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• W2982463915 abstract "B cell maturation antigen is highly expressed on malignant plasma cells in human multiple myeloma and has recently emerged as a very promising target for therapeutic interventions. Nucleic-acid-based aptamers are small oligonucleotides with high selective targeting properties and functional advantages over monoclonal antibodies, as both diagnostic and therapeutic tools. Here, we describe the generation of the first-ever-described nuclease resistant RNA aptamer selectively binding to B cell maturation antigen. We adopted a modified cell-based systematic evolution of ligands by exponential enrichment approach allowing the enrichment for internalizing aptamers. The selected 2′Fluoro-Pyrimidine modified aptamer, named apt69.T, effectively and selectively bound B cell maturation antigen-expressing myeloma cells with rapid and efficient internalization. Interestingly, apt69.T inhibited APRIL-dependent nuclear factor κB (NF-κB) pathway in vitro. Moreover, the aptamer was conjugated to microRNA-137 (miR-137) and anti-miR-222, demonstrating high potential against tumor cells. In conclusion, apt69.T is a novel tool suitable for direct targeting and delivery of therapeutics to B cell maturation antigen-expressing myeloma cells. B cell maturation antigen is highly expressed on malignant plasma cells in human multiple myeloma and has recently emerged as a very promising target for therapeutic interventions. Nucleic-acid-based aptamers are small oligonucleotides with high selective targeting properties and functional advantages over monoclonal antibodies, as both diagnostic and therapeutic tools. Here, we describe the generation of the first-ever-described nuclease resistant RNA aptamer selectively binding to B cell maturation antigen. We adopted a modified cell-based systematic evolution of ligands by exponential enrichment approach allowing the enrichment for internalizing aptamers. The selected 2′Fluoro-Pyrimidine modified aptamer, named apt69.T, effectively and selectively bound B cell maturation antigen-expressing myeloma cells with rapid and efficient internalization. Interestingly, apt69.T inhibited APRIL-dependent nuclear factor κB (NF-κB) pathway in vitro. Moreover, the aptamer was conjugated to microRNA-137 (miR-137) and anti-miR-222, demonstrating high potential against tumor cells. In conclusion, apt69.T is a novel tool suitable for direct targeting and delivery of therapeutics to B cell maturation antigen-expressing myeloma cells. Multiple myeloma (MM) is an aggressive hematologic disease that accounts for 1% of all cancers and about 13% of all hematologic malignancies. It is characterized by an abnormal proliferation and accumulation of malignant immunoglobulin-producing plasma cells (PCs) in the bone marrow (BM), associated with systemic signs including osteolytic bone lesions. Despite considerable recent advances in MM therapy that have significantly improved the overall survival of patients, it still remains in most cases an incurable lethal disease. Indeed, currently available standard-of-care therapies for MM patients, which include autologous or allogeneic stem cell transplantation, innovative immunomodulatory agents, CD38- and SLAMF7-directed monoclonal antibodies (mAbs), proteasome inhibitors, and dendritic cell-based vaccines, show effectiveness in a limited subset of patients.1Kumar S. Emerging options in multiple myeloma: targeted, immune, and epigenetic therapies.Hematology (Am. Soc. Hematol. Educ. Program). 2017; 2017: 518-524Crossref PubMed Scopus (19) Google Scholar,2Larocca A. Mina R. Gay F. Bringhen S. Boccadoro M. Emerging drugs and combinations to treat multiple myeloma.Oncotarget. 2017; 8: 60656-60672Crossref PubMed Scopus (32) Google Scholar Thus, new effective treatments are urgently awaited to improve patient clinical outcome. In recent years, among several new investigational therapeutic strategies toward new targets,3Rossi M. Di Martino M.T. Morelli E. Leotta M. Rizzo A. Grimaldi A. Misso G. Tassone P. Caraglia M. Molecular targets for the treatment of multiple myeloma.Curr. Cancer Drug Targets. 