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Ibba M. L., Ciccone G., Condorelli G. et al.
Aptamer-based RNA-bio-drugs for the combined therapy of GBM
© IBBA M. L., CICCONE G., CONDORELLI G., DE FRANCISCIS V., CATUOGNO S., MORYACHKOV R. V., MOROZOV E., ESPOSITO C. L. UDC 576.310.31
DOI: 10.20333/25000136-2022-5-114
Aptamer-based RNA-bio-drugs for the combined therapy of GBM
M. L. Ibba1, G. Ciccone2, G. Condorelli2,3, V. de Franciscis2,3, S. Catuogno2, R. V. Moryachkov5, E. V. Morozov5, E. V. Kuligina6, C. L. Esposito2,3
'Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples 80131, Italy 2Istitute for Experimental Endocrinology and Oncology, Research National Council (CNR), Naples 80145, Italy 3Institute of Genetic and Biomedical Research (IRGB), Research National Council (CNR), Milan, Italy
4IRCCS Neuromed (Istituto di Ricovero e Cura a Carattere Scientifico Neuromed) Istituto Neurologico Mediterraneo, Pozzilli 86077, Italy 5Federal Research Center "Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences", Krasnoyarsk, Russian Federation 6Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk, Russian Federation
Abstract. This paper describes a novel combined approach to targeting GBM with multiple RNA-based therapeutics. Overall, the results demonstrate the good potential of a smart safe and clinically applicable combined regimen for the treatment of glioblastoma, opening up a new avenue in the treatment of this aggressive disease.
Key words: cancer, aptamer, RNA therapeutics, targeted delivery.
Conflict of interest. The authors declare the absence of obvious and potential conflicts of interest associated with the publication of this article. Citation: Ibba ML, Ciccone G, Condorelli G, de Franciscis V, Catuogno S, Moryachkov RV, Morozov E, Esposito CL. Aptamer-based RNA-bio-drugs for the combined therapy of GBM. Siberian Medical Review. 2022;(5):114. DOI: 10.20333/25000136-2022-5-114
Glioblastoma multiforme (GBM) is the most common aggressive and incurable brain cancer in adults, with a very dismal prognosis for patients [1]. Nucleic acid therapeutics, including siRNAs and miRNAs/antimiRs, are emerging highly promising molecules for the precise treatment of refractory aggressive GBM. However, the clinical use of oligonucle-otide-based therapies required development of precise and safe targeted cell delivery strategies. In the last decade, nucleic acid aptamers-synthetic RNA/DNA molecules acting as high affinity ligands - or antagonists of their selected target - have provided very promising carriers for therapeutic oligonucle-otides [2]. Here we describe a novel combinational approach to target GBM with multiple RNA-based therapeutics. We designed two conjugates containing two aptamers that bind to, and inhibit, the receptor tyrosine kinases, Axl and PDGFR^, as targeted carriers of therapeutic RNAs inhibiting two key players of GBM (STAT3 and miR-10b) [3]. We have demonstrated that both the conjugates hamper GBM cell growth and migration and effectively and specifically prevent patient-derived glioblastoma stem cell (GSC) function and expansion [4, 5]. MRI spectroscopy was used to prove the effectiveness of innovative drugs based on aptamers in vivo. Most importantly, we demonstrate the therapeutic efficacy of such molecules in vivo in patient-derived GBM models and we show that the developed chimeras synergise both in vitro and in vivo. Collectively our results highlight the potential of a smart, safe and clinically translatable combined regime for GBM, opening a new path in the treatment of this aggressive disease.
Development of the glioma tumor model in immunosup-pressed mice was supported by the Russian Science Foundation grant No. 22-64-00041 (M.A.D.), https://rscf.ru/en/ project/22-64-00041/. MRI and cell culture was funded by the Ministry of Science and Higher Education of the Russian Federation; project FWES-2022-0005 (A.S.K.).
