Abstract
[D]-H6L9, 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]-H6L9-modified liposomes could not actively target to tumor area. Therefore, integrin αvβ3-targeted peptide RGD was co-modified with [D]-H6L9 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 αvβ3-positive) with significantly improved efficiency compared with other groups, which was contributed by both RGD and [D]-H6L9, while RGD did not increase the cellular uptake performance on MCF-7 cells (integrin αvβ3-negative). Results showed that RGD could decrease cellular uptake of (R + D)-Lip while [D]-H6L9 could increase it, implying the role of both RGD and [D]-H6L9 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]-H6L9 respectively, and achieve remarkable tumor inhibition effect on C26 tumor models.
Highlights
[D]-H6L9, and (R + D)-Lip could escape the entrapment of endo/lysosomes with the aid of the pHresponsive peptide [D]-H6L9
This was due to the protonation of histidines in peptide [D]-H6L9, which has already been evidenced by our previous work[16,17]
A dual-functionalized liposomal delivery system co-modified by RGD and pH-responsive AMP [D]-H6L9 has been devised by us [(R + D)-Lip]
Summary
[D]-H6L9, and (R + D)-Lip could escape the entrapment of endo/lysosomes with the aid of the pHresponsive peptide [D]-H6L9. Cell penetrating peptides for augmented tumor-targeted delivery in multi-functional nano-carriers[25,26,27,28,29,30,31]. Together with cell penetrating peptides such as TAT, an enhanced photodynamic therapy of Hela cells and Hela tumor-bearing mice could be acquired[27]. TAT, as a typical cell penetrating peptide and without shielding from a hydrophilic protection layer such as PEG, could interact directly with blood serums which altered its pharmacokinetic profiles, jeopardizing its in vivo application. We engineered a dual-functional liposome [donated as (R + D)-Lip], which was co-decorated by a pH-responsive anti-microbial peptide [D]-H6L9 and a specific ligand RGD for tumor delivery. The cell permeation by [D]-H6L9 could be potentiated in the acidified tumor environment (pH 6.3), boosting tumor-specific delivery of liposome and its cargos. (Fig. 1)
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