2012; 12: 757-767Crossref PubMed Scopus (62) Google Scholar, 4Amodio N. Di Martino M.T. Neri A. Tagliaferri P. Tassone P. Non-coding RNA: a novel opportunity for the personalized treatment of multiple myeloma.Expert Opin. Biol. Ther. 2013; 13: S125-S137Crossref PubMed Scopus (69) Google Scholar, 5Botta C. Gullà A. Correale P. Tagliaferri P. Tassone P. Myeloid-derived suppressor cells in multiple myeloma: pre-clinical research and translational opportunities.Front. Oncol. 2014; 4: 348Crossref PubMed Scopus (54) Google Scholar, 6Misso G. Zappavigna S. Castellano M. De Rosa G. Di Martino M.T. Tagliaferri P. Tassone P. Caraglia M. Emerging pathways as individualized therapeutic target of multiple myeloma.Expert Opin. Biol. Ther. 2013; 13: S95-S109Crossref PubMed Scopus (36) Google Scholar B cell maturation antigen (BCMA) has emerged as promising for immunotherapy against MM. Also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17), BCMA is a member of the TNF receptor superfamily and is functionally related to the transmembrane activator and calcium modulator and cyclophilin ligand (TACI or TNFRSF13B) and B cell activating factor receptor (BAFF-R or TNFRSF13C) receptors. BCMA is found on the cell surface of late-stage normal B lymphocytes and highly expressed on malignant PCs from MM patients.7Novak A.J. Darce J.R. Arendt B.K. Harder B. Henderson K. Kindsvogel W. Gross J.A. Greipp P.R. Jelinek D.F. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival.Blood. 2004; 103: 689-694Crossref PubMed Scopus (414) Google Scholar, 8Claudio J.O. Masih-Khan E. Tang H. Gonçalves J. Voralia M. Li Z.H. Nadeem V. Cukerman E. Francisco-Pabalan O. Liew C.C. et al.A molecular compendium of genes expressed in multiple myeloma.Blood. 2002; 100: 2175-2186Crossref PubMed Scopus (161) Google Scholar, 9Tai Y.T. Li X.F. Breitkreutz I. Song W. Neri P. Catley L. Podar K. Hideshima T. Chauhan D. Raje N. et al.Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment.Cancer Res. 2006; 66: 6675-6682Crossref PubMed Scopus (198) Google Scholar The binding of its specific ligands, BAFF and the proliferation-inducing ligand (APRIL or TNFSF13), induces activation of canonical and non-canonical nuclear factor κB (NF-κB) pathway and promotes long-lived PCs survival.10Rickert R.C. Jellusova J. Miletic A.V. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease.Immunol. Rev. 2011; 244: 115-133Crossref PubMed Scopus (228) Google Scholar,11O’Connor B.P. Raman V.S. Erickson L.D. Cook W.J. Weaver L.K. Ahonen C. Lin L.L. Mantchev G.T. Bram R.J. Noelle R.J. BCMA is essential for the survival of long-lived bone marrow plasma cells.J. Exp. Med. 2004; 199: 91-98Crossref PubMed Scopus (770) Google Scholar Recently, it has been demonstrated that BCMA also exists in a soluble form.12Sanchez E. Smith E.J. Yashar M.A. Patil S. Li M. Porter A.L. Tanenbaum E.J. Schlossberg R.E. Soof C.M. Hekmati T. et al.The Role of B-Cell Maturation Antigen in the Biology and Management of, and as a Potential Therapeutic Target in, Multiple Myeloma.Target. Oncol. 2018; 13: 39-47Crossref PubMed Scopus (22) Google Scholar Different evidences showed that serum BCMA (sBCMA) is a promising marker for monitoring the course of the disease in MM patients and that it does not represent an obstacle to the success of the anti-BCMA-targeted therapies.13Laurent S.A. Hoffmann F.S. Kuhn P.H. Cheng Q. Chu Y. Schmidt-Supprian M. Hauck S.M. Schuh E. Krumbholz M. Rübsamen H. et al.γ-Secretase directly sheds the survival receptor BCMA from plasma cells.Nat. Commun. 2015; 6: 7333Crossref PubMed Scopus (197) Google Scholar On the basis of these considerations, mAbs targeting BCMA have been developed as tools for MM-targeted therapy. These mAbs inhibit APRIL-dependent activation of downstream NF-κB and support immune-mediated killing of tumor cells.14Oden F. Marino S.F. Brand J. Scheu S. Kriegel C. Olal D. Takvorian A. Westermann J. Yilmaz B. Hinz M. et al.Potent anti-tumor response by targeting B cell maturation antigen (BCMA) in a mouse model of multiple myeloma.Mol. Oncol. 