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[D]-H 6 L 9 , as a pH-responsive anti-microbial peptide (AMP), has been evidenced by us to be an excellent choice in tumor microenvironment-responsive delivery as it could render liposomes responsive to the acidified tumor microenvironment. However, [D]-H 6 L 9 -modified liposomes could not actively target to tumor area. Therefore, integrin α v β 3 -targeted peptide RGD was co-modified with [D]-H 6 L 9  onto liposomes [(R + D)-Lip] for improved tumor delivery efficiency. Under pH 6.3, (R + D)-Lip could be taken up by C26 cells and C26 tumor spheroids (integrin α v β 3 -positive) with significantly improved efficiency compared with other groups, which was contributed by both RGD and [D]-H 6 L 9 , while RGD did not increase the cellular uptake performance on MCF-7 cells (integrin α v β 3 -negative). Results showed that RGD could decrease cellular uptake of (R + D)-Lip while [D]-H 6 L 9  could increase it, implying the role of both RGD and [D]-H 6 L 9  in cellular internalization of (R + D)-Lip. On the other hand, (R + D)-Lip could escape the entrapment of lysosomes. PTX-loaded (R + D)-Lip could further increase the cellular toxicity against C26 cells compared with liposomes modified only with RGD and [D]-H 6 L 9  respectively, and achieve remarkable tumor inhibition effect on C26 tumor models.

Dual-functionalized liposomal delivery system for solid tumors based on RGD and a pH-responsive antimicrobial peptide