Near-Infrared-Triggered Photodynamic Therapy with Multitasking Upconversion Nanoparticles in Combination with Checkpoint Blockade for Immunotherapy of Colorectal Cancer
Near-Infrared-Triggered Photodynamic Therapy with Multitasking Upconversion Nanoparticles in Combination with Checkpoint Blockade for Immunotherapy of Colorectal Cancer
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DOI：
10.1021/acsnano.7b00715
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发表时间：
2017-05-01
期刊：
影响因子：
17.1
通讯作者：
Liu, Zhuang
中科院分区：
文献类型：
--
作者：
Xu, Jun;Xu, Ligeng;Liu, Zhuang
虽然近年来免疫疗法已成为癌症治疗的一个非常有前途的范例，但人们早已认识到光动力疗法（PDT）具有触发抗肿瘤免疫应答的能力。然而，由可见光触发的常规PDT具有有限的穿透深度，并且其产生的免疫反应可能不足以消除肿瘤。本文中，上转换纳米颗粒（UCNP）同时负载有二氢卟酚e6（Ce 6）（光敏剂）和咪喹莫特（R837）（Toll样受体-7激动剂）。在近红外（NIR）照射下获得的具有增强的组织穿透深度的多任务UCNP-Ce 6-R837纳米颗粒将能够有效地光动力破坏肿瘤以产生肿瘤相关抗原的库，其在作为佐剂的那些含有R837的纳米颗粒的存在下能够促进强的抗肿瘤免疫应答。更重要的是，PDT与UCNP-Ce 6-R837结合细胞毒性T淋巴细胞相关蛋白4（CTLA-4）检查点阻断不仅在消除暴露于NIR激光的肿瘤方面显示出优异的功效，而且还产生强的抗肿瘤免疫力以抑制PDT治疗后留下的远处肿瘤的生长。此外，这种癌症免疫治疗策略具有长期免疫记忆功能，以保护治疗的小鼠免受肿瘤细胞再攻击。这项工作提出了一种免疫刺激的基于UCNP的PDT策略，结合CTLA-4检查点阻断，以有效地破坏光暴露下的原发性肿瘤，抑制光难以到达的远处肿瘤，并通过免疫记忆效应防止肿瘤复发。
While immunotherapy has become a highly promising paradigm for cancer treatment in recent years, it has long been recognized that photodynamic therapy (PDT) has the ability to trigger antitumor immune responses. However, conventional PDT triggered by visible light has limited penetration depth, and its generated immune responses may not be robust enough to eliminate tumors. Herein, upconversion nanoparticles (UCNPs) are simultaneously loaded with chlorin e6 (Ce6), a photosensitizer, and imiquimod (R837), a Toll-like-receptor-7 agonist. The obtained multitasking UCNP-Ce6-R837 nanoparticles under near-infrared (NIR) irradiation with enhanced tissue penetration depth would enable effective photodynamic destruction of tumors to generate a pool of tumor-associated antigens, which in the presence of those R837 containing nanoparticles as the adjuvant are able to promote strong antitumor immune responses. More significantly, PDT with UCNP-Ce6-R837 combination with the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint blockade not only shows excellent efficacy in eliminating tumors exposed to the NIR laser but also results in strong antitumor immunities to inhibit the growth of distant tumors left behind after PDT treatment. Furthermore, such a cancer immunotherapy strategy has a long-term immune memory function to protect treated mice from tumor cell rechallenge. This work presents an immune-stimulating UCNP-based PDT strategy in combination with CTLA-4 checkpoint blockade to effectively destroy primary tumors under light exposure, inhibit distant tumors that can hardly be reached by light, and prevent tumor reoccurrence via the immune memory effect.