2015; 9: 1348-1358Crossref PubMed Scopus (22) Google Scholar,15Ryan M.C. Hering M. Peckham D. McDonagh C.F. Brown L. Kim K.M. Meyer D.L. Zabinski R.F. Grewal I.S. Carter P.J. Antibody targeting of B-cell maturation antigen on malignant plasma cells.Mol. Cancer Ther. 2007; 6: 3009-3018Crossref PubMed Scopus (71) Google Scholar To improve the antitumor potential of approaches targeting BCMA, a mAb has been modified by conjugation to cytotoxic drugs, such as monomethylauristatin F, a potent inhibitor of tubulin polymerization.16Tai Y.T. Mayes P.A. Acharya C. Zhong M.Y. Cea M. Cagnetta A. Craigen J. Yates J. Gliddon L. Fieles W. et al.Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma.Blood. 2014; 123: 3128-3138Crossref PubMed Scopus (296) Google Scholar,17Hipp S. Tai Y.T. Blanset D. Deegen P. Wahl J. Thomas O. Rattel B. Adam P.J. Anderson K.C. Friedrich M. A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo.Leukemia. 2017; 31: 2278Crossref PubMed Scopus (14) Google Scholar Moreover, BCMA/CD3 bispecific mAbs and T cells genetically engineered to express chimeric antigen receptors (CAR-Ts) targeting BCMA have demonstrated significant anti-MM activity and are currently in early clinical trials.7Novak A.J. Darce J.R. Arendt B.K. Harder B. Henderson K. Kindsvogel W. Gross J.A. Greipp P.R. Jelinek D.F. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival.Blood. 2004; 103: 689-694Crossref PubMed Scopus (414) Google Scholar,17Hipp S. Tai Y.T. Blanset D. Deegen P. Wahl J. Thomas O. Rattel B. Adam P.J. Anderson K.C. Friedrich M. A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo.Leukemia. 2017; 31: 2278Crossref PubMed Scopus (14) Google Scholar, 18Seckinger A. Delgado J.A. Moser S. Moreno L. Neuber B. Grab A. Lipp S. Merino J. Prosper F. Emde M. et al.Target Expression, Generation, Preclinical Activity, and Pharmacokinetics of the BCMA-T Cell Bispecific Antibody EM801 for Multiple Myeloma Treatment.Cancer Cell. 2017; 31: 396-410Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 19Mikkilineni L. Kochenderfer J.N. Chimeric antigen receptor T-cell therapies for multiple myeloma.Blood. 2017; 130: 2594-2602Crossref PubMed Scopus (147) Google Scholar, 20Ali S.A. Shi V. Maric I. Wang M. Stroncek D.F. Rose J.J. Brudno J.N. Stetler-Stevenson M. Feldman S.A. Hansen B.G. et al.T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma.Blood. 2016; 128: 1688-1700Crossref PubMed Scopus (503) Google Scholar, 21Rotolo A. Caputo V. Karadimitris A. The prospects and promise of chimeric antigen receptor immunotherapy in multiple myeloma.Br. J. Haematol. 2016; 173: 350-364Crossref PubMed Scopus (15) Google Scholar, 22Carpenter R.O. Evbuomwan M.O. Pittaluga S. Rose J.J. Raffeld M. Yang S. Gress R.E. Hakim F.T. Kochenderfer J.N. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma.Clin. Cancer Res. 2013; 19: 2048-2060Crossref PubMed Scopus (422) Google Scholar, 23D’Agostino M. Boccadoro M. Smith E.L. Novel Immunotherapies for Multiple Myeloma.Curr. Hematol. Malig. Rep. 2017; 12: 344-357Crossref PubMed Scopus (28) Google Scholar In last decades, nucleic acid aptamers have emerged as effective therapeutics for a wide range of human pathologies, including solid and hematological tumors.24Shigdar S. Ward A.C. De A. Yang C.J. Wei M. Duan W. Clinical applications of aptamers and nucleic acid therapeutics in haematological malignancies.Br. J. Haematol. 2011; 155: 3-13Crossref PubMed Scopus (30) Google Scholar Aptamers are also called “nucleic acid monoclonal antibodies” due to their capacity to fold in particular three-dimensional shapes and to bind specific targets. They show many advantages over monoclonal antibodies as diagnostic and therapeutic tools, such as low immunogenicity, small size, high batch fidelity, easy production, increased chemical stability, and versatility. Interestingly, aptamers directed against cell surface receptors represent very attractive options for therapeutic targeted delivery.25Zhou J. Rossi J. Aptamers as targeted therapeutics: current potential and challenges.Nat. Rev. Drug Discov. 