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Nucleic-Acid-Based Strategies and Nanotechnology Applications for Targeted Therapy

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: 20 May 2025 | Viewed by 21630

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Dr. Andrea Patrizia Falanga

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Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
Interests: peptide nucleic acid; G-quadruplex; delivery; solid-phase synthesis; small molecule-DNA interactions
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Dr. Stefano D’Errico

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Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
Interests: nucleosides; nucleotides and analogues; chemistry and biological/biotechnological applications; oligonucleotides; platinum complexes in cancer therapy
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Dr. Monica Terracciano

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Guest Editor

HybridBioSystems Lab, Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
Interests: surface functionalization chemistry; nanostructured materials; hybrid materials; chemical characterization; diagnostics; drug delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In consideration of the recent attention and the growing potential that nucleic acids have gained, together with the demand for improving current controlled-release systems, we are pleased to announce the Special Issue “Nucleic-acid-Based Strategies and Nanotechnology Applications for Targeted Therapy”. The purpose of this Special Issue is to collect papers reporting on, but not limited to, oligonucleotide synthesis, biochemical and biophysical characterization of nucleic acids, new oligonucleotide-based delivery systems, as well as biomaterial and polymer development. Articles embracing originality and novelty will be welcome. We look forward to receiving your contributions.

Dr. Andrea Patrizia Falanga
Dr. Stefano D’Errico
Dr. Monica Terracciano
Guest Editors

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Keywords

nucleic acids
drug delivery
nanomedicine
biotechnology
material science.

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Published Papers (9 papers)

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Research

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14 pages, 4051 KiB

Open AccessCommunication

Towards Aptamer-Targeted Drug Delivery to Brain Tumors: The Synthesis of Ramified Conjugates of an EGFR-Specific Aptamer with MMAE on a Cathepsin B-Cleavable Linker

by Vladimir A. Brylev, Ekaterina V. Ryabukhina, Ekaterina V. Nazarova, Nadezhda S. Samoylenkova, Evgeny L. Gulyak, Ksenia A. Sapozhnikova, Fatima M. Dzarieva, Alexey V. Ustinov, Igor N. Pronin, Dmitry Y. Usachev, Alexey M. Kopylov, Andrey V. Golovin, Galina V. Pavlova, Dmitry Yu. Ryazantsev and Vladimir A. Korshun

Pharmaceutics 2024, 16(11), 1434; https://doi.org/10.3390/pharmaceutics16111434 - 11 Nov 2024

Viewed by 1662

Abstract

Background/Objectives: Targeted delivery of chemotherapeutic agents is a well-established approach to cancer therapy. Antibody–drug conjugates (ADCs) typically carry toxic payloads attached to a tumor-associated antigen-targeting IgG antibody via an enzyme-cleavable linker that releases the drug inside the cell. Aptamers are a promising alternative to antibodies in terms of antigen targeting; however, their polynucleotide nature and smaller size result in a completely different PK/PD profile compared to an IgG. This may prove advantageous: owing to their lower molecular weight, aptamer-drug conjugates may achieve better penetration of solid tumors compared to ADCs. Methods: On the way to therapeutic aptamer–drug conjugates, we aimed to develop a versatile and modular approach for the assembly of aptamer–enzymatically cleavable payload conjugates of various drug–aptamer ratios. We chose the epidermal growth factor receptor (EGFR), a transmembrane protein often overexpressed in brain tumors, as the target antigen. We used the 46 mer EGFR-targeting DNA sequence GR-20, monomethylauristatin E (MMAE) on the cathepsin-cleavable ValCit-p-aminobenzylcarbamate linker as the payload, and pentaerythritol-based tetraazide as the branching point for the straightforward synthesis of aptamer–drug conjugates by means of a stepwise Cu-catalyzed azide–alkyne cycloaddition (CuAAC) click reaction. Results: Branched aptamer conjugates of 1:3, 2:2, and 3:1 stoichiometry were synthesized and showed higher cytotoxic activity compared to a 1:1 conjugate, particularly on several glioma cell lines. Conclusions: This approach is convenient and potentially applicable to any aptamer sequence, as well as other payloads and cleavable linkers, thus paving the way for future development of aptamer–drug therapeutics by easily providing a range of branched conjugates for in vitro and in vivo testing. Full article

(This article belongs to the Special Issue Nucleic-Acid-Based Strategies and Nanotechnology Applications for Targeted Therapy)

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20 pages, 11463 KiB

Open AccessArticle

Targeting Liver Xor by GalNAc-siRNA Is an Effective Strategy for Hyperuricemia Therapy

by Huiyan Sun, Xinxia Wang, Yongqiang Li, Yingzhi Shen, Lin Zhang, Yingjie Xu, Junling Liu and Xuemei Fan

Pharmaceutics 2024, 16(7), 938; https://doi.org/10.3390/pharmaceutics16070938 - 14 Jul 2024

Viewed by 2580

Abstract

Hyperuricemia, i.e., increased plasma uric acid concentration, is a common problem in clinical practice, leading to gout or nephrolithiasis, and is associated with other disorders, such as metabolic syndrome, cardiovascular disease, and chronic renal disease. Xanthine oxidoreductase (XOR) is a critical rate-limiting enzyme involved in uric acid synthesis and a promising target for hyperuricemia therapy. However, XOR inhibitors currently face clinical problems such as a short half-life and side effects. Here, we found that specifically targeting liver Xor with GalNAc-siRNAs had a good therapeutic effect on hyperuricemia. First, siRNAs were designed to target various sites in the homologous region between Homo sapiens and Mus musculus Xor mRNA and were screened in primary mouse hepatocytes. Then, the siRNAs were modified to increase their stability in vivo and conjugated with GalNAc for liver-specific delivery. The effects of GalNAc-siRNAs were evaluated in three hyperuricemia mouse models, including potassium oxonate and hypoxanthine administration in WT and humanized XDH mice and Uox knockout mice. Febuxostat, a specific XOR inhibitor used for hyperuricemia treatment, was used as a positive control. Targeting liver Xor with GalNAc-siRNAs by subcutaneous administration reduced plasma uric acid levels, uric acid accumulation in the kidney, renal inflammation, and fibrosis, thereby alleviating kidney damage in hyperuricemia mouse models without hepatoxicity. The results demonstrated that targeting liver Xor with GalNAc-siRNAs was a promising strategy for hyperuricemia therapy. Full article

