Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control. Issue 15 (28th March 2018)

• Record Type: Journal Article
• Authors: Evans, Michael A.; Huang, Po-Ju; Iwamoto, Yuji; Ibsen, Kelly N.; Chan, Emory M.; Hitomi, Yutaka; Ford, Peter C.; Mitragotri, Samir
• Is Part Of: Chemical science. Volume 9:Issue 15(2018)
• Page Start: 3729
• Page End: 3741
• Publication Date: 2018-03-28
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c8sc00015h
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : Macrophage-mediated targeting and photochemical release provides spatial-temporal control of nitric oxide delivery to tumor spheroids. 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 Nd 3+ -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.