Self-assembling protein nanocarrier for selective delivery of cytotoxic polypeptides to CXCR4+ head and neck squamous cell carcinoma tumors

Rioja-Blanco, Elisa; Arroyo‐Solera, Irene; Álamo, Patricia; Casanova, Isolda; Gallardo, Alberto; Unzueta, Ugutz; Serna, Naroa; Sánchez‐García, Laura; Quer, Miquel; Villaverde, Antonio; Vázquez, Esther; Mangues, Ramón; Alba-Castellón, Lorena; León, Xavier

doi:10.1016/j.apsb.2021.09.030

Cited by 17 publications

(19 citation statements)

References 54 publications

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“…In this framework, the T22-DITOX-H6 nanotoxin represents a promising approach for HNSCC treatment, as it aims to deliver cytotoxic compounds exclusively to CXCR4 + cancer cells. Our previous work demonstrated the selective accumulation of nanoparticles in CXCR4-overexpressing tumor tissues [21], together with a CXCR4dependent cytotoxic effect and a potent antitumor effect in vivo [22]. Here, we demonstrate, for the first time, that the T22-DITOX-H6 nanotoxin induces potent anti-invasive and antimetastatic effects in vivo.…”

Section: Discussionsupporting

confidence: 55%

“…UM-SCC-74B (74B) human-papillomavirus-negative (HPV − ) HNSCC cell line [20] was kindly provided by Dr. Gregory Oakley. The 74B-Luci cell line was obtained by lentiviral transduction with the plasmid pLenti-III-UbC-luc (abm, Vancouver, BC, Canada) as already described in previous work [21]. The 74B-Luci cell line was cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% fetal bovine serum (FBS), 100 U/mL penicillin/streptomycin, and 2 mM glutamine (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) and incubated at 37 • C and 5% CO 2 in a humidified atmosphere.…”

Section: Cell Lines and Culturementioning

confidence: 99%

“…The 74B-Luci cell line was cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% fetal bovine serum (FBS), 100 U/mL penicillin/streptomycin, and 2 mM glutamine (Gibco, Thermo Fisher Scientific, Waltham, MA, USA) and incubated at 37 • C and 5% CO 2 in a humidified atmosphere. CXCR4 expression in 74B-Luci has already been evaluated in previous work [21].…”

Section: Cell Lines and Culturementioning

confidence: 99%

“…The detection of these CXCR4 + tumor cells in the invasive front of the primary tumors exhorted us to investigate the potential anti-invasive effect of the T22-DITOX-H6 nanotoxin. T22-DITOX-H6 includes the CXCR4 ligand T22, fused to the cytotoxic domain of the diphtheria toxin, which is able to selectively internalize and eliminate CXCR4 + HNSCC cancer cells [21,22]. In this context, we generated an orthotopic HNSCC mouse model through the inoculation of the 74B-Luci cells in the mouse tongues.…”

Section: T22-ditox-h6 Nanotoxin Treatment Abrogates Tumor-cell Invasi...mentioning

confidence: 99%

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A Novel CXCR4-Targeted Diphtheria Toxin Nanoparticle Inhibits Invasion and Metastatic Dissemination in a Head and Neck Squamous Cell Carcinoma Mouse Model

et al. 2022

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Loco-regional recurrences and metastasis represent the leading causes of death in head and neck squamous cell carcinoma (HNSCC) patients, highlighting the need for novel therapies. Chemokine receptor 4 (CXCR4) has been related to loco-regional and distant recurrence and worse patient prognosis. In this regard, we developed a novel protein nanoparticle, T22-DITOX-H6, aiming to selectively deliver the diphtheria toxin cytotoxic domain to CXCR4+ HNSCC cells. The antimetastatic effect of T22-DITOX-H6 was evaluated in vivo in an orthotopic mouse model. IVIS imaging system was utilized to assess the metastatic dissemination in the mouse model. Immunohistochemistry and histopathological analyses were used to study the CXCR4 expression in the cancer cells, to evaluate the effect of the nanotoxin treatment, and its potential off-target toxicity. In this study, we report that CXCR4+ cancer cells were present in the invasive tumor front in an orthotopic mouse model. Upon repeated T22-DITOX-H6 administration, the number of CXCR4+ cancer cells was significantly reduced. Similarly, nanotoxin treatment effectively blocked regional and distant metastatic dissemination in the absence of systemic toxicity in the metastatic HNSCC mouse model. The repeated administration of T22-DITOX-H6 clearly abrogates tumor invasiveness and metastatic dissemination without inducing any off-target toxicity. Thus, T22-DITOX-H6 holds great promise for the treatment of CXCR4+ HNSCC patients presenting worse prognosis.

