Targeting Radiation Resistance in Oesophageal Adenocarcinoma with Pyrazinib-Functionalised Gold Nanoparticles
Only 20-30% of oesophageal adenocarcinoma (OAC) patients achieve a complete response to neoadjuvant chemo-radiotherapy for locally advanced tumours. Enhancing the response to radiation therapy is critical for improving outcomes in this aggressive cancer. Pyrazinib (P3) is a promising compound with r...
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| Veröffentlicht in: | Cancers 2024-12, Vol.16 (23), p.4007 |
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| creator | Marcone, Simone Spadavecchia, Jolanda Khan, Memona Vella, Gabriele O'Connell, Fiona Pendino, Marzia Menon, Meghana Donohoe, Claire Narayanasamy, Ravi Reynolds, John V Maher, Stephen G Lynam-Lennon, Niamh Kennedy, Breandán Prina-Mello, Adriele O'Sullivan, Jacintha |
| description | Only 20-30% of oesophageal adenocarcinoma (OAC) patients achieve a complete response to neoadjuvant chemo-radiotherapy for locally advanced tumours. Enhancing the response to radiation therapy is critical for improving outcomes in this aggressive cancer. Pyrazinib (P3) is a promising compound with radiosensitizing, anti-angiogenic, anti-inflammatory, and anti-metabolic properties. However, its limited solubility and bioavailability have hindered its therapeutic potential.
To overcome these limitations, pyrazinib was conjugated with gold nanoparticles (AuNP-P3), creating a novel formulation designed to enhance solubility, maintain bioactivity, and enable targeted delivery to tumour sites.
In an isogenic model of OAC radioresistance, AuNP-P3 significantly reduced the surviving fraction following irradiation, demonstrating its radiosensitizing properties. It also reduced mitochondrial metabolism and modulated the secretion of inflammatory mediators in both in vitro models of OAC radioresistance and human ex vivo OAC tumour explants. Furthermore, AuNP-P3 exhibited potent anti-angiogenic activity, significantly inhibiting blood vessel formation in vivo using zebrafish embryo models.
These results collectively confirm that P3, in its conjugated formulation with gold nanoparticles, retains its therapeutic properties, highlighting the potential of AuNP-P3 as a novel therapeutic radiosensitizer for oesophageal adenocarcinoma and supporting its further development for clinical applications. |
| doi_str_mv | 10.3390/cancers16234007 |
| format | Article |
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To overcome these limitations, pyrazinib was conjugated with gold nanoparticles (AuNP-P3), creating a novel formulation designed to enhance solubility, maintain bioactivity, and enable targeted delivery to tumour sites.
In an isogenic model of OAC radioresistance, AuNP-P3 significantly reduced the surviving fraction following irradiation, demonstrating its radiosensitizing properties. It also reduced mitochondrial metabolism and modulated the secretion of inflammatory mediators in both in vitro models of OAC radioresistance and human ex vivo OAC tumour explants. Furthermore, AuNP-P3 exhibited potent anti-angiogenic activity, significantly inhibiting blood vessel formation in vivo using zebrafish embryo models.
