Enhancement of antitumor effect of radiotherapy via combination with Au@SiO2 nanoparticles targeted to tumor-associated macrophages

Mi Sun Kim; Jae Sang Lee; Jung Eun Kim; Jae-Won Kim; Seoyeon Bok; Ki Chang Keum; Won-Gun Koh; Woong Sub Koom

Journal of Industrial and Engineering Chemistry, Vol.84, 349-357, April, 2020

DOI10.1016/j.jiec.2020.01.017 Export Citation

Enhancement of antitumor effect of radiotherapy via combination with Au@SiO2 nanoparticles targeted to tumor-associated macrophages

Mi Sun Kim, Jae Sang Lee¹, Jung Eun Kim², Jae-Won Kim², Seoyeon Bok², Ki Chang Keum², Won-Gun Koh^{1, †}, and Woong Sub Koom^{2, †}

Graduate School, Yonsei University College of Medicine, Yonsei-ro 50-1, Seodaemoon-gu, Seoul, 03722, Republic of Korea
¹Department of Chemical and Biomolecular Engineering, Yonsei University, Yonsei-ro 50, Seodaemoon-gu, Seoul, 03722, Republic of Korea
²Department of Radiation Oncology, Yonsei University College of Medicine, Yonsei-ro 50-1, Seodaemoon-gu, Seoul, 03722, Republic of Korea

E-mail:,

Tumor-associated macrophages (TAMs) exhibit the M2 phenotype and serve as critical tumor-promoting immune cells in the tumor microenvironment. As TAMs are an important target, we examined the effect of gold nanoparticles (AuNPs) with radiotherapy (RT) on M2 TAMs in tumors. We synthesized CD163 antibody-conjugated, silica-coated AuNPs (CD163-GNPs) that were specifically recognized by M2 TAMs. Bone marrow-derived macrophages and Raw 264.7 macrophages were polarized into M1 and M2 phenotypes. The effect of CD163-GNPs combined with RT was evaluated in a CT26 syngeneic mouse model (BALB/c mice). Immunostaining, flow cytometry, microscopic analyses, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction (qRT-PCR), and tumor growth delay assay were performed following irradiation combined with CD163-GNP treatment. We observed selective phagocytosis of CD163-GNPs by Raw 264.7 macrophages following M1/M2 polarization. Immunostaining analyses revealed higher numbers of CD163-GNPs taken up by M2 macrophages than M0 or M1 type. CD163-GNPs combined with RT significantly reduced tumor growth in the CT26 syngeneic mouse model. Macrophages subjected to the combination treatment showed increased expression of M1 markers. The depletion of M2 TAMs in tumors upon combination treatment with CD163-GNPs enhances the efficiency of RT.

Keywords:Tumor-associated macrophage (TAM);M2 TAM-targeting gold nanoparticles;Radiotherapy combined with gold nanoparticles;Tumor microenvironment

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[2] Xu J, Escamilla J, Mok S, David J, Priceman S, West B, Bollag G, McBride W, Wu L, Cancer Res., 73, 2782 (2013)

[3] Pinto AT, Pinto ML, Cardoso AP, Monteiro C, et al., Sci. Rep., 6, 18765 (2016)

[4] Miao X, Leng X, Zhang Q, Int. J. Mol. Sci., 18 (2017)

[5] Pollard JW, Nat. Rev. Cancer, 4, 71 (2004)

[6] Cardoso AP, Pinto ML, Pinto AT, Oliveira MI, Pinto MT, Goncalves R, Relvas JB, Figueiredo C, Seruca R, Mantovani A, Mareel M, Barbosa MA, Oliveira MJ, Oncogene, 33, 2123 (2014)

[7] Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M, Trends Immunol., 25, 677 (2004)

[8] Cardoso AP, Pinto ML, Pinto AT, Pinto MT, Monteiro C, Oliveira MI, Santos SG, Relvas JB, Seruca R, Mantovani A, Mareel M, Barbosa MA, Oliveira MJ, BMC Cancer, 15, 456 (2015)

[9] Vinogradov S, Warren G, Wei X, Nanomedicine, 9, 695 (2014)

