ArticleBMC cancer2011
Challenges associated with the targeted delivery of gelonin to claudin-expressing cancer cells with the use of activatable cell penetrating peptides to enhance potency.
Article in BMC cancer, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 33 citations in OpenAlex.
- Potentiation of Gelonin Cytotoxicity by Pulsed Electric Fields.International journal of molecular sciences · 2025Article
- Intracellular Delivery of Therapeutic Protein via Ultrathin Layered Double Hydroxide Nanosheets.Pharmaceutics · 2024Article
- A cleavable chimeric peptide with targeting and killing domains enhances LPS neutralization and antibacterial properties against multi-drug resistant E. coli.Communications biology · 2023Article
- Bacteria-derived chimeric toxins as potential anticancer agents.Frontiers in oncology · 2022Review
- Development of chimeric peptides to facilitate the neutralisation of lipopolysaccharides during bactericidal targeting of multidrug-resistant Escherichia coli.Communications biology · 2020Article
- In silico design of a novel chimeric shigella IpaB fused to C terminal of clostridium perfringens enterotoxin as a vaccine candidate.Bioengineered · 2018Article
- PTD-Modified ATTEMPTS for Enhanced Toxin-based Cancer Therapy: An In Vivo Proof-of-Concept Study.Pharmaceutical research · 2015Article
- Recombinant TAT-gelonin fusion toxin: synthesis and characterization of heparin/protamine-regulated cell transduction.Journal of biomedical materials research. Part A · 2015Article
- Characterization of a monoclonal antibody capable of reliably quantifying expression of human Copper Transporter 1 (hCTR1).Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) · 2014Article
- Integrin αV modulates the cellular pharmacology of copper and cisplatin by regulating expression of the influx transporter CTR1.Oncoscience · 2014Article
- Fusion protein linkers: property, design and functionality.Advanced drug delivery reviews · 2013Review
- Targeted tumor therapy by epidermal growth factor appended toxin and purified saponin: an evaluation of toxicity and therapeutic potential in syngeneic tumor bearing mice.Molecular oncology · 2013Article
- Synergistic antitumor activity from two-stage delivery of targeted toxins and endosome-disrupting nanoparticles.Biomacromolecules · 2013Article
- Optimizing molecular-targeted therapies in ovarian cancer: the renewed surge of interest in ovarian cancer biomarkers and cell signaling pathways.Journal of oncology · 2012Article
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4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTreatment of tumors with macromolecular toxins directed to cytoplasmic targets requires selective endocytosis followed by release of intact toxin from the endosomal/lysosomal compartment. The latter step remains a particular challenge. Claudins 3 and 4 are tight junction proteins that are over-expressed in many types of tumors. This study utilized the C-terminal 30 amino acid fragment of C. perfringens enterotoxin (CPE), which binds to claudins 3 and 4, to deliver a toxin in the form of recombinant gelonin (rGel) to the cytoplasm of the human ovarian carcinoma cell line 2008.
resultsCPE was fused to rGel at its N-terminal end via a flexible G4S linker. This CPE-G4S-rGel molecule was internalized into vesicles from which location it produced little cytotoxicity. To enhance release from the endosomal/lysosomal compartment a poly-arginine sequence (R9) was introduced between the CPE and the rGel. CPE-R9-rGel was 10-fold more cytotoxic but selectivity for claudin-expressing cells was lost. The addition of a poly-glutamic acid sequence (E9) through a G4S linker to R9-rGel (E9-G4S-R9-rGel) largely neutralized the non-selective cell membrane penetrating activity of the R9 motif. However, introduction of CPE to the E9-G4S-R9-rGel fusion protein (CPE-E9-G4S-R9-rGel) further reduced its cytotoxic effect. Treatment with the endosomolytic reagent chloroquine increased the cytotoxicity of CPE-E9-G4S-R9-rGel. Several types of linkers susceptible to cleavage by furin and endosomal cathepsin B were tested for their ability to enhance R9-rGel release but none of these modifications further enhanced the cytotoxicity of CPE-E9-G4S-R9-rGel.
conclusionWe conclude that while a claudin-3 and -4 ligand serves to deliver rGel into 2008 cells the delivered molecules were entrapped in intracellular vesicles. Incorporation of R9 non-specifically increased rGel cytotoxicity and this effect could be masked by inclusion of an E9 sequence. However, the putative protease cleavable sequences tested were inadequate for release of R9-rGel from CPE-E9-G4S-R9-rGel.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.