Cell penetrating peptides (CPPs) were widely used for
drug delivery to
tumor. However, the nonselective in vivo penetration greatly limited the application of CPPs-mediated drug delivery systems. And the treatment of malignant
tumors is usually followed by poor prognosis and relapse due to the existence of extravascular core regions of
tumor. Thus it is important to endue selective targeting and stronger intratumoral diffusion abilities to CPPs. In this study, an RGD reverse sequence dGR was conjugated to a
CPP octa-
arginine to form a CendR (R/KXXR/K) motif contained tandem
peptide R8-dGR (RRRRRRRRdGR) which could bind to both
integrin αvβ3 and
neuropilin-1 receptors. The dual receptor recognizing
peptide R8-dGR displayed increased cellular uptake and efficient penetration ability into
glioma spheroids in vitro. The following in vivo studies indicated the active targeting and intratumoral diffusion capabilities of R8-dGR modified
liposomes. When
paclitaxel was loaded in the
liposomes, PTX-R8-dGR-Lip induced the strongest anti-proliferation effect on both
tumor cells and cancer stem cells, and inhibited the formation of vasculogenic mimicry channels in vitro. Finally, the R8-dGR liposomal drug delivery system prolonged the medium survival time of intracranial C6 bearing mice by 2.1-fold compared to the untreated group, and achieved an exhaustive anti-
glioma therapy including anti-
tumor cells, anti-vasculogenic mimicry and anti-
brain cancer stem cells. To sum up, all the results demonstrated that R8-dGR was an ideal dual receptor recognizing
CPP with selective
glioma targeting and efficient intratumoral diffusion, which could be further used to equip drug delivery system for effective
glioma therapy.