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Section: Discussionsupporting

confidence: 55%

Section: Cell Lines and Culturementioning

confidence: 99%

Section: Cell Lines and Culturementioning

confidence: 99%

Section: T22-ditox-h6 Nanotoxin Treatment Abrogates Tumor-cell Invasi...mentioning

confidence: 99%

See 2 more Smart Citations

A Novel CXCR4-Targeted Diphtheria Toxin Nanoparticle Inhibits Invasion and Metastatic Dissemination in a Head and Neck Squamous Cell Carcinoma Mouse Model

et al. 2022

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“…From another point of view and taking advantage of its selective CXCR4 binding, T22 has been largely exploited as a targeting agent, for precision therapies against diverse CXCR4 + human cancers. Among others, these include leukemia, lymphoma, head and neck and colorectal cancer [5][6][7][8][9][10][11][12][13][14], in which CXCR4 is overexpressed in metastatic cancer stem cells. In this context, when T22 is engineered as an N-terminal peptide in H6-tagged proteins it promotes, due to its cationic character [15], protein self-assembly into homomeric nanoparticles [16], which include around 10 monomers positioned in a regular, toroidal architecture [17].…”

Section: Introductionmentioning

confidence: 99%

Antibacterial Activity of T22, a Specific Peptidic Ligand of the Tumoral Marker CXCR4

et al. 2021

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CXCR4 is a cytokine receptor used by HIV during cell attachment and infection. Overexpressed in the cancer stem cells of more than 20 human neoplasias, CXCR4 is a convenient antitumoral drug target. T22 is a polyphemusin-derived peptide and an effective CXCR4 ligand. Its highly selective CXCR4 binding can be exploited as an agent for the cell-targeted delivery and internalization of associated antitumor drugs. Sharing chemical and structural traits with antimicrobial peptides (AMPs), the capability of T22 as an antibacterial agent remains unexplored. Here, we have detected T22-associated antimicrobial activity and biofilm formation inhibition over Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, in a spectrum broader than the reference AMP GWH1. In contrast to GWH1, T22 shows neither cytotoxicity over mammalian cells nor hemolytic activity and is active when displayed on protein-only nanoparticles through genetic fusion. Under the pushing need for novel antimicrobial agents, the discovery of T22 as an AMP is particularly appealing, not only as its mere addition to the expanding catalogue of antibacterial drugs. The recognized clinical uses of T22 might allow its combined and multivalent application in complex clinical conditions, such as colorectal cancer, that might benefit from the synchronous destruction of cancer stem cells and local bacterial biofilms.

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Protein‐basierte Nanopartikel: Von Wirkstofftransport zu Bildgebung, Nanokatalyse und Proteintherapie

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2023

Angewandte Chemie

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Proteine und Enzyme sind äußerst vielseitige Biomaterialien, die aufgrund ihrer hohen Spezifität für Rezeptoren und Substrate, ihrer Abbaubarkeit, geringen Toxizität und insgesamt guten Biokompatibilität hervorragend für ein breites Spektrum medizinischer Anwendungen geeignet sind. Durch die Anordnung mehrerer nativer oder modifizierter Proteine zu nanometergroßen Protein‐Nanopartikeln können zusätzliche vorteilhafte Eigenschaften wie eine erhöhte Stabilität im Blutstrom erreicht werden. In diesem Aufsatz konzentrieren wir uns auf künstliche Nanopartikelsysteme, bei denen Proteine das Hauptstrukturelement sind und nicht nur als eingeschlossene Wirkstoffe transportiert werden. Während unter natürlichen Bedingungen lediglich bestimmte Proteine definierte Aggregate und Nanopartikel bilden, können durch chemische Modifikationen oder Veränderungen in der physikalischen Umgebung Nanopartikel aus vielen verschiedenen globulären Proteinen und Enzymen hergestellt werden. Fortschritte bei den Herstellungsmethoden von proteinbasierten Nanopartikeln haben zu einer neuen Generation von Nanosystemen geführt, die über einfache Wirkstofftransporter hinausgehen und vielfältige Anwendungen ermöglichen, wie z.B. gezielte Arzneimittelabgabe, Theranostik, Nanokatalyse und Proteintherapie.

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Self-assembling protein nanocarrier for selective delivery of cytotoxic polypeptides to CXCR4+ head and neck squamous cell carcinoma tumors

Cited by 17 publications

References 54 publications

A Novel CXCR4-Targeted Diphtheria Toxin Nanoparticle Inhibits Invasion and Metastatic Dissemination in a Head and Neck Squamous Cell Carcinoma Mouse Model

A Novel CXCR4-Targeted Diphtheria Toxin Nanoparticle Inhibits Invasion and Metastatic Dissemination in a Head and Neck Squamous Cell Carcinoma Mouse Model

Antibacterial Activity of T22, a Specific Peptidic Ligand of the Tumoral Marker CXCR4

Protein‐basierte Nanopartikel: Von Wirkstofftransport zu Bildgebung, Nanokatalyse und Proteintherapie

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