Toxin-Mediated siRNA Delivery

Zhao, Spencer; Karp, Jeffrey M.; Joshi, Nitin

doi:10.1016/j.tips.2020.06.006

Cited by 2 publications

(4 citation statements)

References 11 publications

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Section: Bacterial Toxinsmentioning

confidence: 99%

“…Bacterial toxins (specifically AB-type toxins), such as anthrax toxin (AT) and diphtheria toxin (DT) or Pseudomonas exotoxin have been tested as promising tools for RNAi delivery (124). As these toxins have natural mechanisms to penetrate the cells, they can be further modified for drug delivery purposes (124)(125)(126). Besides, their distinctive structure allows their natural transport via receptor-mediated endocytosis and crossing the endosomal membranes via a transmembrane pore (124).…”

Section: Bacterial Toxinsmentioning

confidence: 99%

“…As these toxins have natural mechanisms to penetrate the cells, they can be further modified for drug delivery purposes (124)(125)(126). Besides, their distinctive structure allows their natural transport via receptor-mediated endocytosis and crossing the endosomal membranes via a transmembrane pore (124). When detoxified DT chimeras were used as protein-delivery vectors, high translocating efficiencies of cargo proteins of variable sizes (>100 kDa), structural motifs, and diverse stabilities were obtained (125).…”

Section: Bacterial Toxinsmentioning

confidence: 99%

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Targeting Non-coding RNA for Glioblastoma Therapy: The Challenge of Overcomes the Blood-Brain Barrier

Sharma

Calderón

Vivas‐Mejía

2021

Front. Med. Technol.

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Glioblastoma (GBM) is the most malignant form of all primary brain tumors, and it is responsible for around 200,000 deaths each year worldwide. The standard therapy for GBM treatment includes surgical resection followed by temozolomide-based chemotherapy and/or radiotherapy. With this treatment, the median survival rate of GBM patients is only 15 months after its initial diagnosis. Therefore, novel and better treatment modalities for GBM treatment are urgently needed. Mounting evidence indicates that non-coding RNAs (ncRNAs) have critical roles as regulators of gene expression. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are among the most studied ncRNAs in health and disease. Dysregulation of ncRNAs is observed in virtually all tumor types, including GBMs. Several dysregulated miRNAs and lncRNAs have been identified in GBM cell lines and GBM tumor samples. Some of them have been proposed as diagnostic and prognostic markers, and as targets for GBM treatment. Most ncRNA-based therapies use oligonucleotide RNA molecules which are normally of short life in circulation. Nanoparticles (NPs) have been designed to increase the half-life of oligonucleotide RNAs. An additional challenge faced not only by RNA oligonucleotides but for therapies designed for brain-related conditions, is the presence of the blood-brain barrier (BBB). The BBB is the anatomical barrier that protects the brain from undesirable agents. Although some NPs have been derivatized at their surface to cross the BBB, optimal NPs to deliver oligonucleotide RNA into GBM cells in the brain are currently unavailable. In this review, we describe first the current treatments for GBM therapy. Next, we discuss the most relevant miRNAs and lncRNAs suggested as targets for GBM therapy. Then, we compare the current drug delivery systems (nanocarriers/NPs) for RNA oligonucleotide delivery, the challenges faced to send drugs through the BBB, and the strategies to overcome this barrier. Finally, we categorize the critical points where research should be the focus in order to design optimal NPs for drug delivery into the brain; and thus move the Oligonucleotide RNA-based therapies from the bench to the clinical setting.

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Section: Bacterial Toxinsmentioning

confidence: 99%

Section: Bacterial Toxinsmentioning

confidence: 99%

Section: Bacterial Toxinsmentioning

confidence: 99%

See 1 more Smart Citation

Targeting Non-coding RNA for Glioblastoma Therapy: The Challenge of Overcomes the Blood-Brain Barrier

Sharma

Calderón

Vivas‐Mejía

2021

Front. Med. Technol.

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“…The DT TD has been used for the active translocation of protein modules to the cytosol, proving its ability to assist in the membrane crossing of polypeptides different from CD [29,30]. Although the precise mechanism by which proteins are translocated to the cytosol by the DT TD is a controversial subject [31,32], the DT TD, free from the active catalytic domain, it is an agent of potential interest in drug delivery [33,34]. In addition, as far as we know, there are no existing reports about the potential role of TD in promoting cell surface internalization previous to receptor-mediated endosomal uptake.…”

Section: Introductionmentioning

confidence: 99%

The Diphtheria Toxin Translocation Domain Impairs Receptor Selectivity in Cancer Cell-Targeted Protein Nanoparticles

et al. 2022

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Protein-based materials intended as nanostructured drugs or drug carriers are progressively gaining interest in nanomedicine, since their structure, assembly and cellular interactivity can be tailored by recruiting functional domains. The main bottleneck in the development of deliverable protein materials is the lysosomal degradation that follows endosome maturation. This is especially disappointing in the case of receptor-targeted protein constructs, which, while being highly promising and in demand in precision medicines, enter cells via endosomal/lysosomal routes. In the search for suitable protein agents that might promote endosome escape, we have explored the translocation domain (TD) of the diphtheria toxin as a functional domain in CXCR4-targeted oligomeric nanoparticles designed for cancer therapies. The pharmacological interest of such protein materials could be largely enhanced by improving their proteolytic stability. The incorporation of TD into the building blocks enhances the amount of the material detected inside of exposed CXCR4+ cells up to around 25-fold, in absence of cytotoxicity. This rise cannot be accounted for by endosomal escape, since the lysosomal degradation of the new construct decreases only moderately. On the other hand, a significant loss in the specificity of the CXCR4-dependent cellular penetration indicates the unexpected role of the toxin segment as a cell-penetrating peptide in a dose-dependent and receptor-independent fashion. These data reveal that the diphtheria toxin TD displayed on receptor-targeted oligomeric nanoparticles partially abolishes the exquisite receptor specificity of the parental material and it induces nonspecific internalization in mammalian cells.

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Toxin-Mediated siRNA Delivery

Cited by 2 publications

References 11 publications

Targeting Non-coding RNA for Glioblastoma Therapy: The Challenge of Overcomes the Blood-Brain Barrier

Targeting Non-coding RNA for Glioblastoma Therapy: The Challenge of Overcomes the Blood-Brain Barrier

The Diphtheria Toxin Translocation Domain Impairs Receptor Selectivity in Cancer Cell-Targeted Protein Nanoparticles

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