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

Mann, Kristine; Kullberg, Max

doi:10.1038/cgt.2016.21

Cited by 13 publications

(14 citation statements)

References 29 publications

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“…LLO has been used as a tool in medical applications, such as vaccine adjuvans, or gene and other cargo delivery agents 24 25 26 27 and there is clearly a high demand for understanding its biochemical and biophysical properties. Here we engineered an LLO mutant Y406A, which has an unprecedented pH-dependent pore-forming ability mediated through allosteric effects.…”

mentioning

confidence: 99%

Engineering a pH responsive pore forming protein

Kisovec

Rezelj

Knap

et al. 2017

Sci Rep

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Listeriolysin O (LLO) is a cytolysin capable of forming pores in cholesterol-rich lipid membranes of host cells. It is conveniently suited for engineering a pH-governed responsiveness, due to a pH sensor identified in its structure that was shown before to affect its stability. Here we introduced a new level of control of its hemolytic activity by making a variant with hemolytic activity that was pH-dependent. Based on detailed structural analysis coupled with molecular dynamics and mutational analysis, we found that the bulky side chain of Tyr406 allosterically affects the pH sensor. Molecular dynamics simulation further suggested which other amino acid residues may also allosterically influence the pH-sensor. LLO was engineered to the point where it can, in a pH-regulated manner, perforate artificial and cellular membranes. The single mutant Tyr406Ala bound to membranes and oligomerized similarly to the wild-type LLO, however, the final membrane insertion step was pH-affected by the introduced mutation. We show that the mutant toxin can be activated at the surface of artificial membranes or living cells by a single wash with slightly acidic pH buffer. Y406A mutant has a high potential in development of novel nanobiotechnological applications such as controlled release of substances or as a sensor of environmental pH.

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mentioning

confidence: 99%

Engineering a pH responsive pore forming protein

Kisovec

Rezelj

Knap

et al. 2017

Sci Rep

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“…The other issues include the delayed onset of the effect, uncertain duration and level of expression, and whether the transformation is transient or permanent (especially when using such vectors as polyplexes, liposomes, adenoviruses). However, extensive research into the development of promising new nucleic acid delivery systems, including tissue-specific variants ( Durymanov et al, 2013 ; Mann and Kullberg, 2016 ; Kim et al, 2017 ) for various gene therapy applications have led to a number of clinical trials and a few already clinically approved approaches ( Pearson et al, 2004 ; Yla-Herttuala, 2012 ; Buning, 2013 ; Zhang W.W. et al, 2018 ) favor the introduction of intrabody-based therapy to the clinic.…”

Section: Strategies For Intracellular Targeting Of Antibodies Their mentioning

confidence: 99%

Targeted Intracellular Delivery of Antibodies: The State of the Art

et al. 2018

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A dominant area of antibody research is the extension of the use of this mighty experimental and therapeutic tool for the specific detection of molecules for diagnostics, visualization, and activity blocking. Despite the ability to raise antibodies against different proteins, numerous applications of antibodies in basic research fields, clinical practice, and biotechnology are restricted to permeabilized cells or extracellular antigens, such as membrane or secreted proteins. With the exception of small groups of autoantibodies, natural antibodies to intracellular targets cannot be used within living cells. This excludes the scope of a major class of intracellular targets, including some infamous cancer-associated molecules. Some of these targets are still not druggable via small molecules because of large flat contact areas and the absence of deep hydrophobic pockets in which small molecules can insert and perturb their activity. Thus, the development of technologies for the targeted intracellular delivery of antibodies, their fragments, or antibody-like molecules is extremely important. Various strategies for intracellular targeting of antibodies via protein-transduction domains or their mimics, liposomes, polymer vesicles, and viral envelopes, are reviewed in this article. The pitfalls, challenges, and perspectives of these technologies are discussed.

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“…Besides their direct therapeutic application, monoclonal antibodies can be used to confer target selectivity to a wide range of nanoparticles [17]. For instance, trastuzumab functionalization of nanocomplexes enveloping DNA or RNA molecules, including siRNA against B-cell lymphomaextra large (BCL-XL), CXC chemokine receptor 4 (CXCR4), HER2, PLK1, and signal transducer and activator of transcription-3 (STAT3), can be used for the specific targeting of HER2overexpressing breast cancer cells, resulting in an effective therapeutic strategy that combine targeted and gene therapies [27,37,47,80,81].…”

Section: Combinatorial Treatmentsmentioning

confidence: 99%

Progress in nonviral gene therapy for breast cancer and what comes next?

Bottai

Truffi

Corsi

et al. 2017

Expert Opinion on Biological Therapy

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The possibility of correcting defective genes and modulating gene expression through gene therapy has emerged as a promising treatment strategy for breast cancer. Furthermore, the relevance of tumor immune microenvironment in supporting the oncogenic process has paved the way for novel immunomodulatory applications of gene therapy. Areas covered: In this review, the authors describe the most relevant delivery systems, focusing on nonviral vectors, along with the description of the major approaches used to modify target cells, including gene transfer, RNA interference (RNAi), and epigenetic regulation. Furthermore, they highlight innovative therapeutic strategies and the application of gene therapy in clinical trials for breast cancer. Expert opinion: Gene therapy has the potential to impact breast cancer research. Further efforts are required to increase the clinical application of RNAi-based therapeutics, especially in combination with conventional treatments. Innovative strategies, including genome editing and stem cell-based systems, may contribute to translate gene therapy into clinical practice. Immune-based approaches have emerged as an attractive therapeutic opportunity for selected breast cancer patients. However, several challenges need to be addressed before considering gene therapy as an actual option for the treatment of breast cancer.

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

Cited by 13 publications

References 29 publications

Engineering a pH responsive pore forming protein

Engineering a pH responsive pore forming protein

Targeted Intracellular Delivery of Antibodies: The State of the Art

Progress in nonviral gene therapy for breast cancer and what comes next?

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