放射性標靶微脂體E[c(RGDyK)]2-188Re-Liposome之研發與植有C26腫瘤小鼠之療效評估

Abstract

Angiogenesis is of a general property and is critical for tumor growth, where αvβ3 integrin is overexpressed on angiogenic endothelium in and around tumor tissue. αvβ3 integrin may therefore represent a possible target for drug delivery. In this study, a drug delivery system by a modified liposome specifically aiming at angiogenic tumor endothelial cells was developed. E[c(RGDyK)]2 peptide with affinity to this integrin was adopted to conjugate on the liposome surface and the 188Re radionuclide was simultaneously encapsulated in the liposome core. The resulted liposome, referred to E[c(RGDyK)]2-188Re-liposome, was investigated for its application potential in radionuclide therapy and diagnostic imaging for tumors. Methods: In this study, an angiogenesis-targeting liposome system was constructed to have dimeric RGD peptide E[c(RGDyK)]2 conjugated on the liposome surface and a rhenium-188 radionuclide complex encapsulated inside the liposome core. The in vitro cellular uptake by radiotracing and fluorescence microscope imaging was studied using human umbilical vein endothelial cells with overexpression of αvβ3 integrin receptor. For animal trial, the main works comprised microSPECT/CT imaging and biodistribution study and investigation of antitumor efficacy of E[c(RGDyK)]2-188Re-liposomes in comparison with non E[c(RGDyK)]2 conjugated liposome using C26 murine colon tumor-bearing animal model. Results: The in vitro stability study showed that E[c(RGDyK)]2-188Re-liposome was quite stable in rat plasma significantly for a long time, i.e., at least 72 h. The in vitro cell binding study demonstrated that the active targeting liposome surpassed non-targeted liposome in about four-fold higher of the cellular as observed from cellular uptake and cell staining. For in vivo studies, both of microSPECT/CT images and biodistribution studies indicated that the accumulation in the reticuloendothelial system for E[c(RGDyK)]2-188Re-liposome was apparently higher than the non-targeted liposome. The tumor uptake of E[c(RGDyK)]2-188Re-liposome was about six-fold lower than the non-targeted liposomes. Nevertheless, E[c(RGDyK)]2-188Re-liposome did inhibit the tumor growth as compared to untreated controls but no significant difference was observed in comparison with the non-targeted liposome. Conclusion: This study demonstrated the high cell binding affinity and stability of the active targeting liposome in the cell experiments. It was revealed from this study that the decrease of 188Re radioactivity accumulation in the colon tumor was relevant to the RES system uptake of E[c(RGDyK)]2-188Re-liposome. Modification on the E[c(RGDyK)]2-188Re-liposome surface to enhance the tumor uptake would be the future work to be investigated.