Publicação
Transferrin Receptor 1-targeted nanoparticle therapy for Colorectal Cancer
| Resumo: | Colorectal cancer (CRC) is a major global health concern, ranking among the most common cancers and the third leading cause of cancer-related deaths. The high mortality associated with CRC is attributed mainly to difficulties in early detection and the lack of effective targeted therapies. The Transferrin receptor 1 (TfR1) is particularly attractive as a therapy target given its notable overexpression in tumor cells, particularly in CRC. This study explored the potential of a nanoparticle (NPs)-based drug delivery system targeting TfR1 to improve the precision and efficacy of CRC treatment. First, we characterized three human colorectal cancer cell lines (SW480, HT-29, and HCT116), a healthy human intestinal epithelial cell line (hIECs), and a murine CRC cell line (MC38) using western blot and immunofluorescence assays to confirm TfR1 expression. Next, we engineered NPs composed of poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA), functionalized with the T7 peptide (HAIYPRH) to enhance their specificity for TfR1-expressing cells. Targeting efficiency of these NPs was assessed across all cell lines by evaluating the cellular uptake using flow cytometry. Upon establishing the optimal formulation for these NPs for TfR1-targeting, we encapsulated doxorubicin (DOX) to evaluate their therapeutic potential. Both in vitro and in vivo studies were performed to assess the efficacy of these DOX-loaded TfR1-targeted NPs. In vitro studies demonstrated selective delivery of DOX to CRC cells, suggesting a marked reduction in off-target effects. In vivo studies in a murine model of CRC further supported these findings, showing that DOX-loaded TfR1-targeted NPs significantly improved survival rates and reduced tumor growth compared to free DOX or PBS treatments. These results highlight the promise of TfR1-targeted NPs as a precise strategy for CRC therapy, offering enhanced treatment efficacy while reducing systemic toxicity. This novel approach could lead to the development of more targeted and less harmful cancer treatments. |
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| Autores principais: | Pina, Ariana Santos |
| Assunto: | cancro colorretal recetor de transferrina nanopartículas polimersomas doxorubicina Teses de mestrado - 2024 |
| Ano: | 2024 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso embargado |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Colorectal cancer (CRC) is a major global health concern, ranking among the most common cancers and the third leading cause of cancer-related deaths. The high mortality associated with CRC is attributed mainly to difficulties in early detection and the lack of effective targeted therapies. The Transferrin receptor 1 (TfR1) is particularly attractive as a therapy target given its notable overexpression in tumor cells, particularly in CRC. This study explored the potential of a nanoparticle (NPs)-based drug delivery system targeting TfR1 to improve the precision and efficacy of CRC treatment. First, we characterized three human colorectal cancer cell lines (SW480, HT-29, and HCT116), a healthy human intestinal epithelial cell line (hIECs), and a murine CRC cell line (MC38) using western blot and immunofluorescence assays to confirm TfR1 expression. Next, we engineered NPs composed of poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA), functionalized with the T7 peptide (HAIYPRH) to enhance their specificity for TfR1-expressing cells. Targeting efficiency of these NPs was assessed across all cell lines by evaluating the cellular uptake using flow cytometry. Upon establishing the optimal formulation for these NPs for TfR1-targeting, we encapsulated doxorubicin (DOX) to evaluate their therapeutic potential. Both in vitro and in vivo studies were performed to assess the efficacy of these DOX-loaded TfR1-targeted NPs. In vitro studies demonstrated selective delivery of DOX to CRC cells, suggesting a marked reduction in off-target effects. In vivo studies in a murine model of CRC further supported these findings, showing that DOX-loaded TfR1-targeted NPs significantly improved survival rates and reduced tumor growth compared to free DOX or PBS treatments. These results highlight the promise of TfR1-targeted NPs as a precise strategy for CRC therapy, offering enhanced treatment efficacy while reducing systemic toxicity. This novel approach could lead to the development of more targeted and less harmful cancer treatments. |
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