2017; 16: 440Crossref PubMed Scopus (48) Google Scholar,26Catuogno S. Esposito C.L. de Franciscis V. Aptamer-Mediated Targeted Delivery of Therapeutics: An Update.Pharmaceuticals (Basel). 2016; 9: E69Crossref PubMed Scopus (84) Google Scholar Indeed, upon binding, aptamers undergo intracellular uptake mediated by the target receptor and have been used to drive therapeutic molecules selectively to cells overexpressing the specific target. In this work, we address the generation and the characterization of a 2′Fluoro-Pyrimidine (2′F-Py) RNA aptamer, named apt69.T, selectively binding BCMA. We provide here proof-of-concept data that support the apt69.T anti-BCMA aptamer as potential new tool for the experimental treatment of MM. In order to select aptamers specific for binding to BCMA receptor, and able to internalize in a receptor-mediated manner as well, we adopted a variant of the conventional cell-SELEX (systematic evolution of ligands by exponential enrichment)27Catuogno S. Esposito C.L. Aptamer Cell-Based Selection: Overview and Advances.Biomedicines. 2017; 5: E49Crossref PubMed Scopus (53) Google Scholar procedure (see Table S1), introducing in the last three rounds a partitioning step of high-salt-resistant aptamers thus enriching for aptamers capable of rapid and selective cell internalization (cell-internalizing SELEX).28Thiel W.H. Thiel K.W. Flenker K.S. Bair T. Dupuy A.J. McNamara 2nd, J.O. Miller F.J. Giangrande P.H. Cell-internalization SELEX: method for identifying cell-internalizing RNA aptamers for delivering siRNAs to target cells.Methods Mol. Biol. 2015; 1218: 187-199Crossref PubMed Scopus (54) Google Scholar,29Catuogno S. Esposito C.L. de Franciscis V. Developing Aptamers by Cell-Based SELEX.Methods Mol. Biol. 2016; 1380: 33-46Crossref PubMed Scopus (15) Google Scholar As shown in Figure S1A, in the counter-selection step, a starting 2′F-Py RNA aptamer library pool was incubated with parental COS-7 BCMA-negative cells, and then, in the positive selection step, unbound aptamers were recovered and incubated with the same cell line transiently transfected with BCMA receptor (COS-7-BCMA). Overexpression of BCMA in COS-7 parental cells upon transfection was confirmed by western blot analysis (Figure S1B). Following 11 rounds of cell-SELEX (rounds 1–8 followed by intracellular rounds 9–11), the final aptamer pool was cloned and 11 aptamer sequences, each present in two or three copies in the alignment (Figure S1C), were validated for the binding activity on BCMA-expressing cells. As assessed by qRT-PCR-based binding assay, among the 11 analyzed aptamers, the apt69 and the apt29 showed the capacity to discriminate COS-7-BCMA cells from parental COS-7 cells at 100 nM concentration (Figures S2A and S2B). Further investigations revealed that apt69 holds the best binding ability and is able to effectively discriminate COS-7-BCMA cells from parental COS-7 cells in a dose-dependent analysis (Figure 1A). Specificity of the binding was also confirmed comparing apt69 binding ability with that of an unrelated control aptamer (UnrelApt) on COS-7-BCMA cells (see Figure S3). Further, the ability of the apt69 to internalize into BCMA expressing target cells has been evaluated by qRT-PCR to be ~16.8% of the total aptamer bound (Figure 1B). Based on the obtained results, apt69 was chosen for further characterization. We thus proceeded by reducing apt69 to a length compatible with chemical synthesis. Based on bioinformatic prediction of its secondary structure (RNAstructure, https://rna.urmc.rochester.edu and RNAfold, http://rna.tbi.univie.ac.at), we designed a shorter apt69 version in which the two central stem loops were preserved while the entire 5′ and part of the 3′-constant regions were removed (Figure 2A). The resulting 50-mer aptamer, named apt69.T, was then validated in vitro for target binding. As assessed by qRT-PCR-based binding assay, the shorter aptamer apt69.T preserves the ability to selectively bind to COS-7-BCMA cells and efficiently discriminates them from parental COS-7 cells (Figure 2B) with an apparent dissociation constant (KD = 79.4 nM) (Figure 2C). Further, we also determined the BCMA-dependent binding of the apt69.T to human malignant myeloma cells. As shown, the apt69.T revealed that it preferentially binds human B lymphocytes from MM, U266, and NCI-H929 BCMA-expressing cells, as compared with T lymphoblastoid cell line (CCRF-CEM) acute lymphoblastic leukemia T lymphoblasts that do not express detectable levels of BCMA (Figure 2D, left and right panels). On the other hand, the CCRF-CEM cells express TACI30Sanda T. Tyner J.W. Gutierrez A. Ngo V.N. Glover J. Chang B.H. Yost A. Ma W. Fleischman A.G. Zhou W. et al.TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia.Cancer Discov. 2013; 3: 564-577Crossref PubMed Scopus (113) Google Scholar but neither BCMA nor BAFF-R,31Zhou J. Tiemann K. Chomchan P. Alluin J. Swiderski P. Burnett J. Zhang X. Forman S. Chen R. Rossi J. Dual functional BAFF receptor aptamers inhibit ligand-induced proliferation and deliver siRNAs to NHL cells.Nucleic Acids Res. 2013; 41: 4266-4283Crossref PubMed Scopus (57) Google Scholar while U266 (BCMA+) cells express TACI, but not BAFF-R;32Moreaux J. Legouffe E. Jourdan E. Quittet P. Rème T. Lugagne C. Moine P. Rossi J.F. Klein B. Tarte K. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone.Blood. 2004; 103: 3148-3157Crossref PubMed Scopus (435) Google Scholar and NCI-H929 (BCMA+) cells do not express TACI and show a moderate expression of BAFF-R.15Ryan M.C. Hering M. Peckham D. McDonagh C.F. Brown L. Kim K.M. Meyer D.L. Zabinski R.F. Grewal I.S. Carter P.J. Antibody targeting of B-cell maturation antigen on malignant plasma cells.Mol. Cancer Ther. 2007; 6: 3009-3018Crossref PubMed Scopus (71) Google Scholar Results shown well support the binding of apt69.T to BCMA expressed on the cell surface of MM cells, but not, or poorly, to the functional related receptors for either APRIL and BAFF or TACI and BAFF-R. Finally, we confirmed binding of the apt69.T to BCMA by performing an aptamer-mediated affinity pull-down assay. To this end, MM U266 BCMA-expressing cells were treated with biotin-tagged apt69.T and total cell extracts purified on streptavidin-coated beads, followed by immunoblotting with anti-BCMA antibody. As shown in Figure 2E, the apt69.T is able to interact with BCMA, whereas no binding was obtained with an unrelated 2′F-Py RNA aptamer used as a negative control. Taken together, these data indicate that the short version of apt69, the apt 69.T, is a highly specific affinity ligand for the BCMA receptor. An important obstacle to the development of RNA-based drugs is represented by their rapid clearance and poor stability in the circulation. Indeed, RNA is highly sensitive to the degradation by the presence of nucleases in serum. Apt69.T contains 2′F-Py modifications that confer to the aptamer increased resistance to nuclease degradation.33Lok C.N. Viazovkina E. Min K.L. Nagy E. Wilds C.J. Damha M.J. Parniak M.A. Potent gene-specific inhibitory properties of mixed-backbone antisense oligonucleotides comprised of 2′-deoxy-2′-fluoro-D-arabinose and 2′-deoxyribose nucleotides.Biochemistry. 2002; 41: 3457-3467Crossref PubMed Scopus (55) Google Scholar In order to evaluate apt69.T serum stability, we incubated the aptamer in 80% human serum at 37°C for increasing times, up to 72 h. Then, the integrity of RNA samples was analyzed by denaturing PAGE (Figure 3A, left panel). As shown, the aptamer remained almost stable up to 8 h and then gradually degraded. Then, in order to calculate the approximate half-life, band intensities have been quantified by using ImageJ program (Figure 3A, right panel). The estimated half-life for the apt69.T in 80% human serum is calculated to be ~20 h. Further, in order to investigate whether the apt69.T binding causes functional inhibition of the ligand-dependent BCMA activity, we evaluated the APRIL-dependent activation of NF-κB pathway upon aptamer treatments. In order to exclude any interference from the TACI receptor, of which APRIL is a shared ligand, we decided to perform this analysis on NCI-H929 B cells that express a high level of BCMA but do not express TACI.30Sanda T. Tyner J.W. Gutierrez A. Ngo V.N. Glover J. Chang B.H. Yost A. Ma W. Fleischman A.G. Zhou W. et al.TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia.Cancer Discov. 