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)dpaq^NO₂]BPh₄(dpaq^NO₂ = 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.

中文翻译：

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巨噬细胞介导的光活化一氧化氮前药的递送，具有空间，时间和浓度控制功能†

如果可以精确控制其浓度和位置，一氧化氮（NO）有望作为治疗癌症缺氧的方法。在这里，我们报告“特洛伊木马”策略，以在目标组织上提供此类药物递送疗法的必要空间，时间和剂量控制。描述了一个独特的包装，该包装包括（1）锰-亚硝酰基配合物，它是光活化的NO释放部分（photoNORM），以及掺入（2）可生物降解的聚合物微粒中的Nd ³⁺掺杂的上转换纳米颗粒（Nd-UCNP）。被（3）骨髓来源的鼠巨噬细胞吸收。都是photoNORM [Mn（NO）dpaq ^{NO ₂} ] BPh ₄（dpaq ^{NO ₂} = 2- [ N，N-双（吡啶-2-基-甲基）]-氨基-N（5-硝基-喹啉-8-乙酰氨基）和Nd-UCNPs被组织穿透的〜800 nm的近红外（NIR）光激活。因此，可以使用NIR二极管激光源实现同时的治疗性NO输送和光致发光（PL）成像。在没有光照的情况下，负载的微粒对其巨噬细胞宿主无毒。携带微粒的巨噬细胞深深地渗透到NIH-3T3 / 4T1肿瘤球体模型中，当用NIR光照射渗透的球体时，NO以可定量释放，而Nd-UCNPs的发射则提供了微粒位置的图像。此外，改变NIR激发的强度可以对NO的释放进行光化学控制。低剂量可降低肿瘤细胞中缺氧诱导因子1α（HIF-1α）的水平，而高剂量则具有细胞毒性。