Glioma targeted delivery strategy of doxorubicin-loaded liposomes by dual-ligand modification

The blood-brain barrier (BBB) is the protective parclose of brain safety, but it is also the main obstacle of the drug delivery to cerebral parenchyma, which hamper therapy for brain diseases. In this work, a glioma targeted drug delivery system was developed through loading doxorubicin into Angiopep-2 and TAT peptide dual-modified liposomes (DOX-TAT-Ang-LIP). Low-density lipoprotein receptor-related protein-1 (LRP1) was one receptor overexpressed on both BBB and glioma cytomembranes. Angiopep-2, a specific ligand of LRP1, exhibited high LRP1 binding efficiency. Additionally, TAT could penetrate through cell membranes without selectivity via an unsaturated pathway. To avoid the receptor saturation of Angiopep-2, TAT was also conjugated on the surface of liposomes, providing that the liposomes not only have effective BBB penetrating effect, but also have the glioma targeting function. The prepared DOX liposomes appeared good stability and narrow dispersity in serum with a diameter of 90 nm, and exhibited sustained DOX release behaviors. The conjunctions of Angiopep-2 and TAT were confirmed by 1H NMR spectra. The BBB model, cellular uptake observations, antiproliferation study, and the cell ultrastructure analyses suggested that DOX-TAT-Ang-LIP could not only penetrate through BBB via transcytosis, but also concentrate in glioma, then enter into glioma cells and finally result in the necrosis of glioma cells.