Nucleic acid therapeutics最新文献

{"title":"Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides.","authors":"Aurélie Goyenvalle,&nbsp;Cecilia Jimenez-Mallebrera,&nbsp;Willeke van Roon,&nbsp;Sabine Sewing,&nbsp;Arthur M Krieg,&nbsp;Virginia Arechavala-Gomeza,&nbsp;Patrik Andersson","doi":"10.1089/nat.2022.0061","DOIUrl":"https://doi.org/10.1089/nat.2022.0061","url":null,"abstract":"<p><p>The nucleic acid therapeutics field has made tremendous progress in the past decades. Continuous advances in chemistry and design have led to many successful clinical applications, eliciting even more interest from researchers including both academic groups and drug development companies. Many preclinical studies in the field focus on improving the delivery of antisense oligonucleotide drugs (ONDs) and/or assessing their efficacy in target tissues, often neglecting the evaluation of toxicity, at least in early phases of development. A series of consensus recommendations regarding regulatory considerations and expectations have been generated by the Oligonucleotide Safety Working Group and the Japanese Research Working Group for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S6 and Related Issues (WGS6) in several white papers. However, safety aspects should also be kept in sight in earlier phases while screening and designing OND to avoid subsequent failure in the development phase. Experts and members of the network \"DARTER,\" a COST Action funded by the Cooperation in Science and Technology of the EU, have utilized their collective experience working with OND, as well as their insights into OND-mediated toxicities, to generate a series of consensus recommendations to assess OND toxicity in early stages of preclinical research. In the past few years, several publications have described predictive assays, which can be used to assess OND-mediated toxicity <i>in vitro</i> or <i>ex vivo</i> to filter out potential toxic candidates before moving to <i>in vivo</i> phases of preclinical development, that is, animal toxicity studies. These assays also have the potential to provide translational insight since they allow a safety evaluation in human <i>in vitro</i> systems. Yet, small preliminary <i>in vivo</i> studies should also be considered to complement this early assessment. In this study, we summarize the state of the art and provide guidelines and recommendations on the different tests available for these early stage preclinical assessments.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 1","pages":"1-16"},"PeriodicalIF":4.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9940817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10799186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevation of SHANK3 Levels by Antisense Oligonucleotides Directed Against the 3'-UTR of the Human <i>SHANK3</i> mRNA.","authors":"Nadine Stirmlinger,&nbsp;Jan Philipp Delling,&nbsp;Stefanie Pfänder,&nbsp;Tobias M Boeckers","doi":"10.1089/nat.2022.0048","DOIUrl":"https://doi.org/10.1089/nat.2022.0048","url":null,"abstract":"<p><p>SHANK3 is a member of the SHANK family of scaffolding proteins that localize to the postsynaptic density of excitatory synapses. Mutations within the <i>SHANK3</i> gene or <i>SHANK3</i> haploinsufficiency is thought to be one of the major causes for Phelan-McDermid Syndrome (PMDS) that is characterized by a broad spectrum of autism-related behavioral alterations. Several approaches have already been proposed to elevate SHANK3 protein levels in PMDS patients like transcriptional activation or inhibition of SHANK3 degradation. We undertook a systematic screening approach and tested whether defined antisense oligonucleotides (ASOs) directed against the 3' untranslated region (3'-UTR) of the human <i>SHANK3</i> mRNA are suitable to elevate SHANK3 protein levels. Using human induced pluripotent stem cells (hiPSCs) and hiPSCs-derived motoneurons from controls and PMDS patients we eventually identified two 18 nucleotide ASOs (ASO 4-5.2-4 and 4-5.2-6) that were able to increase SHANK3 protein levels <i>in vitro</i> by about 1.3- to 1.6-fold. These findings were confirmed by co-transfection of the identified ASOs with a GFP-SHANK3-3'-UTR construct in HEK293T cells using GFP protein expression as read-out. Based on these results we propose a novel approach to elevate SHANK3 protein concentrations by 3'-UTR specific ASOs. Further research is needed to test the suitability of <i>SHANK3</i>-specific ASOs as pharmacological compounds also <i>in vivo</i>.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 1","pages":"58-71"},"PeriodicalIF":4.