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Issue 15, 2018
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Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control

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Abstract

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.

Graphical abstract: Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control

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Publication details

The article was received on 02 Jan 2018, accepted on 12 Mar 2018 and first published on 16 Mar 2018


Article type: Edge Article
DOI: 10.1039/C8SC00015H
Citation: Chem. Sci., 2018,9, 3729-3741
  • Open access: Creative Commons BY-NC license
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    Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control

    M. A. Evans, P. Huang, Y. Iwamoto, Kelly N. Ibsen, E. M. Chan, Y. Hitomi, P. C. Ford and S. Mitragotri, Chem. Sci., 2018, 9, 3729
    DOI: 10.1039/C8SC00015H

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