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

[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.