Publication
Lactate-coated polyurea-siRNA dendriplex: a gene therapy-directed and metabolism-based strategy to impair glioblastoma (GBM)
| datacite.subject.fos | Ciências Médicas::Ciências da Saúde | |
| datacite.subject.sdg | 03:Saúde de Qualidade | |
| dc.contributor.author | Martins, Filipa | |
| dc.contributor.author | Arada, Renata | |
| dc.contributor.author | Barros, Hélio | |
| dc.contributor.author | Matos, Paulo | |
| dc.contributor.author | Ramalho, José | |
| dc.contributor.author | Ceña, Valentín | |
| dc.contributor.author | Bonifácio, Vasco D.B. | |
| dc.contributor.author | Gonçalves, Luís G. | |
| dc.contributor.author | Serpa, Jacinta | |
| dc.date.accessioned | 2025-11-12T16:53:52Z | |
| dc.date.available | 2025-11-12T16:53:52Z | |
| dc.date.issued | 2025-04-27 | |
| dc.description | Correction: Cancer Gene Ther. 2025 Aug;32(8):911. Epub 2025 Jul 10. https://doi.org/10.1038/s41417-025-00933-5 | |
| dc.description.abstract | Glioblastoma (GBM) is a highly lethal disease with limited treatment options due to its infiltrative nature and the lack of efficient therapy able to cross the protective blood-brain barrier (BBB). GBMs are metabolically characterized by increased glycolysis and glutamine dependence. This study explores a novel metabolism-based therapeutic approach using a polyurea generation 4 dendrimer (PURE) surface functionalized with lactate (LA) (PURE-LA), to take advantage of glucose-dependent monocarboxylate transporters (MCTs) overexpression, loaded with selenium-chrysin (SeChry) and temozolomide (TMZ) or complexed with anti-glutaminase (GLS1) siRNAs to abrogate glutamine dependence. The nanoparticles (PURE-LA) were efficient vehicles for cytotoxic compounds delivery, since SeChry@PURE-LA and TMZ@PURE-LA induced significant cell death in GBM cell lines, particularly in U251, which exhibits higher MCT1 expression. The anti-GLS1 siRNA-dendriplex with PURE-LA (PURE-LA-anti-GLS1-siRNA) knocked down GLS1 in the GBM cell lines. In two in vitro BBB models, these dendriplexes successfully crossed the BBB, decreased GLS1 expression and altered the exometabolome of GBM cell lines, concomitantly with autophagy activation. Our findings highlight the potential of targeting glucose and glutamine pathways in GBM using dendrimer-based nanocarriers, overcoming the BBB and disrupting key metabolic processes in GBM cells. PURE-LA-anti-GLS1-siRNA dendriplexes cross the blood-brain barrier (BBB) and impair glioblastoma (GBM) metabolism. The BBB is formed by a thin monolayer of specialized brain microvascular endothelial cells joined together by tight junctions that selectively control the passage of substances from the blood to the brain. It is a major obstacle in the treatment of GBM, since many chemotherapeutic drugs are unable to penetrate the brain. Therefore, we developed a strategy to overcome this obstacle: a lactate-coated polyurea dendrimer generation 4 (PURE) able to cross the BBB in vitro, that act as a nanocarrier of drugs and siRNA to the GBM cells. PURE-LA are nanoparticles functionalized with lactate (LA) to target MCT1, a lactate transporter highly expressed by GBM cells. Moreover, a complex of this nanoparticle with anti-GLS1 (glutaminase) siRNA (PURE-LA-anti-GLS1-siRNA) was made, to target glutamine metabolism. It efficiently knocked down GLS1. Moreover, PURE-LA loaded with SeChry led to BBB disruption. | eng |
| dc.description.sponsorship | The institutions are funded by Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior (FCT/MCTES, Portugal) through national funds to iNOVA4Health (UIDB/04462/2020 and UIDP/04462/2020), to MOSTMICRO-ITQB (UIDB/04612/2020 and UIDP/04612/2020), to BioISI (Center Grant doi 10.54499/UIDB/ 04046/2020), and the Associated Laboratory LS4FUTURE (LA/P/0087/2020). Filipa Martins was funded by a FCT individual Ph.D. fellowship (2020.04780.BD). Luis G. Gonçalves was financed by a FCT contract according to DL57/2016, [SFRH/BPD/ 111100/2015]. Data availability in a public repository is supported by NIH U2C DK119886 and OT2-OD030544 grants. | |
| dc.identifier.citation | Cancer Gene Ther. 2025 Jun;32(6):690-705. doi: 10.1038/s41417-025-00906-8. Epub 2025 Apr 27 | |
| dc.identifier.doi | 10.1038/s41417-025-00906-8 | |
| dc.identifier.issn | 0929-1903 | |
| dc.identifier.pmid | 40289180 | |
| dc.identifier.uri | http://hdl.handle.net/10400.18/10601 | |
| dc.language.iso | eng | |
| dc.peerreviewed | yes | |
| dc.publisher | Springer Nature [academic journals on nature.com] | |
| dc.relation | iNOVA4Health - Programme in Translational Medicine (iBET, CEDOC/FCM, IPOLFG e ITQB) | |
| dc.relation | Carboxydotrophs for alkane production: from CO/CO2 to fuel | |
| dc.relation.hasversion | https://www.nature.com/articles/s41417-025-00906-8 | |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
| dc.subject | Glioblastoma | |
| dc.subject | Metabolism | |
| dc.subject | Cancer | |
| dc.subject | Nanoparticles | |
| dc.subject | Vias de Transdução de Sinal e Patologias Associadas | |
| dc.title | Lactate-coated polyurea-siRNA dendriplex: a gene therapy-directed and metabolism-based strategy to impair glioblastoma (GBM) | eng |
| dc.type | journal article | |
| dcterms.references | https://static-content.springer.com/esm/art%3A10.1038%2Fs41417-025-00906-8/MediaObjects/41417_2025_906_MOESM1_ESM.pdf | |
| dspace.entity.type | Publication | |
| oaire.awardTitle | iNOVA4Health - Programme in Translational Medicine (iBET, CEDOC/FCM, IPOLFG e ITQB) | |
| oaire.awardTitle | Carboxydotrophs for alkane production: from CO/CO2 to fuel | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04462%2F2020/PT | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F111100%2F2015/PT | |
| oaire.citation.endPage | 705 | |
| oaire.citation.issue | 6 | |
| oaire.citation.startPage | 690 | |
| oaire.citation.title | Cancer Gene Therapy | |
| oaire.citation.volume | 32 | |
| oaire.fundingStream | 6817 - DCRRNI ID | |
| oaire.version | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
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