Abstract
Therapeutic outcome for the treatment of glioma was often limited due to the non-targeted nature of drugs and the physiological barriers, including the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB). An ideal glioma-targeted delivery system must be sufficiently potent to cross the BBB and BBTB and then target glioma cells with adequate optimized physiochemical properties and biocompatibility. However, it is an enormous challenge to the researchers to engineer the above-mentioned features into a single nanocarrier particle. New frontiers in nanomedicine are advancing the research of new biomaterials. In this study, we demonstrate a strategy for glioma targeting by encapsulating vincristine sulfate (VCR) into a naturally available apoferritin nanocage-based drug delivery system with the modification of GKRK peptide ligand (GKRK-APO). Apoferritin (APO), an endogenous nanosize spherical protein, can specifically bind to brain endothelial cells and glioma cells via interacting with the transferrin receptor 1 (TfR1). GKRK is a peptide ligand of heparan sulfate proteoglycan (HSPG) over-expressed on angiogenesis and glioma, presenting excellent glioma-homing property. By combining the dual-targeting delivery effect of GKRK peptide and parent APO, GKRK-APO displayed higher glioma localization than that of parent APO. After loading with VCR, GKRK-APO showed the most favorable antiglioma effect in vitro and in vivo. These results demonstrated that GKRK-APO is an important potential drug delivery system for glioma-targeted therapy.
Highlights
The efficient treatment for glioma, which is the most frequent primary malignant brain tumor with a median survival less than 2 years after first diagnosis, remains a challenging task
The GKRK peptide was introduced maleimide group (-MAL), and the peptide was conjugated to APO via the sulfhydryl-maleimide coupling reaction, which enabled GKRK peptide to be conjugated at a specific site (-MAL)
To confirm GKRK peptide was functionalized to APO, we analyzed the binding ability of the GKRKAPO to purified heparan sulfate proteoglycan (HSPG)
Summary
The efficient treatment for glioma, which is the most frequent primary malignant brain tumor with a median survival less than 2 years after first diagnosis, remains a challenging task. Glioma is difficult to treat because of the special pathological and physiological characteristics. Due to the infiltrate growth of glioma, it is hard to completely remove the glioma through surgery (Donahue et al, 2008). Chemotherapy is indispensable for subsequent treatment after surgery. The clinical therapeutic effect of glioma by chemotherapy is very unsatisfying. The blood-brain barrier (BBB) rigorously prevents 98% of drugs from reaching the infiltrative glioma cells, resulting in glioma recurrence after surgical resection. The non-targeted nature of drugs often causes severe side effects because they produce a similar cytotoxicity in both cancerous and healthy cell
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