2013; 3: 564-577Crossref PubMed Scopus (113) Google Scholar Starved NCI-H929 cells were treated for 30 min with 400 nM of apt69.T and then stimulated with human APRIL ligand for 5 or 10 min in the presence or not of the aptamer. We noticed that the apt69.T is able to reduce APRIL-induced phosphorylation of p65 reaching a reduction of ~50% following 10 min of stimulation. We also observed a clear inhibition of downstream effectors extracellular signal-regulated kinase (ERK) 1/2 phosphorylation (Figure 3B), up to 75% at 10 min of APRIL stimulation. Taken together, these data indicate that the apt69.T is able to inhibit BCMA downstream pathway. In order to verify that the truncation process does not alter the capacity of the aptamer to internalize into target cells, we then analyzed the in vitro aptamer uptake in BCMA-expressing MM cells. As assessed by binding for high-salt-resistant aptamer, we observed that apt69.T rapidly internalizes into U266 and H929 cells, showing approximately 35% of internalization following 15 min treatment in both cell lines (Figure 4A, left and right panel). Aptamer internalization was further increased following longer incubation times, reaching to ~50% following 2 h of exposition (Figure S4). Taking into account that the apt69.T half-life is of about 20 h (Figure 3A), apt69.T may represent a promising carrier for targeted therapy in MM. Emerging evidence demonstrates that aptamers, thanks to their advantageous properties over monoclonal antibodies, are ideal carrier molecules for selective delivery of a potential huge variety of therapeutics. As proof-of-concept study, we studied the potential delivery of non-coding RNAs (ncRNAs) or synthetic oligonucleotides (ONs), such as small interfering RNAs (siRNAs), microRNAs (miRNAs), and miRNA antagonists that have been widely demonstrated to exert anti-tumor activity in different tumors, including MM.4Amodio N. Di Martino M.T. Neri A. Tagliaferri P. Tassone P. Non-coding RNA: a novel opportunity for the personalized treatment of multiple myeloma.Expert Opin. Biol. Ther. 2013; 13: S125-S137Crossref PubMed Scopus (69) Google Scholar,25Zhou J. Rossi J. Aptamers as targeted therapeutics: current potential and challenges.Nat. Rev. Drug Discov. 2017; 16: 440Crossref PubMed Scopus (48) Google Scholar,34Catuogno S. Esposito C.L. Condorelli G. de Franciscis V. Nucleic acids delivering nucleic acids.Adv. Drug Deliv. Rev. 2018; 134: 79-93Crossref PubMed Scopus (39) Google Scholar, 35Yoon S. Rossi J.J. Emerging cancer-specific therapeutic aptamers.Curr. Opin. 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Zappavigna S. Russo M. Amler E. Di Martino M.T. Amodio N. Tagliaferri P. Tassone P. Caraglia M. Evidence of novel miR-34a-based therapeutic approaches for multiple myeloma treatment.Sci. Rep. 2017; 7: 17949Crossref PubMed Scopus (33) Google Scholar, 41Nuzzo S. Catuogno S. Capuozzo M. Fiorelli A. Swiderski P. Boccella S. de Nigris F. Esposito C.L. Axl-Targeted Delivery of the Oncosuppressor miR-137 in Non-small-Cell Lung Cancer.Mol. Ther. Nucleic Acids. 2019; 17: 256-263Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar As shown in Figure 4B, by using a stick-end based approach, previously described for the targeted delivery of RNA therapeutics,25Zhou J. Rossi J. Aptamers as targeted therapeutics: current potential and challenges.Nat. Rev. Drug Discov. 2017; 16: 440Crossref PubMed Scopus (48) Google Scholar,36Catuogno S. Rienzo A. Di Vito A. Esposito C.L. de Franciscis V. Selective delivery of therapeutic single strand antimiRs by aptamer-based conjugates.J. Control. Release. 2015; 210: 147-159Crossref PubMed Scopus (41) Google Scholar,42Esposito C.L. Nuzzo S. Kumar S.A. Rienzo A. Lawrence C.L. Pallini R. Shaw L. Alder J.E. Ricci-Vitiani L. Catuogno S. de Franciscis V. A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells.J. Control. Release. 