultra-high drug loading (45%) and sustained drug release, and could selectively recognize the diseased cells for anti-inflammatory effect. The in vivo therapeutic evaluation suggested that the MOFs could enhance the anti-rheumatic activity of MTX while minimizing its toxic effects by targeted drug delivery, resulting in improved therapeutic index. This work provides a biocompatible nano-platform to deliver MTX for RA treatment, and importantly, calls for special attention to the gap between MOFs design and their biological applications, and the gap needs to be filled by careful evaluation of in vivo stability and burst drug release.
甲氨蝶呤（MTX）已被用作治疗类风湿关节炎（RA）的锚定药物，而长期接受 MTX 治疗的患者则会遭受严重的副作用。为此，纳米医学靶向递送 MTX 引起了极大的兴趣。在这项工作中，我们旨在利用金属有机框架（MOFs）作为纳米载体，通过其简便、绿色的制备方法和极高的载药能力来递送 MTX。虽然 MTX 可以通过不同的 MOF 构建策略（如直接配位、物理包封和共价键合）轻松有效地负载，但我们发现大多数负载 MTX 的 MOF 表现出过早和突释的药物释放，这归因于 MTX 与金属之间不稳定的配位。为了解决这个问题，我们通过以 2:1 M 的摩尔比将 MTX 与鞣酸（TA）偶联，然后与铁离子（Fe）配位，再进行透明质酸（HA）表面修饰，从而合理设计了 MOF。所得 MOF 实现了超高的药物负载量（45%）和持续的药物释放，并能选择性识别病变细胞以发挥抗炎作用。体内治疗评价表明，MOF 可以通过靶向药物递送增强 MTX 的抗风湿活性，同时最大限度地减少其毒性作用，从而提高治疗指数。这项工作为治疗 RA 提供了一种生物相容性的纳米平台，重要的是，它呼吁人们特别关注 MOF 设计与其生物应用之间的差距，需要通过对体内稳定性和突释药物释放的仔细评估来填补这一差距。
