Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control.
Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control.
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DOI：
10.1039/c8sc00015h
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发表时间：
2018-04-21
期刊：
影响因子：
8.4
通讯作者：
Mitragotri S
中科院分区：
文献类型：
--
作者：
Evans MA;Huang PJ;Iwamoto Y;Ibsen KN;Chan EM;Hitomi Y;Ford PC;Mitragotri S
巨噬细胞介导的靶向和光化学释放提供了一氧化氮递送至肿瘤球体的时空控制。如果一氧化氮（NO）的浓度和定位能够精确控制，那么它作为癌症缺氧的治疗方法具有巨大的前景。在这里，我们报告了一种“特洛伊木马”策略，为目标组织的此类药物输送疗法提供必要的空间、时间和剂量控制。所描述的是一种独特的包装，由 (1) 锰-亚硝酰复合物组成，它是光激活 NO 释放部分 (photoNORM)，加上掺入 (2) 可生物降解聚合物微粒中的 Nd3+ 掺杂上转换纳米粒子 (Nd-UCNP)，这些微粒被 (3) 骨髓来源的鼠巨噬细胞吸收。 photoNORM [Mn(NO)dpaqNO2]BPh4(dpaqNO2 = 2-[N,N-bis(pyridin-2-yl-methyl)]-amino-N'-5-硝基-喹啉-8-yl-acetamido) 和 Nd-UCNP 均被~800 nm 的组织穿透近红外 (NIR) 光激活。因此，使用 NIR 二极管激光源可以同时实现治疗性 NO 输送和光致发光 (PL) 成像。在没有光的情况下，负载的微粒对其巨噬细胞宿主是无毒的。携带微粒的巨噬细胞深入渗透到 NIH-3T3/4T1 肿瘤球体模型中，当用近红外光照射渗透的球体时，NO 会以可量化的量释放，同时 Nd-UCNP 的发射提供了微粒位置的图像。此外，改变近红外激发的强度可以实现对 NO 释放的光化学控制。低剂量会降低肿瘤细胞中缺氧诱导因子 1 α (HIF-1α) 的水平，而高剂量则具有细胞毒性。使用巨噬细胞将具有近红外光激活治疗诊断有效负载的微粒携带到肿瘤中，克服了NO治疗给药经常面临的挑战，并提供了利用单一系统进行多种治疗策略的潜力。
Macrophage-mediated targeting and photochemical release provides spatial-temporal control of nitric oxide delivery to tumor spheroids. Nitric oxide (NO) holds great promise as a treatment for cancer hypoxia, if its concentration and localization can be precisely controlled. Here, we report a “Trojan Horse” strategy to provide the necessary spatial, temporal, and dosage control of such drug-delivery therapies at targeted tissues. Described is a unique package consisting of (1) a manganese–nitrosyl complex, which is a photoactivated NO-releasing moiety (photoNORM), plus Nd3+-doped upconverting nanoparticles (Nd-UCNPs) incorporated into (2) biodegradable polymer microparticles that are taken up by (3) bone-marrow derived murine macrophages. Both the photoNORM [Mn(NO)dpaqNO2]BPh4(dpaqNO2 = 2-[N,N-bis(pyridin-2-yl-methyl)]-amino-N′-5-nitro-quinolin-8-yl-acetamido) and the Nd-UCNPs are activated by tissue-penetrating near-infrared (NIR) light at ∼800 nm. Thus, simultaneous therapeutic NO delivery and photoluminescence (PL) imaging can be achieved with a NIR diode laser source. The loaded microparticles are non-toxic to their macrophage hosts in the absence of light. The microparticle-carrying macrophages deeply penetrate into NIH-3T3/4T1 tumor spheroid models, and when the infiltrated spheroids are irradiated with NIR light, NO is released in quantifiable amounts while emission from the Nd-UCNPs provides images of microparticle location. Furthermore, varying the intensity of the NIR excitation allows photochemical control over NO release. Low doses reduce levels of hypoxia inducible factor 1 alpha (HIF-1α) in the tumor cells, while high doses are cytotoxic. The use of macrophages to carry microparticles with a NIR photo-activated theranostic payload into a tumor overcomes challenges often faced with therapeutic administration of NO and offers the potential of multiple treatment strategies with a single system.
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