Dihydropyridine-based Nanoparticles EfficientTransfection of siRNA in Glioblastoma Cells by Dihydropyridine-based Nanoparticles

Valentín Ceña(1,2), Irene Rodriguez-Clemente(1,2), Angel Buendía-Buendía(1,2), Krzysztof Sztandera(1,2), Martins Rucins(3), Martins Kaukulis(3), Cristina de la Torre(4), Julie Earl(5), Mariángeles Vaz-Salgado(6), Roberto García-Leal(7), Arkadij Sobolev(3) & Aiva Ploltniece(3)

(1) CIBER, Instituto de Salud Carlos III, Madrid, Spain. valentin.cena@gmail.com

(2) Unidad Asociada Neurodeath, INAMOL, Universidad de Castilla-La Mancha, Albacete, Spain

(3) Latvian Instituute of Organic Synthesis, Riga, Latvia

(4) University of Aarhus, Aarhus, Denmark

(5) IRYCIS, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain

(6) Hospital Ramón y Cajal; Madrid, Spain

(7) Hospital General Universitario Gregorio Marañón, Madrid, Spain

Although different approaches have been used to increase Blood-Brain Barrier (BBB) crossing by nanoparticles (NPs) [1], there are still significant restrictions for NPs to access the central nervous system (CNS) in significant amounts. Small interference RNAs (siRNAs) are gaining increasing interest as therapeutic options in several diseases [2]. We have synthesized several dihydropyridine (DHP)-based NPs and studied the cytotoxicity induced by the NPs on commercial GBM cell lines, astrocytes and neurons as well as on patient-derived GBM cells. Finally, we labeled the NPs with a fluorescent probe and studied the NP biodistribution in mice. We have found that the DHP-based NPs bound siRNA and protected it from degradation by RNAses. The NPs were not toxic by themselves to GBM cells, astrocytes and neurons. Moreover, they were able to transport specific siRNAs into the GBM cell interior and decrease the intracellular levels of the target proteins to about 10% of control values in 72 hours. In addition, biodistribution studies showed a marked accumulation of the labeled NPs in both brain and spinal medulla. The results strongly suggest that the DHP-derived NPs can represent a very efficient scaffold to transport siRNA and drugs into the CNS.

Acknowledgments: The authors acknowledge the excellent technical support from Vanesa Guijarro. This research was supported by MCIN with funding from European Union NextGenerationEU (PRTR-C17.I1) and MICIN (project PID2020-120134RB-I00 Financiado por MCIN/AEI/10.13039/501100011033).

References:
[1] M. Agrawal et al. Expert Opin Drug Deliv 19(1): 87-102. (2022).
[2] Pérez-Carrión et al. Pharmacol Res. 2024 Mar;201:107102.

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