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1.
Mol Imaging Biol ; 22(4): 1043-1053, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32125599

RESUMO

PURPOSE: The aim of this study was to perform radiotheranostics with radioiodinated monoclonal antibodies (mAbs) for targeting cancer stem cells (CSCs) in human colorectal cancer xenografts and evaluate the relative advantage of a cocktail containing both [131I]CD133 mAb and [131I]CD44 mAb. PROCEDURES: Tumor-bearing mice were randomly divided into eight groups: [131I]CD133mAb, [131I]CD44 mAb, [131I]IgG isotype control, radioiodinated mAb cocktail, CD133 mAb, CD44 mAb, unradioiodinated mAb cocktail, and saline groups. In vivo single photon emission computed tomography (SPECT) imaging was used to monitor dynamically changes in the CSC population after treatment. The radioactivity uptake of tumors was quantified ex vivo. The expression of CD133 and CD44 after treatment was also assessed by immunohistochemistry and western blot. Tumor growth curves and survival curves were generated to assess treatment efficacy. Cell apoptosis and proliferation in xenografts 30 days after treatment were measured by TdT-mediated dUTP-biotin nick end labeling (aka, TUNEL) and Ki67 staining. The expression levels of biomarkers in xenografts 30 days after treatment were measured by flow cytometry. RESULTS: The radioimmunoimaging (RII) with in vivo SPECT showed that the CSC-targeting radioimmunotherapy (RIT) groups ([131I]CD133 mAb, [131I]CD44 mAb, and radioiodinated mAb cocktail groups) had intense accumulations of radiolabeled agents in the tumor areas. The ex vivo biodistribution confirmed these findings. In the CSC-targeting RIT groups, immunohistochemistry and western blot indicated significant reduction of specific target expression in the xenografts. The tumor growth curves and survival curves showed that the CSC-targeting RIT significantly inhibited tumor growth and prolonged mean survival, respectively. Significantly increased apoptosis and decreased proliferation in xenografts further confirmed the therapeutic efficacy of CSC-targeting RIT. Flow cytometry showed that the decreases in CSCs correlated with the presence of the corresponding antibodies. CONCLUSIONS: Our results suggest that the CSC-targeting RIT can effectively reduce CSCs which consequently inhibits tumor development. The radioiodinated mAb cocktail may generate enhanced CSC-targeting specificity.


Assuntos
Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/terapia , Células-Tronco Neoplásicas/patologia , Compostos Radiofarmacêuticos/química , Ensaios Antitumorais Modelo de Xenoenxerto , Antígeno AC133/metabolismo , Animais , Peso Corporal , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Humanos , Receptores de Hialuronatos/metabolismo , Antígeno Ki-67/metabolismo , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único
2.
Oncotarget ; 8(27): 44004-44014, 2017 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-28430648

RESUMO

Accumulating evidence indicates that cancer stem cells (CSCs) are the cause of tumor drug/radio-resistance or distant metastasis; therefore, it is essential to eliminate CSCs to cure cancer completely. The purpose of this study was to utilize radioimmunotherapy (RIT) to target CD133(+) colonic CSCs and observe whether this prevented tumor development, by assessing the maximum tolerated dose (MTD) of HCT116 tumor-bearing nude mice with escalating doses of 131I-AC133.1 monoclonal antibody (mAb), and determining the therapeutic efficacy of RIT with 131I-AC133.1 mAb. For RIT trials, animals were randomly divided into 4 groups of 6 per group, and injected with 131I-AC133.1 mAb (16.65 MBq/100 µl), AC133.1 mAb (173.1 µg/100 µl), saline (100 µl), or unrelated IgG1 as an isotype control. Iodine-131 was radiolabeled to AC133.1 mAb by conjugation with N-succinimidyl 3-(tri-n-butylstannyl) benzoate. The MTD of HCT116 tumor-bearing nude mice was 16.65 MBq. Both of the tumor volume doubling time and the survival time of the 131I-AC133.1 mAb group were significant longer than other groups (P < 0.001). CD133 expression was assessed by flow cytometry. Protein levels of cancer stem-like biomarkers (CD133, ALDH1, Lgr5, Vimentin, Snail1), and the proliferative rate of 131I-AC133.1 mAb group were lower than other groups (P<0.001); while its protein level of E-cadherin was higher than other groups. Furthermore, a large proportion of tumor necrosis was also observed in the 131I-AC133.1 mAb group, suggesting that RIT can destroy CSCs and effectively inhibit tumor development.


Assuntos
Antígeno AC133/metabolismo , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Células-Tronco Neoplásicas/metabolismo , Radioimunoterapia , Animais , Proliferação de Células , Neoplasias do Colo/mortalidade , Neoplasias do Colo/terapia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia , Radioisótopos do Iodo , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Nus , Radioimunoterapia/métodos , Distribuição Tecidual , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
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