Abstract
Therapeutic treatment on epithelial cancer is still limited by low internalization activity and passive transportation. Traditional chemotherapeutic agents usually accompany with severe side effects due to nonspecific drug biodistribution. The development of new methods for improving translational research for cancer therapy is contingent on specific recognition of ligands on the surface of cancer cells. Here, a novel cell penetrating peptide derived from core heparan sulfate binding motif of human eosinophil cationic protein (hECP), CPPecp, possesses cell surface glycosaminoglycan (GAG) binding, epithelial cell binding, cell penetrating, and cargo delivery activities. Cell surface GAGs are important co-receptors between cell surface receptor and growth factors, and regulate cell proliferation, adhesion, migration and signaling, especially during cancer progression. In this study we have successfully conjugated CPPecp to a phospholipid containing linker and developed a novel CPPecp-based modification methodology of liposomal drug. As expected, in vitro cellular uptake efficiency of CPPecp-modified liposomal drug toward lung epithelial cancer cells is evidently higher than that of unmodified liposomal drug, leading to enhancement of anti-tumor activity. In addition, 3D culture of epithelial cancer spheroid mimicking solid tumor microtissues shows higher permeability of CPPecp-modified liposomal drug than that of unmodified liposomal drug. Moreover, in vivo epithelial tumor-bearing mouse model with treatment of CPPecp-modified liposomal drug demonstrates no dramatic weight decrease as original drug does, suggesting low side effects during medication. Our new formulation inhibits in vivo tumor progression to a much significant extent than unmodified liposomal drug. Our engineering strategy provides an alternative solution for unmet medical need to reduce the dosage of liposomal drugs and alleviate chemotherapeutic side effects in cancer therapy, which in turn contributes to further development of translational medicine.