Cell-permeable NF-κB inhibitor-conjugated liposomes for treatment of glioma.

Application of liposomes-based drug delivery in treatment of glioma has been hampered by the poor permeability of blood-brain barrier and the low uptake efficiency by glioma tissues. Moreover, many chemotherapy drugs promote the activation of the NF-κB, which plays a role in the development and progression of cancer and chemoresistance. In this report, CB5005 peptide, designed for its dual function in cell membrane penetration and NF-κB inhibition, was conjugated to PEGylated liposomes loaded with doxorubicin (CB5005-LS/DOX) or a fluorescent dye (CB5005-LS/dye). These CB5005-modified liposomes were utilized for targeting and penetrating glioma. Both qualitative and quantitative evaluations of CB5005-LS/dye showed that modification by CB5005 significantly increased cellular uptake of the liposomes by glioma cells, and substantially improved permeability of the liposomes into tumor spheroids. Intracellular localization studies demonstrated that CB5005-modified liposomes could not only penetrate into glioma cells but also deliver DOX into the nucleus. Cytotoxicity assay indicated that compared with the unmodified DOX liposomes (LS/DOX), CB5005-LS/DOX increased the efficiency of killing glioma cells by more than fivefold. In vivo imaging illustrated that CB5005-modified liposomes, via intravenous injection, distributed fluorescence into the brain and accumulated at tumor xenograft and intracranial glioblastoma in different animal models. More importantly, CB5005-LS/DOX treatment significantly prolonged the survival time of nude mice bearing intracranial glioblastoma. In summary, CB5005-modified liposomes represent a promising drug delivery system for cancer treatment attributing to its unique ability not only to transfer drugs to the tumor sites but also to function as a synergist for chemotherapy of glioma and other human tumors.