2016; 238: 43-57Crossref PubMed Scopus (60) Google Scholar we designed two different conjugates. In the first, the passenger strand of the mature human miR-137 was conjugated with the 3′ end of the apt69.T, reported to be a tumor suppressor miRNA in MM.43Abdi J. Jian H. Chang H. Role of micro-RNAs in drug resistance of multiple myeloma.Oncotarget. 2016; 7: 60723-60735Crossref PubMed Scopus (30) Google Scholar,44Yang Y. Li F. Saha M.N. Abdi J. Qiu L. Chang H. miR-137 and miR-197 Induce Apoptosis and Suppress Tumorigenicity by Targeting MCL-1 in Multiple Myeloma.Clin. Cancer Res. 2015; 21: 2399-2411Crossref PubMed Scopus (100) Google Scholar In the second, the apt69.T was instead conjugated to a single strand antagonist of miR-222, an oncogenic miRNA found overexpressed in MM.45Di Martino M.T. Gullà A. Gallo Cantafio M.E. Lionetti M. Leone E. Amodio N. Guzzi P.H. Foresta U. Conforti F. Cannataro M. et al.In Vitro and in Vivo Anti-tumor Activity of miR-221/222 Inhibitors in Multiple Myeloma.Oncotarget. 2013; 4: 242-255Crossref PubMed Scopus (122) Google Scholar U266 cells, expressing basal low levels of miR-137, comparable to that expressed by CCRF-CEM, were treated with aptamer 69.T-miR-137 stick conjugate (indicated as apt69.T-137). The apt69.T-137 conjugate demonstrated that it induces a strong upregulation of the miR-137 in BCMA-expressing-U266 cells. A minimal increase of cellular miR-137 expression is also observed in CCRF-CEM cells, probably due to a slight aspecific cell uptake. However, induced miR-137 expression level was ~170-fold lower than that observed in BCMA-expressing U266 cells (Figure 4C). We then explored the effect of apt69.T-137 conjugate on myeloma cell growth and observed a clear reduction (~40%) of cell viability in BCMA-expressing-U266 cells, following 72 h treatment with 400 nM apt69.T-137 conjugate (Figure 4D). Further, NCI-H929 BCMA-expressing cells and CCRF-CEM control cells, showing similar measurable miR-222 basal levels, were treated with the apt69.T-anti-miR-222 stick conjugate (indicated as apt69.T-222), and miR-222 levels were measured by qRT-PCR. An evident downregulation of miR-222 expression levels (~80%) was observed in NCI-H929 cells, while no detectable effect was observed in CCRF-CEM BCMA-negative cells (Figure 4E). Collectively, these data indicate that apt69.T can be developed as an efficient and specific delivery carrier of therapeutic RNAs. MM is an incurable malignancy and much effort has been devoted over the years in the translational research for the identification of novel agents specifically targeting tumor cells, including the use of nucleic-acid-based agents.37Caracciolo D. Montesano M. Altomare E. Scionti F. Di Martino M.T. Tagliaferri P. Tassone P. The potential role of miRNAs in multiple myeloma therapy.Expert Rev. Hematol. 2018; 11: 793-803Crossref PubMed Scopus (20) Google Scholar,39Di Martino M.T. Rossi M. Caracciolo D. Gullà A. Tagliaferri P. Tassone P. Mir-221/222 are promising targets for innovative anticancer therapy.Expert Opin. Ther. Targets. 2016; 20: 1099-1108Crossref PubMed Scopus (40) Google Scholar,46Morelli E. Biamonte L. Federico C. Amodio N. Di Martino M.T. Gallo Cantafio M.E. Manzoni M. Scionti F. Samur M.K. Gullà A. et al.Therapeutic vulnerability of multiple myeloma to MIR17PTi, a first-in-class inhibitor of pri-miR-17-92.Blood. 2018; 132: 1050-1063Crossref PubMed Scopus (49) Google Scholar, 47Gallo Cantafio M.E. Nielsen B.S. Mignogna C. Arbitrio M. Botta C. Frandsen N.M. Rolfo C. Tagliaferri P. Tassone P. Di Martino M.T. Pharmacokinetics and Pharmacodynamics of a 13-mer LNA-inhibitor-miR-221 in Mice and Non-human Primates.Mol. Ther. Nucleic Acids. 2016; 5: E326Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 48Pitari M.R. Rossi M. Amodio N. Botta C. Morelli E. Federico C." @default.
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• W2982463915 title "An Anti-BCMA RNA Aptamer for miRNA Intracellular Delivery" @default.
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