Liposomes co-modified with cholesterol anchored cleavable PEG and octaarginines for tumor targeted drug delivery

Tumor targeted drug delivery system with high efficiency of tumor accumulation, cell internalization and endosomal escape was considered ideal for cancer therapy. Herein, a cleavable polyethylene glycol (PEG) and octaarginines (R8) co-modified liposome (CL-R8-LP) was developed, in which the cholesterol was used as an alternative anchor to the commonest phospholipids for the diversified development of surface modification. The in vitro hemolysis assay and bio-distribution study demonstrated that CL-R8-LP improved biocompatibility and tumor accumulation compared with the single R8 modified liposomes (R8-LP), since the strong positive charges, toxicity and non-specificity of R8 were efficiently shielded by the outer cleavable PEG. And the cellular uptake, cytotoxicity and apoptosis of CL-R8-LP on C26 cells were much stronger than that of control liposomes in which R8 was not included or exposed. In addition, it was confirmed that CL-R8-LP entered cells via clathrin-mediated endocytosis and the macropinocytosis, and followed by a more efficient endosomal escape compared with R8-LP due to the topology change of R8. The enhanced in vivo delivery efficiency and anti-tumor efficacy were validated in C26 bearing mice. In conclusion, the results demonstrated that CL-R8-LP was a promising vehicle for enhancing the chemotherapy of solid cancers.