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

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 ?v?3-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 ?v?3-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 ?v?3-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.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC4740748 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Zhang Qianyu Q Lu Libao L Zhang Li L Shi Kairong K Cun Xingli X Yang Yuting Y Liu Yayuan Y Gao Huile H He Qin Q

Scientific reports 20160204

[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 ...[more]

PMID: 26842655

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Project description:Protein subunit vaccines offer important potential advantages over live vaccine vectors but generally elicit weaker and shorter-lived cellular immune responses. Here we investigate the use of pH-responsive, endosomolytic polymer nanoparticles that were originally developed for RNA delivery as vaccine delivery vehicles for enhancing cellular and humoral immune responses. Micellar nanoparticles were assembled from amphiphilic diblock copolymers composed of an ampholytic core-forming block and a redesigned polycationic corona block doped with thiol-reactive pyridyl disulfide groups to enable dual-delivery of antigens and immunostimulatory CpG oligodeoxynucleotide (CpG ODN) adjuvants. Polymers assembled into 23 nm particles with simultaneous packaging of CpG ODN and a thiolated protein antigen, ovalbumin (ova). Conjugation of ova to nanoparticles significantly enhanced antigen cross-presentation in vitro relative to free ova or an unconjugated, physical mixture of the parent compounds. Subcutaneous vaccination of mice with ova-nanoparticle conjugates elicited a significantly higher CD8(+) T cell response (0.5% IFN-γ(+) of CD8(+)) compared to mice vaccinated with free ova or a physical mixture of the two components. Significantly, immunization with ova-nanoparticle conjugates electrostatically complexed with CpG ODN (dual-delivery) enhanced CD8(+) T cell responses (3.4% IFN-γ(+) of CD8(+)) 7-, 18-, and 8-fold relative to immunization with conjugates, ova administered with free CpG, or a formulation containing free ova and CpG complexed to micelles, respectively. Similarly, dual-delivery carriers significantly increased CD4(+)IFN-γ(+) (Th1) responses and elicited a balanced IgG1/IgG2c antibody response. Intradermal administration further augmented cellular immune responses, with dual-delivery carriers inducing ∼7% antigen-specific CD8(+) T cells. This work demonstrates the ability of pH-responsive, endosomolytic nanoparticles to actively promote antigen cross-presentation and augment cellular and humoral immune responses via dual-delivery of protein antigens and CpG ODN. Hence, pH-responsive polymeric nanoparticles offer promise as a delivery platform for protein subunit vaccines.

Dataset Information

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

Publications

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

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