Therapeutic outcome for the treatment of glioma was often limited due to drug resistance and low permeability of drug across the multiple physiological barriers, including the blood-brain barrier (BBB), and the blood-tumor barrier (BTB). In order to overcome these hurdles, we designed T7 and A7R dual peptides-modified liposomes (abbreviated as T7/A7R-LS) to efficiently co-delivery doxorubicin (DOX) and vincristine (VCR) to glioma in this study. T7 is a seven-peptide ligand of transferrin receptors (TfR) capable of circumventing the BBB and then targeting glioma. A7R is a d-peptide ligand of vascular endothelial growth factor receptor 2 (VEGFR 2) overexpressed on angiogenesis, presenting excellent glioma-homing property. By combining the dual-targeting delivery effect, the dual-modified liposomes displayed higher glioma localization than that of single ligand-modified liposomes or free drug. After loading with DOX and VCR, T7/A7R-LS showed the most favorable antiglioma effect in vivo. In conclusion, this dual-targeting, co-delivery strategy provides a potential method for improving brain drug delivery and antiglioma treatment efficacy.

An ideal brain-targeted nanocarrier must be sufficiently potent to penetrate the blood-brain barrier (BBB) and sufficiently competent to target the cells of interest with adequate optimized physiochemical features and biocompatibility. However, it is an enormous challenge to the researchers to organize the above-mentioned properties into a single nanocarrier particle. New frontiers in nanomedicine are advancing the research of new biomaterials. Herein, we demonstrate a straightforward strategy for brain targeting by encapsulating doxorubicin (DOX) into a naturally available and unmodified apoferritin nanocage (DOX-loaded APO). APO can specifically bind to cells expressing transferrin receptor 1 (TfR1). Because of the high expression of TfR1 in both brain endothelial and glioma cells, DOX-loaded APO can cross the BBB and deliver drugs to the glioma with TfR1. Subsequent research demonstrated that the DOX-loaded APO had good physicochemical properties (particle size of 12.03 ± 0.42 nm, drug encapsulation efficiency of 81.8 ± 1.1%) and significant penetrating and targeting effects in the coculture model of bEnd.3 and C6 cells in vitro. In vivo imaging revealed that DOX-loaded APO accumulated specifically in brain tumor tissues. Additionally, in vivo tumor therapy experiments (at a dosage of 1 mg/kg DOX) demonstrated that a longer survival period was observed in mice that had been treated with DOX-loaded APO (30 days) compared with mice receiving free DOX solution (19 days).

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.