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9940809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10793817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consensus Guidelines for the Design and <i>In Vitro</i> Preclinical Efficacy Testing N-of-1 Exon Skipping Antisense Oligonucleotides.","authors":"Annemieke Aartsma-Rus,&nbsp;Alejandro Garanto,&nbsp;Willeke van Roon-Mom,&nbsp;Erin M McConnell,&nbsp;Victoria Suslovitch,&nbsp;Winston X Yan,&nbsp;Jonathan K Watts,&nbsp;Timothy W Yu","doi":"10.1089/nat.2022.0060","DOIUrl":"https://doi.org/10.1089/nat.2022.0060","url":null,"abstract":"<p><p>Antisense oligonucleotides (ASOs) can modulate pre-mRNA splicing. This offers therapeutic opportunities for numerous genetic diseases, often in a mutation-specific and sometimes even individual-specific manner. Developing therapeutic ASOs for as few as even a single patient has been shown feasible with the development of Milasen for an individual with Batten disease. Efforts to develop individualized ASOs for patients with different genetic diseases are ongoing globally. The N = 1 Collaborative (N1C) is an umbrella organization dedicated to supporting the nascent field of individualized medicine. N1C recently organized a workshop to discuss and advance standards for the rigorous design and testing of splice-switching ASOs. In this study, we present guidelines resulting from that meeting and the key recommendations: (1) dissemination of standardized experimental designs, (2) use of standardized reference ASOs, and (3) a commitment to data sharing and exchange.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 1","pages":"17-25"},"PeriodicalIF":4.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9940807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9102107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Assessment of Phase 2 Data on GalNAc₃-Conjugated 2'-<i>O</i>-Methoxyethyl-Modified Antisense Oligonucleotides.","authors":"Brenda F Baker,&nbsp;Shuting Xia,&nbsp;Wesley Partridge,&nbsp;T Jesse Kwoh,&nbsp;Sotirios Tsimikas,&nbsp;Sanjay Bhanot,&nbsp;Richard S Geary","doi":"10.1089/nat.2022.0044","DOIUrl":"10.1089/nat.2022.0044","url":null,"abstract":"<p><p>Receptor-mediated delivery of an antisense oligonucleotide (ASO) using the ligand-conjugated antisense technology is establishing a new benchmark for antisense therapeutics. The triantennary <i>N</i>-acetylgalactosamine (GalNAc₃) cluster is the first conjugated ligand to yield a marked increase in ASO potency for RNA targets expressed by hepatocytes, compared to the unconjugated form. In this study, we present an integrated safety assessment of data available from randomized, placebo-controlled, phase 2 studies for six GalNAc₃-conjugated 2'-<i>O</i>-methoxyethyl (2'MOE)-modified ASOs. The total study population included 642 participants (130 placebo; 512 ASO) with up to 1 year of exposure. The primary measures were the incidence of signals from standardized laboratory tests and the mean test results over time. The GalNAc₃-conjugated ASOs were well tolerated with no class effect identified across all doses tested compared to placebo. These results extend prior observations from phase 1 studies, now with treatment up to 1 year.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"33 1","pages":"72-80"},"PeriodicalIF":4.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10623620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10798666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-Species Translation of Biophase Half-Life and Potency of GalNAc-Conjugated siRNAs.","authors":"Alessandro Boianelli,&nbsp;Yasunori Aoki,&nbsp;Maxim Ivanov,&nbsp;Anders Dahlén,&nbsp;Peter Gennemark","doi":"10.1089/nat.2022.0010","DOIUrl":"https://doi.org/10.1089/nat.2022.0010","url":null,"abstract":"<p><p>Small interfering RNAs (siRNAs) with <i>N</i>-acetylgalactosamine (GalNAc) conjugation for improved liver uptake represent an emerging class of drugs to treat liver diseases. Understanding how pharmacokinetics and pharmacodynamics translate is pivotal for <i>in vivo</i> study design and human dose prediction. However, the literature is sparse on translational data for this modality, and pharmacokinetics in the liver is seldom measured. To overcome these difficulties, we collected time-course biomarker data for 11 GalNAc-siRNAs in various species and applied the kinetic-pharmacodynamic modeling approach to estimate the biophase (liver) half-life and the potency. Our analysis indicates that the biophase half-life is 0.6-3 weeks in mouse, 1-8 weeks in monkey, and 1.5-14 weeks in human. For individual siRNAs, the biophase half-life is 1-8 times longer in human than in mouse, and generally 1-3 times longer in human than in monkey. The analysis indicates that the siRNAs are more potent in human than in mouse and monkey.