References
1. Taylor OG, Brzozowski JS, Skelding KA. Glioblastoma Multiforme: An Overview of Emerging Therapeutic Targets. Frontiers in Oncology. 2019;9(963). Doi:10.3389/fonc.2019.00963
2. Esposito CL, Catuogno S, Condorelli G, Ungaro P, de Franciscis V. Aptamer Chimeras for Therapeutic Delivery: The Challenging Perspectives. Genes (Basel). 2018;9(11).
3. Kwiatkowska A, Symons M. Signaling determinants of glioma cell invasion. Advances in Experimental Medicine and Biology. 2013;(986):121-141.
4. Esposito CL, Nuzzo S, Catuogno S, Romano S, de Nigris F, de Franciscis V. STAT3 Gene Silencing by Aptamer-siRNA Chimera as Selective Therapeutic for Glioblastoma. Molecular Therapy-Nucleic Acids. 2018;2(10):398-411.
5. Esposito CL, Nuzzo S, Ibba ML, Ricci-Vitiani L, Pallini R, Condorelli G, Catuogno S, de Franciscis V. Combined Targeting of Glioblastoma Stem-Like Cells by Neutralizing RNA-Bio-Drugs for STAT3. Cancers (Basel). 2020;(12):1434.
Author information
Michael Ibba, researcher, Department of Molecular Medicine and Medical Biotechnology,"Federico II" University of Naples; Address: 80131 Naples, Italy; Phone:+7(391)2201893; e-mail; gecondor@unina. it; https://orcid.org/0000-0002-5318-1605
Giuseppe Ciccone, Institute Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR); Address: 80145 Naples, Italy; Phone:+7(391)2201893; e-mail: gecondor@unina.it; https://orcid.org/0000-0002-7677-6257
Gerolama Condorelli, Professor, Institute Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR); Address: 80145 Naples, Italy; Institute of Genetic and Biomedical Research (IRGB), Research National Council (CNR); Address: 09042 Monserrato (CA), Milan, Italy; Phone:+7(391)2201893; e-mail: gecondor@unina.it; https:// orcid.org/0000-0003-0177-8829
Vittorio de Franciscis, Professor, Institute Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR); Address: 80145 Naples, Italy; Institute of Genetic and Biomedical Research (IRGB), Research National Council (CNR); Address: 09042 Monserrato (CA), Milan, Italy; Phone:+7(391)2201893; e-mail: defranci@unina.it; https://orcid.org/0000-0001-6601-1181 Silvia Catuogno, PhD, Institute for Experimental Endocrinology and Oncology, Research National Council (CNR); Address: 80145 Naples, Italy; Phone:+7(391)2201893; e-mail: s.catuogno@ieos.cnr.it
Roman. V. Moryachkov, researcher, Laboratory for Digital Controlled Drugs and Theranostics, Federal Research Center "Krasnoyarsk Science Center SB RAS"; Address: 50, Akademgorodok, Krasnoyarsk, Russian Federation 660036; Phone: +7-913-511-38-16; e-mail: romanautilus@gmail.com, https://orcid.org/0000-0002-0409-779X
Evgeniy Morozov, PhD, Federal Research Center"Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences"; Address: Krasnoyarsk 660036, Russian Federation; Phone: +7-903-923-84-02; e-mail: morozov_if@mail.ru; https://orcid.org/0000-0003-1561-3937
Elena V. Kuligina, PhD, Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences; Address: 8, Lavrentyev Avenue, Novosibirsk, Russian Federation 630090; Phone: +7-913-511-38-16; e-mail: kuligina@niboch.nsc.ru; https://orcid. org/0000-0003-3145-1878
Carla L. Esposito, PhD, Institute Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), National Research Council (CNR); Address: 80145 Naples, Italy; Institute of Genetic and Biomedical Research (IRGB), Research National Council (CNR); Address: 09042 Monserrato (CA), Milan, Italy; Phone:+7(391)2201893; e-mail: c.esposito@ieos.cnr.it; https://orcid. org/0000-0002-1961-0832
Received 16 June 2022 Revision Received 21 August 2022 Accepted 30 August 2022
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Siberian Medical Review. 2022;(5):114
