An Injectable Hydrogel Platform for Sustained Delivery of Anti-inflammatory Nanocarriers and Induction of Regulatory T Cells in Atherosclerosis
An Injectable Hydrogel Platform for Sustained Delivery of Anti-inflammatory Nanocarriers and Induction of Regulatory T Cells in Atherosclerosis
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DOI：
10.3389/fbioe.2020.00542
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发表时间：
2020-06
影响因子：
5.7
通讯作者：
Sijia Yi;Nicholas B. Karabin;Jennifer Zhu;Sharan Bobbala;Huijue Lyu;Sophia Li;Yugang Liu;Molly A Frey
中科院分区：
文献类型：
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作者：
Sijia Yi;Nicholas B. Karabin;Jennifer Zhu;Sharan Bobbala;Huijue Lyu;Sophia Li;Yugang Liu;Molly A Frey
慢性未消退的血管炎症是动脉粥样硬化发生发展的关键因素。心血管免疫治疗因此成为最近治疗的焦点，其目的是开发能够通过调节特定免疫细胞群来抑制过度炎症反应的方法。这种免疫调节策略的一个好处是，低剂量刺激关键免疫细胞群，如抗原提呈细胞，随后可以从效应细胞中繁殖出强大的增殖和治疗反应。我们先前已经证明，静脉注射抗炎纳米载体可以提供动脉粥样硬化保护作用，这种保护作用是由淋巴器官和动脉粥样硬化病变中上调的调节性T细胞(Treg)介导的。在这里，我们展示了一种可注射的丝状水凝胶库(FM-DEPOT)，专为低剂量、持续输送抗炎纳米载体而设计。维生素D的生物活性形式1，25-二羟基维生素D3通过细胞内核激素受体维生素D受体抑制促炎转录因子NF-κB，被稳定地负载到聚乙二醇嵌段聚丙硫醚(PEGb-PPS)纤维胶束中。这些AVD负载的细丝在氧化时经历了形态转变，释放了单分散的载药胶束。用低温透射电子显微镜(CryoTEM)和小角X射线散射(SAXS)对这种柱状-胶束转变进行了表征。在与多臂聚乙二醇交联作原位凝胶后，携带avd的FM-depot在ApoE−/−小鼠皮下注射一次后，在淋巴器官和动脉粥样硬化病变中保持了高水平的foxp3+Treg。因此，FM-Depots提供了一个可定制的交付平台，用于开发和测试基于纳米药物的抗炎心血管免疫疗法。
Chronic unresolved vascular inflammation is a critical factor in the development of atherosclerosis. Cardiovascular immunotherapy has therefore become a recent focus for treatment, with the objective to develop approaches that can suppress excessive inflammatory responses by modulating specific immune cell populations. A benefit of such immunomodulatory strategies is that low dosage stimulation of key immune cell populations, like antigen presenting cells, can subsequently propagate strong proliferation and therapeutic responses from effector cells. We have previously demonstrated that intravenous injections of anti-inflammatory nanocarriers provided atheroprotection that was mediated by regulatory T cells (Tregs) upregulated in lymphoid organs and atherosclerotic lesions. Here, we demonstrate an injectable filamentous hydrogel depot (FM-depot) engineered for low dosage, sustained delivery of anti-inflammatory nanocarriers. The bioactive form of vitamin D (aVD; 1, 25-Dihydroxyvitamin D3), which inhibits pro-inflammatory transcription factor NF-κB via the intracellular nuclear hormone receptor vitamin D receptor (VDR), was stably loaded into poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b-PPS) filomicelles. These aVD-loaded filaments underwent morphological transitions to release monodisperse drug-loaded micelles upon oxidation. This cylinder-to-micelle transition was characterized in vitro by cryogenic transmission electron microscopy (CryoTEM) and small angle X-ray scattering (SAXS). Following crosslinking with multi-arm PEG for in situ gelation, aVD-loaded FM-depots maintained high levels of Foxp3+ Tregs in both lymphoid organs and atherosclerotic lesions for weeks following a single subcutaneous injection into ApoE−/− mice. FM-depots therefore present a customizable delivery platform to both develop and test nanomedicine-based approaches for anti-inflammatory cardiovascular immunotherapy.