These results collectively confirm that P3, in its conjugated formulation with gold nanoparticles, retains its therapeutic properties, highlighting the potential of AuNP-P3 as a novel therapeutic radiosensitizer for oesophageal adenocarcinoma and supporting its further development for clinical applications.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers16234007</identifier><identifier>PMID: 39682192</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Adenocarcinoma ; Angiogenesis ; Cancer ; Care and treatment ; Chemotherapy ; Dosage and administration ; Drug resistance ; Esophageal cancer ; Gold ; Health aspects ; Hemodialysis ; Inflammation ; Medical prognosis ; Medical research ; Medicine, Experimental ; Metabolism ; Methods ; Microscopy ; Nanoparticles ; Neovascularization ; Oncology, Experimental ; Particle size ; Phosphorylation ; Pyrazinamide ; Radiation ; Radiation therapy ; Radiotherapy ; Reproducibility ; Research ethics ; Tumors</subject><ispartof>Cancers, 2024-12, Vol.16 (23), p.4007</ispartof><rights>COPYRIGHT 2024 MDPI AG</rights><rights>2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c317t-9e1aab418f50afa3a68a67ad5192a8c1aa7a17519626c5ed149683b33b827213</cites><orcidid>0000-0003-0126-7906 ; 0000-0002-4371-2214 ; 0000-0001-7991-4689 ; 0000-0002-3641-4374</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39682192$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Marcone, Simone</creatorcontrib><creatorcontrib>Spadavecchia, Jolanda</creatorcontrib><creatorcontrib>Khan, Memona</creatorcontrib><creatorcontrib>Vella, Gabriele</creatorcontrib><creatorcontrib>O'Connell, Fiona</creatorcontrib><creatorcontrib>Pendino, Marzia</creatorcontrib><creatorcontrib>Menon, Meghana</creatorcontrib><creatorcontrib>Donohoe, Claire</creatorcontrib><creatorcontrib>Narayanasamy, Ravi</creatorcontrib><creatorcontrib>Reynolds, John V</creatorcontrib><creatorcontrib>Maher, Stephen G</creatorcontrib><creatorcontrib>Lynam-Lennon, Niamh</creatorcontrib><creatorcontrib>Kennedy, Breandán</creatorcontrib><creatorcontrib>Prina-Mello, Adriele</creatorcontrib><creatorcontrib>O'Sullivan, Jacintha</creatorcontrib><title>Targeting Radiation Resistance in Oesophageal Adenocarcinoma with Pyrazinib-Functionalised Gold Nanoparticles</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>Only 20-30% of oesophageal adenocarcinoma (OAC) patients achieve a complete response to neoadjuvant chemo-radiotherapy for locally advanced tumours. Enhancing the response to radiation therapy is critical for improving outcomes in this aggressive cancer. Pyrazinib (P3) is a promising compound with radiosensitizing, anti-angiogenic, anti-inflammatory, and anti-metabolic properties. However, its limited solubility and bioavailability have hindered its therapeutic potential.
To overcome these limitations, pyrazinib was conjugated with gold nanoparticles (AuNP-P3), creating a novel formulation designed to enhance solubility, maintain bioactivity, and enable targeted delivery to tumour sites.
In an isogenic model of OAC radioresistance, AuNP-P3 significantly reduced the surviving fraction following irradiation, demonstrating its radiosensitizing properties. It also reduced mitochondrial metabolism and modulated the secretion of inflammatory mediators in both in vitro models of OAC radioresistance and human ex vivo OAC tumour explants. Furthermore, AuNP-P3 exhibited potent anti-angiogenic activity, significantly inhibiting blood vessel formation in vivo using zebrafish embryo models.
These results collectively confirm that P3, in its conjugated formulation with gold nanoparticles, retains its therapeutic properties, highlighting the potential of AuNP-P3 as a novel therapeutic radiosensitizer for oesophageal adenocarcinoma and supporting its further development for clinical applications.</description><subject>Adenocarcinoma</subject><subject>Angiogenesis</subject><subject>Cancer</subject><subject>Care and treatment</subject><subject>Chemotherapy</subject><subject>Dosage and administration</subject><subject>Drug resistance</subject><subject>Esophageal cancer</subject><subject>Gold</subject><subject>Health aspects</subject><subject>Hemodialysis</subject><subject>Inflammation</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Medicine, Experimental</subject><subject>Metabolism</subject><subject>Methods</subject><subject>Microscopy</subject><subject>Nanoparticles</subject><subject>Neovascularization</subject><subject>Oncology, Experimental</subject><subject>Particle size</subject><subject>Phosphorylation</subject><subject>Pyrazinamide</subject><subject>Radiation</subject><subject>Radiation