ɑ_vβ₃-targeted liposomal drug delivery system with attenuated immunogenicity enabled by linear pentapeptide for glioma...

Owing to the binding capacity to ɑ_vβ₃ integrin overexpressed on glioma, vasculogenic mimicry and neovasculature, the peptide c(RGDyK) has been exploited pervasively to functionalize nanocarriers for targeted delivery of bioactives. The former study in our group substantiated the immunotoxicity of c(RGDyK)-modified liposome, and this unfavorable immunogenicity is known to compromise blood circulation, targeting efficacy and therapeutic outcome. Therefore, we need to find a superior alternative ligand in order to evade the exquisite immuno-sensitization. We developed mn by structure-guided peptide design and retro-inverso isomerization technique, which was experimentally substantiated to have exceptional binding affinity to ɑ_vβ₃ integrin. Besides mn does not have affinity toward normal liver cells and kidney cells, which c(RGDyK) possesses in a certain degree. Warranting that mn and c(RGDyK) anchored ɑ_vβ₃, we formulated peptide-tethered liposomes and investigated in vivo bio-fate. Compared with c(RGDyK)-modified liposome, mn-modified liposome presented longer blood circulation and reduced ingestion by Kupffer cells with decreased retention in liver accordingly, benefitting from attenuated anti-liposome IgG and IgM response elicited by multiple sequential doses. Those merits strengthened the anti-glioma efficacy of ɑ_vβ₃-targeted doxorubicin-loaded liposomes, proving the importance of immunocompatibility in process of targeted drug delivery.