TY - JOUR

T1 - In Vitro Validation of the Therapeutic Potential of Dendrimer-Based Nanoformulations against Tumor Stem Cells

AU - Knauer, Nadezhda

AU - Arkhipova, Valeria

AU - Li, Guanzhang

AU - Hewera, Michael

AU - Pashkina, Ekaterina

AU - Nguyen, Phuong Hien

AU - Meschaninova, Maria

AU - Kozlov, Vladimir

AU - Zhang, Wei

AU - Croner, Roland S.

AU - Caminade, Anne Marie

AU - Majoral, Jean Pierre

AU - Apartsin, Evgeny K.

AU - Kahlert, Ulf D.

N1 - Funding Information: The project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 844217 “EUREKA” to E.K.A. N.K. appreciates the financial support from the Heinrich-Heine University Düsseldorf, Germany within the STIBET programme. This article is based upon work from COST Action CA 17140 “Cancer Nanomedicine from the Bench to the Bedside” supported by COST (European Cooperation in Science and Technology). The financial support from the CNRS is also appreciated. U.D.K. thanks Heinrich Research Academics (HeRA) for supporting the travel to COST Action Meeting in Riga 2019, which essentially was the fundament of establishing this multinational cooperation. This work is a result of the bilateral cooperation grant M-0020 from the Sino-German Center for Research Promotion in Beijing, dedicated to WZ and UDK. U.D.K. wants to thank specifically Sigrun Wegener-Feldbrügge; JUNO HHU for assisting in administrative matters, especially her continuous support in processing and availability on questions related to visa issues with foreign visiting scientists. Publisher Copyright: © 2022 by the author. Licensee MDPI, Basel, Switzerland.

PY - 2022/5/1

Y1 - 2022/5/1

N2 - Tumor cells with stem cell properties are considered to play major roles in promoting the development and malignant behavior of aggressive cancers. Therapeutic strategies that efficiently eradicate such tumor stem cells are of highest clinical need. Herein, we performed the validation of the polycationic phosphorus dendrimer-based approach for small interfering RNAs delivery in in vitro stem-like cells as models. As a therapeutic target, we chose Lyn, a member of the Src family kinases as an example of a prominent enzyme class widely discussed as a potent anti-cancer intervention point. Our selection is guided by our discovery that Lyn mRNA expression level in glioma, a class of brain tumors, possesses significant negative clinical predictive value, promoting its potential as a therapeutic target for future molecular-targeted treatments. We then showed that anti-Lyn siRNA, delivered into Lyn-expressing glioma cell model reduces the cell viability, a fact that was not observed in a cell model that lacks Lyn-expression. Furthermore, we have found that the dendrimer itself influences various parameters of the cells such as the expression of surface markers PD-L1, TIM-3 and CD47, targets for immune recognition and other biological processes suggested to be regulating glioblastoma cell invasion. Our findings prove the potential of dendrimer-based platforms for therapeutic applications, which might help to eradicate the population of cancer cells with augmented chemotherapy resistance. Moreover, the results further promote our functional stem cell technology as suitable component in early stage drug development.

AB - Tumor cells with stem cell properties are considered to play major roles in promoting the development and malignant behavior of aggressive cancers. Therapeutic strategies that efficiently eradicate such tumor stem cells are of highest clinical need. Herein, we performed the validation of the polycationic phosphorus dendrimer-based approach for small interfering RNAs delivery in in vitro stem-like cells as models. As a therapeutic target, we chose Lyn, a member of the Src family kinases as an example of a prominent enzyme class widely discussed as a potent anti-cancer intervention point. Our selection is guided by our discovery that Lyn mRNA expression level in glioma, a class of brain tumors, possesses significant negative clinical predictive value, promoting its potential as a therapeutic target for future molecular-targeted treatments. We then showed that anti-Lyn siRNA, delivered into Lyn-expressing glioma cell model reduces the cell viability, a fact that was not observed in a cell model that lacks Lyn-expression. Furthermore, we have found that the dendrimer itself influences various parameters of the cells such as the expression of surface markers PD-L1, TIM-3 and CD47, targets for immune recognition and other biological processes suggested to be regulating glioblastoma cell invasion. Our findings prove the potential of dendrimer-based platforms for therapeutic applications, which might help to eradicate the population of cancer cells with augmented chemotherapy resistance. Moreover, the results further promote our functional stem cell technology as suitable component in early stage drug development.

KW - 3D tumor models

KW - dendrimers

KW - Lyn

KW - nanomedicine

KW - nucleic acid therapeutics

KW - phosphorus

KW - polyelectrolyte complexes

KW - tumor stem cells

KW - Glioma/metabolism

KW - Humans

KW - RNA, Small Interfering/genetics

KW - Neoplastic Stem Cells/metabolism

KW - Brain Neoplasms/metabolism

KW - Dendrimers/metabolism

KW - Glioblastoma/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85130214948&partnerID=8YFLogxK

U2 - 10.3390/ijms23105691

DO - 10.3390/ijms23105691

M3 - Article

C2 - 35628503

AN - SCOPUS:85130214948

VL - 23

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 10

M1 - 5691

ER -