An electrostatically conjugated-functional MNK1 aptamer reverts the intrinsic antitumor effect of polyethyleneimine-coated iron oxide nanoparticles in vivo in a human triple-negative cancer xenograft
Mulens-Arias, Vladimir (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Portilla, Yadileiny (Centro Nacional de Biotecnología)
Pérez Yagüe, Sonia (Centro Nacional de Biotecnología)
Ferreras Martín, Raquel (Hospital Universitario Ramón y Cajal (Madrid))
Martín, María Elena (Hospital Universitario Ramón y Cajal (Madrid))
González, Víctor M. (Hospital Universitario Ramón y Cajal (Madrid))
Barber, Domingo F. (Centro Nacional de Biotecnología)

Fecha:	2023
Resumen:	Background: Triple-negative breast cancer (TNBC) remains a difficult breast cancer subtype to treat as it exhibits a particularly aggressive behavior. The dysregulation of distinct signaling pathways underlies this aggressive behavior, with an overactivation of MAP kinase interacting kinases (MNKs) promoting tumor cell behavior, and driving proliferation and migration. Therefore, MNK1 is an excellent target to impair the progression of TNBC and indeed, an MNK1-specific aptamer has proved to be efficient in inhibiting TBNC cell proliferation in vitro. Although polyethyleneimine-coated iron oxide nanoparticles (PEI-IONPs) have been used as transfection and immunomodulating agents, no study has yet addressed the benefits of using these nanoparticles as a magnetic carrier for the delivery of a functional aptamer. Results: Here, we tested the antitumor effect of a PEI-IONP complexed to the functional MNK1b-specific aptamer in vitro and in vivo. We demonstrated that these apMNKQ2@PEI-IONP nanoconjugates delivered three times more apMNKQ2 to MDA-MB-231 cells than the aptamer alone, and that this enhanced intracellular delivery of the aptamer had consequences for MNK1 signaling, reducing the amount of MNK1 and its target the phospho(Ser209)-eukaryotic initiation factor 4E (eIF4E). As a result, a synergistic effect of the apMNKQ2 and PEI-IONPs was observed that inhibited MDA-MB-231 cell migration, probably in association with an increase in the serum and glucocorticoid-regulated kinase-1 (SGK1) and the phospho(Thr346)-N-myc down-regulated gene 1 (NDRG1). However, intravenous administration of the apMNKQ2 alone did not significantly impair tumor growth in vivo, whereas the PEI-IONP alone did significantly inhibit tumor growth. Significantly, tumor growth was not inhibited when the apMNKQ2@PEI-IONP nanocomplex was administered, possibly due to fewer IONPs accumulating in the tumor. This apMNKQ2-induced reversion of the intrinsic antitumor effect of the PEI-IONPs was abolished when an external magnetic field was applied at the tumor site, promoting IONP accumulation. Conclusions: Electrostatic conjugation of the apMNKQ2 aptamer with PEI-IONPs impedes the accumulation of the latter in tumors, which appears to be necessary for PEI-IONPs to exert their antitumor activity. Graphical Abstract: [Figure not available: see fulltext. ].
Ayudas:	Instituto de Salud Carlos III DTS18/00029 Ministerio de Educación, Cultura y Deporte FPU15/06170 Agencia Estatal de Investigación PID2020-112685RB-100
Nota:	The authors acknowledge the Scientific and Technical Assistance of the Transmission Electron Microscopy, Flow cytometry, Histology and Animal services at the Centro Nacional de Biotecnología (CNB, CSIC). ICP-OES analysis was carried out in the support laboratories at the Instituto de Ciencia de Materiales de Madrid (ICMM, CSIC). The authors are also grateful to Dr M. Sefton for author editing of the manuscript.
Nota:	Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This study was supported by the DTS18/00029 Grant (to VM Gonzalez and DF Barber) from the Instituto de Salud Carlos III (Plan Estatal de I + D + I 2017-2020), co-financed by the European Development Regional Fund ''A way to achieve Europe'' (ERDF), and by the PID2020-112685RB-100 Grant (to DF Barber) funded by MCIN/AEI/10.13039/501100011033. V. Mulens-Arias was a postdoctoral scholar working under a Juan de La Cierva-Incorporación Contract (IJCI-2017-31447, funded by MCIN/AEI/10.13039/501100011033) and Y. Portilla received a predoctoral FPU Grant (FPU15/06170 funded by MCIN/AEI/10.13039/501100011033 and the ESF Investing in your future). This research work was performed in the framework of the Nanomedicine CSIC HUB and Cancer CSIC HUB.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Aptamer ; MNK1 ; Polyethyleneimine‑coated iron oxide nanoparticles ; Antitumor effect
Publicado en:	Cancer Nanotechnology, Vol. 14 Núm. 1 (december 2023) , p. 64, ISSN 1868-6966

DOI: 10.1186/s12645-023-00204-8

24 p, 3.2 MB

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