Combretastatin A4 Nanoparticles Combined with Hypoxia-Sensitive Imiquimod: A New Paradigm for the Modulation of Host Immunological Responses during Cancer Treatment
Combretastatin A4 Nanoparticles Combined with Hypoxia-Sensitive Imiquimod: A New Paradigm for the Modulation of Host Immunological Responses during Cancer Treatment
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康布他汀 A4 纳米颗粒联合缺氧敏感的咪喹莫特：癌症治疗期间调节宿主免疫反应的新范例
DOI：
10.1021/acs.nanolett.9b03214
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发表时间：
2019-11-01
期刊：
影响因子：
10.8
通讯作者：
Chen, Xuesi
中科院分区：
文献类型：
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作者：
Shen, Na;Wu, Jing;Chen, Xuesi
血管破坏剂（VDAs）在癌症治疗中具有巨大潜力。然而，除了其直接的肿瘤血管塌陷作用外，VDAs还会激活宿主免疫反应，这可能会显著削弱其抗癌功效。在此，一种血管破坏剂纳米药物，聚（L - 谷氨酸） - 接枝 - 甲氧基聚乙二醇/考布他汀A4（CA4 - NPs），被发现可诱导未成熟浆细胞样树突状细胞（pDCs）在肿瘤内浸润，从而削弱抗癌免疫力。为克服这一问题，开发了对缺氧敏感的咪喹莫特（hs - IMQ），它在CA4 - NPs诱导的硝基还原酶（NTR）催化下，在经治疗的肿瘤中选择性地活化为咪喹莫特（IMQ）。与单独使用hs - IMQ治疗相比，hs - IMQ和CA4 - NPs的组合使肿瘤中活性IMQ浓度提高了6.3倍。原位生成的IMQ将肿瘤微环境从免疫抑制状态转变为免疫激活状态。Hs - IMQ通过将未成熟的pDCs转化为其活性形式来实现这一效果，从而导致自然杀伤细胞和细胞毒性T淋巴细胞在经治疗的肿瘤中大量浸润和激活。因此，CA4 - NPs和hs - IMQ联合治疗在4T1荷瘤小鼠中协同抑制肿瘤生长和转移。这项工作为利用肿瘤内pDCs逆转由VDA治疗导致的免疫抑制提供了新方法。这些发现还为将VDAs与Toll样受体激动剂联合使用以触发原位免疫激活并提高抗癌功效提供了机制原理。
Vascular disrupting agents (VDAs) have great potential in cancer treatment. However, in addition to their direct tumoral vascular collapse effect, VDAs activate host immunological responses, which can remarkably impair their anticancer efficacy. Here, a VDA nanomedicine, poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 (CA4-NPs), is found to induce the intratumor infiltration of immature plasmacytoid dendritic cells (pDCs), thereby curtailing anticancer immunity. To overcome this problem, hypoxia-sensitive imiquimod (hs-IMQ) is developed, which is selectively activated into imiquimod (IMQ) in treated tumors following the catalysis of CA4-NPs-induced nitroreductase (NTR). The combination of hs-IMQ and CA4-NPs causes a 6.3-fold enhancement of active IMQ concentration in tumors, as compared to hs-IMQ treatment alone. The in situ-generated IMQ alters the tumor microenvironment from a state of immunosuppression to immune activation. Hs-IMQ achieves this effect through the conversion of immature pDCs into their active form, leading to the robust infiltration and priming of natural killer cells and cytotoxic T-lymphocytes in treated tumors. Thus, the CA4-NPs and hs-IMQ combination treatment synergistically inhibits tumor growth and metastasis in 4T1 tumor-bearing mice. This work offers new approaches to harness intratumor pDCs to reverse the immune suppression resulting from VDA treatment. These findings additionally provide a mechanistic rationale for the use of VDAs in combination with TLR agonists to trigger in situ immune activation and enhance anticancer efficacy.