Transferrin Receptor 1-targeted polymersomes therapy for Colorectal Cancer

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Abstract Colorectal cancer (CRC) is a major global health concern, ranking among the most common cancers and the second 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 polymeric nanoparticle (POs)-based drug delivery system targeting TfR1 to improve the precision and efficacy of CRC treatment. For this study, we used 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). We first engineered POs composed of poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA), functionalized with the T7 peptide to enhance their specificity for TfR1-expressing cells. Targeting efficiency of these POs 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 POs. 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 POs significantly improved survival rates and reduced tumor growth compared to free DOX or PBS treatments. These results highlight the promise of TfR1-targeted POs 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. Graphical abstract Highlights T-7 peptide-functionalized polymersomes exhibit high binding affinity to CRC cell lines Doxorubicin-loaded T7-peptide polymersomes effectively suppress tumor growth and prolong survival in vivo Targeted Doxorubicin delivery via T7-peptide polymersomes minimizes toxicity to healthy tissues

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