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"32 6","pages":"507-512"},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9784597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10812713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Quest for mRNA Vaccines.","authors":"Eli Gilboa,&nbsp;David Boczkowski,&nbsp;Smita K Nair","doi":"10.1089/nat.2021.0103","DOIUrl":"https://doi.org/10.1089/nat.2021.0103","url":null,"abstract":"<p><p>The success of mRNA vaccines against COVID-19 is nothing short of a medical revolution. Given its chemical lability the use of mRNA as a therapeutic has been counterintuitive and met with skepticism. The development of mRNA-based COVID-19 vaccines was the culmination of long and painstaking efforts by many investigators spanning over 30 years and culminating with the seminal studies of Kariko and Weissman. This review will describe one chapter in this saga, studies that have shown that mRNA can function as a therapeutic. It started with our seminal observation that dendritic cells (DCs) transfected with mRNA <i>in vitro</i> administered to mice inhibits tumor growth, and led to first-in-human clinical trials with mRNA vaccines in cancer patients. The clinical development of this patient-specific DCs-mRNA approach and use on a larger scale was hindered by the challenges associated with personalized cell therapies. Confirmed and extended by many investigators, these studies did serve as impetus and motivation that led scientists to persevere, eventually leading to the development of simple, broadly applicable, and highly effective protocols of directly injecting mRNA into patients, culminating in the COVID-19 mRNA vaccines.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"32 6","pages":"449-456"},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10419344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early-Stage Identification and Avoidance of Antisense Oligonucleotides Causing Species-Specific Inflammatory Responses in Human Volunteer Peripheral Blood Mononuclear Cells.","authors":"Sebastien A Burel,&nbsp;Todd Machemer,&nbsp;Brenda F Baker,&nbsp;T Jesse Kwoh,&nbsp;Suzanne Paz,&nbsp;Husam Younis,&nbsp;Scott P Henry","doi":"10.1089/nat.2022.0033","DOIUrl":"https://doi.org/10.1089/nat.2022.0033","url":null,"abstract":"<p><p>A human peripheral blood mononuclear cell (PBMC)-based assay was developed to identify antisense oligonucleotide (ASO) with the potential to activate a cellular innate immune response outside of an acceptable level. The development of this assay was initiated when ISIS 353512 targeting the messenger ribonucleic acid for human C-reactive protein (CRP) was tested in a phase I clinical trial, in which healthy human volunteers unexpectedly experienced increases in interleukin-6 (IL-6) and CRP. This level of immune stimulation was not anticipated following rodent and nonhuman primate safety studies in which no evidence of exaggerated proinflammatory effects were observed. The IL-6 increase induced by ISIS 353512 was caused by activation of B cells. The IL-6 induction was inhibited by chloroquine pretreatment of PBMCs and the nature of ASOs suggested that the response is mediated by a Toll-like receptor (TLR), in all likelihood TLR9. While assessing the inter PBMC donor variability, two classes of human PBMC responders to ISIS 353512 were identified (discriminator and nondiscriminators). The discriminator donor PBMCs were shown to produce low level of IL-6 after 24 h in culture, in the absence of ASO treatment. The PBMC assay using discriminator donors was shown to be reproducible, allowing to assess reliably the immune potential of ASOs by comparison to known benchmark ASO controls that were previously shown to be either safe or inflammatory in clinical trials. Clinical Trial registration numbers: NCT00048321 NCT00330330 NCT00519727.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"32 6","pages":"457-472"},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10432044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing SIRT1 Gene Expression Using Small Activating RNAs: A Novel Approach for Reversing Metabolic Syndrome.","authors":"Pinelopi Andrikakou,&nbsp;Vikash Reebye,&nbsp;Daniel Vasconcelos,&nbsp;Sorah Yoon,&nbsp;Jon Voutila,&nbsp;Andrew J T George,&nbsp;Piotr Swiderski,&nbsp;Robert Habib,&nbsp;Matthew Catley,&nbsp;David Blakey,&nbsp;Nagy A Habib,&nbsp;John J Rossi,&nbsp;Kai-Wen Huang","doi":"10.1089/nat.2021.0115","DOIUrl":"https://doi.org/10.1089/nat.2021.0115","url":null,"abstract":"<p><p>Metabolic syndrome (MetS) is a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Sirtuin 1 (SIRT1), a highly conserved histone deacetylase, is characterized as a key metabolic regulator and protector against aging-associated pathologies, including MetS. In this study, we investigate the therapeutic potential of activating SIRT1 using small activating RNAs (saRNA), thereby reducing inflammatory-like responses and re-establishing normal lipid metabolism. SIRT1 saRNA significantly increased SIRT1 messenger RNA (mRNA) and protein levels in both lipopolysaccharide-stimulated and nonstimulated macrophages. SIRT1 saRNA significantly decreased inflammatory-like responses, by reducing mRNA levels of key inflammatory cytokines, such as Tumor Necrosis Factor alpha, Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), and chemokines Monocyte Chemoattractant Protein-1 and keratinocyte chemoattractant. SIRT1 overexpression also significantly reduced phosphorylation of nuclear factor-κB and c-Jun N-terminal kinase, both key signaling molecules for the inflammatory pathway. To investigate the therapeutic effect of SIRT1 upregulation, we treated a high-fat diet model with SIRT1 saRNA conjugated to a transferrin receptor aptamer for delivery to the liver and cellular internalization. Animals in the SIRT1 saRNA treatment arm demonstrated significantly decreased weight gain with a significant reduction in white adipose tissue, triglycerides, fasting glucose levels, and intracellular lipid accumulation. These suggest treatment-induced changes to lipid and glucose metabolism in the animals. The results of this study demonstrate that targeted activation of SIRT1 by saRNAs is a potential strategy to reverse MetS.