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Evans, Michael

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Evans

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Michael

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Evans, Michael
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    Systemic Tumour Suppression via the Preferential Accumulation of Erythrocyte-Anchored Chemokine-Encapsulating Nanoparticles in Lung Metastases
    (Springer Science and Business Media LLC, 2020-11-16) Zhao, Zongmin; Ukidve, Anvay; Krishnan, Vinu; Fehnel, Alexandra; Pan, Daniel; Gao, Yongsheng; Kim, Jayoung; Evans, Michael; Mandal, Abhirup; Guo, Junling; Muzykantov, Vladimir R.; Mitragotri, Samir
    Eliciting immune responses against primary tumours is hampered by their immunosuppressive microenvironment and by the greater inaccessibility of deeper intratumoural cells. Metastatic tumour cells are however exposed to highly perfused and immunoactive organs, such as the lungs. Here, by taking advantage of the preferential co-localization of intravenously administered erythrocytes with metastases in the lung, we show that chemokine-encapsulating nanoparticles non-covalently anchored on the surface of injected erythrocytes result in local and systemic tumour suppression in mouse models of lung metastasis. Such ‘erythrocyte-anchored’ systemic immunotherapy led to the infiltration of effector immune cells into the lungs, to in situ immunization without the need of exogenous antigens, to the inhibition of the progression of lung metastasis, to significantly extended animal survival, and to systemic immunity that suppressed the growth of distant tumours after rechallenge. Erythrocyte-mediated systemic immunotherapy may represent a general and potent strategy for cancer vaccination.
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    Macrophage-mediated delivery of light activated nitric oxide prodrugs with spatial, temporal and concentration control† †Electronic supplementary information (ESI) available: Includes detailed experimental details plus 10 additional figures. See DOI: 10.1039/c8sc00015h
    (Royal Society of Chemistry, 2018) Evans, Michael; Huang, Po-Ju; Iwamoto, Yuji; Ibsen, Kelly N.; Chan, Emory M.; Hitomi, Yutaka; Ford, Peter C.; Mitragotri, Samir
    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.