Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial{,} temporal and concentration control

TitleMacrophage-mediated delivery of light activated nitric oxide prodrugs with spatial{,} temporal and concentration control
Publication TypeJournal Article
Year of Publication2018
AuthorsEvans MA, Huang P-J, Iwamoto Y, Ibsen K[space]N., Chan EM, Hitomi Y, Ford PC, Mitragotri S
JournalChem. Sci.

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[prime or minute]-5-nitro-quinolin-8-yl-acetamido) and the Nd-UCNPs are activated by tissue-penetrating near-infrared (NIR) light at [similar]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-1[small alpha]) 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.