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"32 6","pages":"486-496"},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10486735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory Non-CpG Antisense Oligonucleotides Are Signaling Through TLR9 in Human Burkitt Lymphoma B Bjab Cells.","authors":"Adam J Pollak,&nbsp;Patrick Cauntay,&nbsp;Todd Machemer,&nbsp;Suzanne Paz,&nbsp;Sagar Damle,&nbsp;Scott P Henry,&nbsp;Sebastien A Burel","doi":"10.1089/nat.2022.0034","DOIUrl":"https://doi.org/10.1089/nat.2022.0034","url":null,"abstract":"<p><p>Nucleic acid-based phosphorothioate containing antisense oligonucleotides (PS-ASOs) have the potential to activate cellular innate immune responses, and the level of activation can vary quite dramatically with sequence. Minimizing the degree of proinflammatory effect is one of the main selection criteria for compounds intended to move into clinical trials. While a recently developed human peripheral blood mononuclear cell (hPBMC)-based assay showed excellent ability to detect innate immune active PS-ASOs, which can then be discarded from the developmental process, this assay is highly resource intensive and easily affected by subject variability. This compelled us to develop a more convenient high-throughput assay. In this study, we describe a new <i>in vitro</i> assay, utilizing a cultured human Bjab cell line, which was developed and validated to identify PS-ASOs that may cause innate immune activation. The assay was calibrated to replicate results from the hPBMC assay. The Bjab assay was designed to be high throughput and more convenient by using RT-qPCR readout of mRNA of the chemokine Ccl22. The Bjab assay was also shown to be highly reproducible and to provide a large dynamic range in determining the immune potential of PS-ASOs through comparison to known benchmark PS-ASO controls that were previously shown to be safe or inflammatory in clinical trials. In addition, we demonstrate that Bjab cells can be used to provide mechanistic information on PS-ASO TLR9-dependent innate immune activation.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"32 6","pages":"473-485"},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10793628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nucleic Acid Aptamers Increase the Anticancer Efficiency and Reduce the Toxicity of Cisplatin-Arabinogalactan Conjugates <i>In Vivo</i>.","authors":"Tatiana N Zamay,&nbsp;Alexander K Starkov,&nbsp;Olga S Kolovskaya,&nbsp;Galina S Zamay,&nbsp;Dmitry V Veprintsev,&nbsp;Natalia Luzan,&nbsp;Elena D Nikolaeva,&nbsp;Kirill A Lukyanenko,&nbsp;Polina V Artyushenko,&nbsp;Irina A Shchugoreva,&nbsp;Yury E Glazyrin,&nbsp;Anastasia A Koshmanova,&nbsp;Alexey V Krat,&nbsp;Dariya S Tereshina,&nbsp;Sergey S Zamay,&nbsp;Yuriy S Pats,&nbsp;Ruslan A Zukov,&nbsp;Felix N Tomilin,&nbsp;Maxim V Berezovski,&nbsp;Anna S Kichkailo","doi":"10.1089/nat.2022.0024","DOIUrl":"https://doi.org/10.1089/nat.2022.0024","url":null,"abstract":"<p><p>Cisplatin is an effective drug for treating various cancer types. However, it is highly toxic for both healthy and tumor cells. Therefore, there is a need to reduce its therapeutic dose and increase targeted bioavailability. One of the ways to achieve this could be the coating of cisplatin with polysaccharides and specific carriers for targeted delivery. Nucleic acid aptamers could be used as carriers for the specific delivery of medicine to cancer cells. Cisplatin-arabinogalactan-aptamer (Cis-AG-Ap) conjugate was synthesized based on Cis-dichlorodiammineplatinum, Siberian larch arabinogalactan, and aptamer AS-42 specific to heat-shock proteins (HSP) 71 kDa (Hspa8) and HSP 90-beta (Hsp90ab1). The antitumor effect was estimated using ascites and metastatic Ehrlich tumor models. Cis-AG-Ap toxicity was assessed by blood biochemistry on healthy mice. Here, we demonstrated enhanced anticancer activity of Cis-AG-Ap and its specific accumulation in tumor foci. It was shown that targeted delivery allowed a 15-fold reduction in the therapeutic dose of cisplatin and its toxicity. Cis-AG-Ap sufficiently suppressed the growth of Ehrlich's ascites carcinoma, the mass and extent of tumor metastasis <i>in vivo</i>. Arabinogalactan and the aptamers promoted cisplatin efficiency by enhancing its bioavailability. The described strategy could be very promising for targeted anticancer therapy.</p>","PeriodicalId":19412,"journal":{"name":"Nucleic acid therapeutics","volume":"32 6","pages":"497-506"},"PeriodicalIF":4.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10486741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}