2, Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, , China
3, Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California, United States
Although antibody-based immunotherapy is considered to be the most potential clinical translational therapy for tumors due to its low toxicity and high specificity, only bevacizumab was approved by US Food and Drug Administration (FDA) for the treatment of recurrent glioblastoma however showed limited effects. Lack of efficient delivery system compromises antibody therapy for glioblastoma. Extracellular release of monoclonal antibody for them to bind with receptor on the surface of glioblastoma cell membrane to inhibit tumor growth still remains challenging. Here, in our present study, for the first time, high expression of metalloproteinase-2 (MMP-2) in tumor environment was utilized for the extracellular release of antibody. A MMP-2 sensitive nanocapsule based on 2-methacryloyloxy ethyl phosphorylcholine (MPC) was constructed. By simply controlling the content of MPC, the cell uptake of these small sized (~30 nm) antibody carriers was inhibited while effective extracellular release of antibody was realized. Besides, the nanosize and MPC-based shell endow the antibody-loaded nanocapsule with long circulation time, fast permeation ability and high accumulation amount in glioblastoma which are requirements for efficient glioblastoma therapy. Nitozumab was used as the model antibody and was capsulated inside the neutral nanocapsule (~30 nm) by an in situ free radical polymerization method. When the molar ratio of MPC to nitozumab was between 4000 and 5000, the nanocapsules can be degraded enzymatically and meanwhile inhibit the internalization of glioblastoma cells making them capable of extracellular release of nitozumab. Animal experiments proved the long circulation time (half-life is about 50h) of the nanocapsules in blood, fast penetration (about 2h after systemic injection) of the nanocapsules into glioblastoma site and higher accumulation amount of nanocapsules in glioblastoma site. Compared with free nitozumab, nitozumab-loaded nanocapsules can efficiently suppress the glioblastoma of glioblastoma-bearing mice and significantly prolong the survival time of glioblastoma-bearing mice (at day 45, more than 50% mice treated by nitozumab-loaded nanocapsules were survived but all mice died when treated by free nitozumab). Additionally, no significant weight loss of mice treated by nitozumab-loaded nanocapsules was observed during the treatment. The results demonstrated the extracellularly released antibody delivery platform may provide a useful tool for immunotherapy for glioblastoma.