therapy</subject><subject>Radiotherapy</subject><subject>Reproducibility</subject><subject>Research 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Adenocarcinoma with Pyrazinib-Functionalised Gold Nanoparticles</title><author>Marcone, Simone ; Spadavecchia, Jolanda ; Khan, Memona ; Vella, Gabriele ; O'Connell, Fiona ; Pendino, Marzia ; Menon, Meghana ; Donohoe, Claire ; Narayanasamy, Ravi ; Reynolds, John V ; Maher, Stephen G ; Lynam-Lennon, Niamh ; Kennedy, Breandán ; Prina-Mello, Adriele ; O'Sullivan, Jacintha</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c317t-9e1aab418f50afa3a68a67ad5192a8c1aa7a17519626c5ed149683b33b827213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adenocarcinoma</topic><topic>Angiogenesis</topic><topic>Cancer</topic><topic>Care and treatment</topic><topic>Chemotherapy</topic><topic>Dosage and administration</topic><topic>Drug resistance</topic><topic>Esophageal cancer</topic><topic>Gold</topic><topic>Health aspects</topic><topic>Hemodialysis</topic><topic>Inflammation</topic><topic>Medical prognosis</topic><topic>Medical research</topic><topic>Medicine, Experimental</topic><topic>Metabolism</topic><topic>Methods</topic><topic>Microscopy</topic><topic>Nanoparticles</topic><topic>Neovascularization</topic><topic>Oncology, Experimental</topic><topic>Particle size</topic><topic>Phosphorylation</topic><topic>Pyrazinamide</topic><topic>Radiation</topic><topic>Radiation therapy</topic><topic>Radiotherapy</topic><topic>Reproducibility</topic><topic>Research ethics</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Marcone, Simone</creatorcontrib><creatorcontrib>Spadavecchia, Jolanda</creatorcontrib><creatorcontrib>Khan, Memona</creatorcontrib><creatorcontrib>Vella, Gabriele</creatorcontrib><creatorcontrib>O'Connell, Fiona</creatorcontrib><creatorcontrib>Pendino, Marzia</creatorcontrib><creatorcontrib>Menon, 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(Basel)</addtitle><date>2024-12-01</date><risdate>2024</risdate><volume>16</volume><issue>23</issue><spage>4007</spage><pages>4007-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>Only 20-30% of oesophageal adenocarcinoma (OAC) patients achieve a complete response to neoadjuvant chemo-radiotherapy for locally advanced tumours. Enhancing the response to radiation therapy is critical for improving outcomes in this aggressive cancer. Pyrazinib (P3) is a promising compound with radiosensitizing, anti-angiogenic, anti-inflammatory, and anti-metabolic properties. However, its limited solubility and bioavailability have hindered its therapeutic potential.
To overcome these limitations, pyrazinib was conjugated with gold nanoparticles (AuNP-P3), creating a novel formulation designed to enhance solubility, maintain bioactivity, and enable targeted delivery to tumour sites.
In an isogenic model of OAC radioresistance, AuNP-P3 significantly reduced the surviving fraction following irradiation, demonstrating its radiosensitizing properties. It also reduced mitochondrial metabolism and modulated the secretion of inflammatory mediators in both in vitro models of OAC radioresistance and human ex vivo OAC tumour explants. Furthermore, AuNP-P3 exhibited potent anti-angiogenic activity, significantly inhibiting blood vessel formation in vivo using zebrafish embryo models.
These results collectively confirm that P3, in its conjugated formulation with gold nanoparticles, retains its therapeutic properties, highlighting the potential of AuNP-P3 as a novel therapeutic radiosensitizer for oesophageal adenocarcinoma and supporting its further development for clinical applications.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>39682192</pmid><doi>10.3390/cancers16234007</doi><orcidid>https://orcid.org/0000-0003-0126-7906</orcidid><orcidid>https://orcid.org/0000-0002-4371-2214</orcidid><orcidid>https://orcid.org/0000-0001-7991-4689</orcidid><orcidid>https://orcid.org/0000-0002-3641-4374</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adenocarcinoma Angiogenesis Cancer Care and treatment Chemotherapy Dosage and administration Drug resistance Esophageal cancer Gold Health aspects Hemodialysis Inflammation Medical prognosis Medical research Medicine, Experimental Metabolism Methods Microscopy Nanoparticles Neovascularization Oncology, Experimental Particle size Phosphorylation Pyrazinamide Radiation Radiation therapy Radiotherapy Reproducibility Research ethics Tumors |
| title | Targeting Radiation Resistance in Oesophageal Adenocarcinoma with Pyrazinib-Functionalised Gold Nanoparticles |
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