Article
A β-Cyclodextrin-Based Nanoparticle with Very High Transfection Efficiency Unveils siRNA-Activated TLR3 Responses in Human Prostate Cancer Cells
Author/s | de la Torre, Cristina
Játiva, Pablo Posadas, Inmaculada Manzanares, Darío Jiménez Blanco, José Luis Ortiz Mellet, Carmen García Fernández, José Manuel Ceña, Valentín |
Department | Universidad de Sevilla. Departamento de Química orgánica |
Publication Date | 2022 |
Deposit Date | 2023-04-14 |
Published in |
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Abstract | Synthetic double-stranded small interfering RNAs (siRNAs) mimic interference RNAs (RNAi) and can bind target mRNAs with a high degree of specificity, leading to selective knockdown of the proteins they encode. However, ... Synthetic double-stranded small interfering RNAs (siRNAs) mimic interference RNAs (RNAi) and can bind target mRNAs with a high degree of specificity, leading to selective knockdown of the proteins they encode. However, siRNAs are very labile and must be both protected and transported by nanoparticles to be efficiently delivered into cells. In this work, we used a Janus-type polycationic amphiphilic β-cyclodextrin derivative to efficiently transfect siRNAs targeting mRNAs encoding mitogen-activated protein kinase (p42-MAPK) or Ras homolog enriched in brain (Rheb) into different cancer cell lines as well as astrocytes. We took advantage of this high transfection efficiency to simultaneously knock down p42-MAPK and Rheb to boost docetaxel (DTX)-mediated toxicity in two human prostate cancer cell lines (LNCaP and PC3). We found that double knockdown of p42-MAPK and Rheb increased DTX-toxicity in LNCaP but not in PC3 cells. However, we also observed the same effect when scramble siRNA was used, therefore pointing to an off-target effect. Indeed, we found that the siRNA we used in this work induced toll-like receptor 3 activation, leading to β-interferon production and caspase activation. We believe that this mechanism could be very useful as a general strategy to elicit an immune response against prostate cancer cells. |
Funding agencies | Ministerio de Ciencia, Innovación y Universidades (MICINN). España Agencia Estatal de Investigación. España Instituto de Salud Carlos III Euronanomed Program Junta de Castilla-La Mancha Junta de Andalucía European Cooperation in Science and Technology (COST) European Regional Development Fund |
Project ID. | PID2020-120134RB-I00
AC19/00075 SBPLY/19/180501/000067 CA17140 RTI2018-097609-B-C21 PID2021-124247OB-C21 PID2019-105858RB-I00 P20_00166 NANO4GLIO |
Citation | de la Torre, C., Játiva, P., Posadas, I., Manzanares, D., Jiménez Blanco, J.L., Ortiz Mellet, C.,...,Ceña, V. (2022). A β-Cyclodextrin-Based Nanoparticle with Very High Transfection Efficiency Unveils siRNA-Activated TLR3 Responses in Human Prostate Cancer Cells. Pharmaceutics, 14 (11). https://doi.org/10.3390/pharmaceutics14112424. |
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