[10] Cho SH, Jones BL, Krishnan S, Phys. Med. Biol., 54, 4889 (2009)

[11] Kim MS, Lee EJ, Kim JW, Chung US, Koh WG, Keum KC, Koom WS, Radiat. Oncol. J., 34, 230 (2016)

[12] Yoo JW, Chambers E, Mitragotri S, Curr. Pharm. Des., 16, 2298 (2010)

[13] Sica A, Schioppa T, Mantovani A, Allavena P, Eur. J. Cancer, 42, 717 (2006)

[14] Allavena P, Mantovani A, Clin. Exp. Immunol., 167, 195 (2012)

[15] Yang L, Zhang Y, J. Hematol. Oncol., 10, 58 (2017)

[16] Bastus NG, Comenge J, Puntes V, Langmuir, 27(17), 11098 (2011)

[17] Solinas G, Germano G, Mantovani A, Allavena P, J. Leukoc. Biol., 86, 1065 (2009)

[18] Gabrilovich DJ, Ostrand-Rosenberg S, Bronte V, Nat. Rev. Immunol., 12, 253 (2012)

[19] Ruffell B, Affara NI, Coussens LM, Trends Immunol., 33, 119 (2012)

[20] Chiang CS, Fu SY, Wang SC, Yu CF, Chen FH, Lin CM, Hong JH, Front. Oncol., 2, 89 (2012)

[21] Weigert A, Brune B, Nitric Oxide Biol. Chem., 19, 95 (2008)

[22] Martinez FO, Helming L, Gordon S, Annu. Rev. Immunol., 27, 451 (2009)

[23] Lu T, Ramakrishnan R, Altiok S, Youn JI, Cheng P, Celis E, Pisarev V, Sherman S, Sporn MB, Gabrilovich D, J. Clin. Invest., 121, 4015 (2011)

[24] Bao X, Albu DI, Huang KC, Wu J, Twine N, Nomoto K, Woodall-Jappe M, Ataman O, Int. J. Radiat. Oncol. Biol. Phys., 96 (2016)

[25] Pal R, Chakraborty B, Nath A, Singh LM, Ali M, Rahman DS, Ghosh SK, Basu A, Bhattacharya S, Baral R, Sengupta M, Int. Immunopharmacol., 38, 332 (2016)

[26] Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J, Fowler N, et al., Sci. Transl. Med., 7, 314ra1 (2015)

[27] Binnemars-Postma K, Storm G, Prakash J, Int. J. Mol. Sci., 18 (2017)

[28] Cardoso AP, Goncalves RM, Antunes JC, Pinto ML, Pinto AT, Castro F, Monteiro C, Barbosa MA, Oliveira MJ, Acta Biomater., 23, 157 (2015)

[29] Sica A, Erreni M, Allavena P, Porta C, Cell. Mol. Life Sci., 72, 4111 (2015)

[30] McWhorter FY, Davis CT, Liu WF, Cell. Mol. Life Sci., 72, 1303 (2015)

[31] Sica A, Mantovani A, J. Clin. Invest., 122, 787 (2012)

[32] Veeraraghavan J, Natarajan M, Aravindan S, Herman TS, Aravindan N, J. Biol. Chem., 286, 21588 (2011)

[33] Kratochvill F, Neale G, Haverkamp JM, Van de Velde LA, Smith AM, Kawauchi D, McEvoy J, Roussel MF, Dyer MA, Qualls JE, Murray PJ, Cell Rep., 12, 1902 (2015)

[34] Sathishkumar S, Dey S, Meigooni AS, Regine WF, Kudrimoti MS, Ahmed MM, Mohiuddin M, Technol. Cancer Res. Treat., 1, 141 (2002)

[35] Fuchs AK, Syrovets T, Haas KA, Loos C, Musyanovych A, Mailander V, Landfester K, Simmet T, Biomaterials, 85, 78 (2016)

[36] Laskar A, Eilertsen J, Li W, Yuan XM, Biochem. Biophys. Res. Commun., 441(4), 737 (2013)

[37] Su L, Zhang W, Wu X, Zhang Y, Chen X, Liu G, Chen G, Jiang M, Small, 11, 4191 (2015)