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Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control
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. De...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939611/ https://www.ncbi.nlm.nih.gov/pubmed/29780505 http://dx.doi.org/10.1039/c8sc00015h |
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author | Evans, Michael A. Huang, Po-Ju Iwamoto, Yuji Ibsen, Kelly N. Chan, Emory M. Hitomi, Yutaka Ford, Peter C. Mitragotri, Samir |
author_facet | Evans, Michael A. Huang, Po-Ju Iwamoto, Yuji Ibsen, Kelly N. Chan, Emory M. Hitomi, Yutaka Ford, Peter C. Mitragotri, Samir |
author_sort | Evans, Michael A. |
collection | PubMed |
description | 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(NO(2))]BPh(4)(dpaq(NO(2)) = 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. |
format | Online Article Text |
id | pubmed-5939611 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-59396112018-05-18 Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control Evans, Michael A. Huang, Po-Ju Iwamoto, Yuji Ibsen, Kelly N. Chan, Emory M. Hitomi, Yutaka Ford, Peter C. Mitragotri, Samir Chem Sci Chemistry 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(NO(2))]BPh(4)(dpaq(NO(2)) = 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. Royal Society of Chemistry 2018-03-16 /pmc/articles/PMC5939611/ /pubmed/29780505 http://dx.doi.org/10.1039/c8sc00015h Text en This journal is © The Royal Society of Chemistry 2018 http://creativecommons.org/licenses/by-nc/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported Licence (CC BY-NC 3.0) |
spellingShingle | Chemistry Evans, Michael A. Huang, Po-Ju Iwamoto, Yuji Ibsen, Kelly N. Chan, Emory M. Hitomi, Yutaka Ford, Peter C. Mitragotri, Samir Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control |
title | Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control
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title_full | Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control
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title_fullStr | Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control
|
title_full_unstemmed | Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control
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title_short | Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control
|
title_sort | macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939611/ https://www.ncbi.nlm.nih.gov/pubmed/29780505 http://dx.doi.org/10.1039/c8sc00015h |
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