RESUMO
Purpose: This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111In and 177Lu, respectively. Methods: We designed F(ab′)2-fragments of cetuximab radiolabeled with 111In and 177Lu. 111In-F(ab′)2-cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111In-F(ab′)2-cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177Lu-F(ab′)2-cetuximab was evaluated in SWISS nude mice bearing A431 tumors. Results: Radiolabeling procedure did not change F(ab′)2-cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111In-DOTAGA-F(ab′)2-cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab′)2-cetuximab. SPECT imaging of 111In-DOTAGA-F(ab′)2-cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177Lu-DOTAGA-F(ab′)2-cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses. Conclusions: 111In-DOTAGA-F(ab′)2-cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177Lu-DOTAGA-F(ab′)2-cetuximab is an interesting theranostic tool allowing therapy and imaging
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Assuntos
Animais , Ratos , Nanomedicina Teranóstica/métodos , Cetuximab/uso terapêutico , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Cutâneas/diagnóstico por imagem , Radioimunoterapia/métodos , Modelos Animais de Doenças , Neoplasias Colorretais/terapia , Neoplasias Cutâneas/terapia , Marcação por Isótopo/métodos , Genes erbB-1/efeitos da radiaçãoRESUMO
PURPOSE: This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111In and 177Lu, respectively. METHODS: We designed F(ab')2-fragments of cetuximab radiolabeled with 111In and 177Lu. 111In-F(ab')2-cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111In-F(ab')2-cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177Lu-F(ab')2-cetuximab was evaluated in SWISS nude mice bearing A431 tumors. RESULTS: Radiolabeling procedure did not change F(ab')2-cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111In-DOTAGA-F(ab')2-cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab')2-cetuximab. SPECT imaging of 111In-DOTAGA-F(ab')2-cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177Lu-DOTAGA-F(ab')2-cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses. CONCLUSIONS: 111In-DOTAGA-F(ab')2-cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177Lu-DOTAGA-F(ab')2-cetuximab is an interesting theranostic tool allowing therapy and imaging.
Assuntos
Cetuximab/farmacologia , Neoplasias Colorretais , Imunoconjugados/farmacologia , Radioimunodetecção/métodos , Neoplasias Cutâneas , Nanomedicina Teranóstica/métodos , Animais , Cetuximab/farmacocinética , Humanos , Imunoconjugados/farmacocinética , Fragmentos Fab das Imunoglobulinas/farmacologia , Radioisótopos de Índio , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In addition to their cytoprotective role in stressful conditions, heat shock proteins (HSPs) are involved in specific differentiation pathways, for example, we have identified a role for HSP90 in macrophage differentiation of human peripheral blood monocytes that are exposed to macrophage colony-stimulating factor (M-CSF). Here, we show that deletion of the main transcription factor involved in heat shock gene regulation, heat shock factor 1 (HSF1), affects M-CSF-driven differentiation of mouse bone marrow cells. HSF1 transiently accumulates in the nucleus of human monocytes undergoing macrophage differentiation, including M-CSF-treated peripheral blood monocytes and phorbol ester-treated THP1 cells. We demonstrate that HSF1 has a dual effect on SPI1/PU.1, a transcription factor essential for macrophage differentiation and whose deregulation can lead to the development of leukemias and lymphomas. Firstly, HSF1 regulates SPI1/PU.1 gene expression through its binding to a heat shock element within the intron 2 of this gene. Furthermore, downregulation or inhibition of HSF1 impaired both SPI1/PU.1-targeted gene transcription and macrophage differentiation. Secondly, HSF1 induces the expression of HSP70 that interacts with SPI1/PU.1 to protect the transcription factor from proteasomal degradation. Taken together, HSF1 appears as a fine-tuning regulator of SPI1/PU.1 expression at the transcriptional and post-translational levels during macrophage differentiation of monocytes.