Gene delivery to Her-2+ breast cancer cells using a two-component delivery system to achieve specificity

Kullberg, Max; McCarthy, Ryan L.; Anchordoquy, Thomas J.

doi:10.1016/j.nano.2014.02.013

Cited by 13 publications

(12 citation statements)

References 28 publications

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“…7), indicating that the pore-forming activity of Sts is not absolutely required for this outcome. In contrast, the effect of LLO incorporated into liposomal vesicles on the enhanced delivery of plasmid DNA was strictly correlated with the endo-somolytic activity of this PFP (85, 86). …”

Section: Discussionmentioning

confidence: 92%

Novel Adjuvant Based on the Pore-Forming Protein Sticholysin II Encapsulated into Liposomes Effectively Enhances the Antigen-Specific CTL-Mediated Immune Response

Laborde

Sanchez-Ferras

Luzardo

et al. 2017

The Journal of Immunology

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Vaccine strategies to enhance CD8+ CTL responses remain a current challenge because they should overcome the plasmatic and endosomal membranes for favoring exogenous Ag access to the cytosol of APCs. As a way to avoid this hurdle, sticholysin (St) II, a pore-forming protein from the Caribbean Sea anemone Stichodactyla helianthus, was encapsulated with OVA into liposomes (Lp/OVA/StII) to assess their efficacy to induce a CTL response. OVA-specific CD8+ T cells transferred to mice immunized with Lp/OVA/StII experienced a greater expansion than when the recipients were injected with the vesicles without St, mostly exhibiting a memory phenotype. Consequently, Lp/OVA/StII induced a more potent effector function, as shown by CTLs, in vivo assays. Furthermore, treatment of E.G7-OVA tumor-bearing mice with Lp/OVA/StII significantly reduced tumor growth being more noticeable in the preventive assay. The contribution of CD4+ and CD8+ T cells to CTL and antitumor activity, respectively, was elucidated. Interestingly, the irreversibly inactive variant of the StI mutant StI W111C, encapsulated with OVA into Lp, elicited a similar OVA-specific CTL response to that observed with Lp/OVA/StII or vesicles encapsulating recombinant StI or the reversibly inactive StI W111C dimer. These findings suggest the relative independence between StII pore-forming activity and its immuno-modulatory properties. In addition, StII-induced in vitro maturation of dendritic cells might be supporting these properties. These results are the first evidence, to our knowledge, that StII, a pore-forming protein from a marine eukaryotic organism, encapsulated into Lp functions as an adjuvant to induce a robust specific CTL response.

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Section: Discussionmentioning

confidence: 92%

Novel Adjuvant Based on the Pore-Forming Protein Sticholysin II Encapsulated into Liposomes Effectively Enhances the Antigen-Specific CTL-Mediated Immune Response

Laborde

Sanchez-Ferras

Luzardo

et al. 2017

The Journal of Immunology

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“…The cRGD-CPE liposomes were more effective at inhibiting RRM1 (76% reduction in RRM1 expression), than the CPE-liposomes (70% reduction) and naked siRNA (16% reduction) [ 92 ]. Kullberg et al [ 94 ] designed a two-component delivery system utilizing neutral liposomes to deliver plasmid DNA encoding a luciferase reporter. The plasmid DNA was first condensed with PEGylated cationic poly-lysine to form PL/DNA.…”

Section: Lipid-based Nanomaterials For Gene Deliverymentioning

confidence: 99%

Recent Advances in Nanomaterials for Gene Delivery—A Review

2017

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With the rapid development of nanotechnology in the recent decade, novel DNA and RNA delivery systems for gene therapy have become available that can be used instead of viral vectors. These non-viral vectors can be made of a variety of materials, including inorganic nanoparticles, carbon nanotubes, liposomes, protein and peptide-based nanoparticles, as well as nanoscale polymeric materials. They have as advantages over viral vectors a decreased immune response, and additionally offer flexibility in design, allowing them to be functionalized and targeted to specific sites in a biological system with low cytotoxicity. The focus of this review is to provide an overview of novel nanotechnology-based methods to deliver DNA and small interfering RNAs into biological systems.

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“…Under the reducing conditions found in endosomes, disulfide-bound LLO is released either from low molecular weight PEIs (24) or from liposomes (2,14,25) such that it can form pores in the endosomal membrane and allow exit of the delivered endosomal contents to the cytoplasm. We have now extended these findings by showing that the disulfide bond between the LLO and the OPN core in our nanocomplexes also appears to be reduced in the endosome, and the released LLO then functions to allow passage of the DNA to the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…However, these genes must be delivered specifically to avoid toxic side effects. Targeted delivery of genes to cancer cells has been achieved in a limited number of laboratories using liposomal delivery systems with antibody to Her2 receptors (1,2), with an RGD peptide specific for integrin (3), or with antibody to prostate-specific membrane antigen (4). …”

Section: Introductionmentioning

confidence: 99%

Trastuzumab-targeted gene delivery to Her2-overexpressing breast cancer cells

Mann

Kullberg

2016

Cancer Gene Ther

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We describe a novel gene delivery system that specifically targets human epidermal growth factor receptor 2 (Her2)-overexpressing breast cancer cells. The targeting complexes consist of a PEGylated polylysine core that is bound to DNA molecules coding for either green fluorescent protein or shrimp luciferase. The complex is disulfide linked to the monoclonal antibody trastuzumab and to a pore-forming protein, Listeriolysin O (LLO). Trastuzumab is responsible for specific targeting of Her2 receptors and uptake of the gene delivery complex into endosomes of recipient cells, whereas LLO ensures that the DNA molecules are capable of transit from the endosomes into the cytoplasm. Omission of either trastuzumab or LLO from the nanocomplexes results in minimal gene product in targeted cells. Treatment of isogeneic MCF7 and MCF7/Her18 cell lines, differing only in number of Her2 receptors, with the complete gene delivery system results in a 30-fold greater expression of luciferase activity in the Her2-overexpressing MCF7/Her18 cells. Our nanocomplexes are small (150–250 nm), stable to storage, nontoxic and generic in make-up such that any plasmid DNA or antibody specific for cell-surface receptors can be coupled to the PEGylated polylysine core.

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Gene delivery to Her-2+ breast cancer cells using a two-component delivery system to achieve specificity

Cited by 13 publications

References 28 publications

Novel Adjuvant Based on the Pore-Forming Protein Sticholysin II Encapsulated into Liposomes Effectively Enhances the Antigen-Specific CTL-Mediated Immune Response

Novel Adjuvant Based on the Pore-Forming Protein Sticholysin II Encapsulated into Liposomes Effectively Enhances the Antigen-Specific CTL-Mediated Immune Response

Recent Advances in Nanomaterials for Gene Delivery—A Review

Trastuzumab-targeted gene delivery to Her2-overexpressing breast cancer cells

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