Rodríguez-Clemente Irene, Karpus Andrii, Buendía Angel, Sztandera Krzystof, Regulska Elzbieta, Bignon Jerome, Caminade Anne-Marie, Romero-Nieto Carlos, Steinmetz Anke, Mignani Serge, Majoral Jean-Pierre, Ceña Valentín
Unidad Asociada Neurodeath, INAMOL, Universidad de Castilla-La Mancha, Albacete 02006, Spain.
CIBER, Instituto de Salud Carlos III, Madrid 28028, Spain.
Biomacromolecules. 2025 Jul 14;26(7):4158-4173. doi: 10.1021/acs.biomac.5c00171. Epub 2025 May 30.
Glioblastoma multiforme (GBM) is the most common type of primary brain tumor in adults and has a poor prognosis. Small interfering RNA (siRNA) can disrupt different mechanisms involved in the genesis of several diseases including GBM. However, siRNA complexation with nonviral cationic carriers is required to transport siRNAs inside cells and promote its function. We have designed and synthesized new cationic phosphorus dendrimers bearing either 6, 12, or 24 pyrrolidinium or piperidinium groups on their surface. These dendrimers bound siRNA, those bearing terminal pyrrolidinium having the highest affinity. However, they showed marked differences in protecting siRNA from RNase-mediated degradation. Molecular modeling suggested that, beyond the overall protonation status, the intrinsic flexibility and individual binding properties of these dendrimers contributed to the modulation of biological profiles. However, these phosphorus dendrimers were unable to transport significant amounts of siRNA into GBM cells and, accordingly, transfection was inefficient.
多形性胶质母细胞瘤（GBM）是成人中最常见的原发性脑肿瘤类型，预后较差。小干扰RNA（siRNA）可以破坏包括GBM在内的多种疾病发生过程中涉及的不同机制。然而，需要将siRNA与非病毒阳离子载体复合，以便将siRNA转运到细胞内并促进其功能。我们设计并合成了新型阳离子磷树枝状大分子，其表面带有6个、12个或24个吡咯烷鎓或哌啶鎓基团。这些树枝状大分子能结合siRNA，其中带有末端吡咯烷鎓的树枝状大分子具有最高的亲和力。然而，它们在保护siRNA免受核糖核酸酶介导的降解方面表现出显著差异。分子模拟表明，除了整体质子化状态外，这些树枝状大分子的固有柔韧性和个体结合特性有助于调节生物学特性。然而，这些磷树枝状大分子无法将大量siRNA转运到GBM细胞中，因此转染效率低下。