(This article belongs to the Special Issue Nucleic-Acid-Based Strategies and Nanotechnology Applications for Targeted Therapy)

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20 pages, 2000 KiB

Open AccessArticle

Novel Efficient Lipid-Based Delivery Systems Enable a Delayed Uptake and Sustained Expression of mRNA in Human Cells and Mouse Tissues

by Artem G. Fedorovskiy, Denis N. Antropov, Anton S. Dome, Pavel A. Puchkov, Daria M. Makarova, Maria V. Konopleva, Anastasiya M. Matveeva, Eugenia A. Panova, Elena V. Shmendel, Mikhail A. Maslov, Sergey E. Dmitriev, Grigory A. Stepanov and Oleg V. Markov

Pharmaceutics 2024, 16(5), 684; https://doi.org/10.3390/pharmaceutics16050684 - 19 May 2024

Cited by 1 | Viewed by 3843

Abstract

Over the past decade, mRNA-based therapy has displayed significant promise in a wide range of clinical applications. The most striking example of the leap in the development of mRNA technologies was the mass vaccination against COVID-19 during the pandemic. The emergence of large-scale technology and positive experience of mRNA immunization sparked the development of antiviral and anti-cancer mRNA vaccines as well as therapeutic mRNA agents for genetic and other diseases. To facilitate mRNA delivery, lipid nanoparticles (LNPs) have been successfully employed. However, the diverse use of mRNA therapeutic approaches requires the development of adaptable LNP delivery systems that can control the kinetics of mRNA uptake and expression in target cells. Here, we report effective mRNA delivery into cultured mammalian cells (HEK293T, HeLa, DC2.4) and living mouse muscle tissues by liposomes containing either 1,26-bis(cholest-5-en-3β-yloxycarbonylamino)-7,11,16,20-tetraazahexacosane tetrahydrochloride (2X3) or the newly applied 1,30-bis(cholest-5-en-3β-yloxycarbonylamino)-9,13,18,22-tetraaza-3,6,25,28-tetraoxatriacontane tetrahydrochloride (2X7) cationic lipids. Using end-point and real-time monitoring of Fluc mRNA expression, we showed that these LNPs exhibited an unusually delayed (of over 10 h in the case of the 2X7-based system) but had highly efficient and prolonged reporter activity in cells. Accordingly, both LNP formulations decorated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG₂₀₀₀) provided efficient luciferase production in mice, peaking on day 3 after intramuscular injection. Notably, the bioluminescence was observed only at the site of injection in caudal thigh muscles, thereby demonstrating local expression of the model gene of interest. The developed mRNA delivery systems hold promise for prophylactic applications, where sustained synthesis of defensive proteins is required, and open doors to new possibilities in mRNA-based therapies. Full article

(This article belongs to the Special Issue Nucleic-Acid-Based Strategies and Nanotechnology Applications for Targeted Therapy)

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16 pages, 2899 KiB

Open AccessArticle

Synthesis and Preliminary Evaluation of an ASGPr-Targeted Polycationic β-Cyclodextrin Carrier for Nucleosides and Nucleotides

by Jang-Ha Ryu, Weizhong Zheng, Xiao-Hong Yang, Hassan Elsaidi, Jim Diakur and Leonard I. Wiebe

Pharmaceutics 2024, 16(3), 323; https://doi.org/10.3390/pharmaceutics16030323 - 26 Feb 2024

Viewed by 1680

Abstract

Most antiviral and anticancer nucleosides are prodrugs that require stepwise phosphorylation to their triphosphate nucleotide form for biological activity. Monophosphorylation may be rate-limiting, and the nucleotides may be unstable and poorly internalized by target cells. Effective targeting and delivery systems for nucleoside drugs, including oligonucleotides used in molecular therapeutics, could augment their efficacy. The development of a carrier designed to effect selective transmembrane internalization of nucleotides via the asialoglycoprotein receptor (ASGPr) is now reported. In this work, the polycationic, polygalactosyl drug delivery carrier heptakis[6-amino-6-deoxy-2-O-(3-(1-thio-β-D-galactopyranosyl)-propyl)]-β-cyclodextrin hepta-acetate salt (GCyDAc), potentially a bifunctional carrier of (poly)nucleotides, was modeled by molecular docking in silico as an ASGPr-ligand, then synthesized for testing. The antivirals arabinosyl adenine (araA, vidarabine, an early generation antiviral nucleoside), arabinosyl adenine 5′-monophosphate (araAMP), and 12-mer-araAMP (p-araAMP) were selected for individual formulation with GCyDAc to develop this concept. Experimentally, beta cyclodextrin was decorated with seven protonated amino substituents on the primary face, and seven thiogalactose residues on its secondary face. AraA, araAMP, and p-araAMP were individually complexed with GCyDAc and complex formation for each drug was confirmed by differential scanning calorimetry (DSC). Finally, the free drugs and their GCyDAc complexes were evaluated for antiviral activity using ASGPr-expressing HepAD38 cells in cell culture. In this model, araA, araAMP, and p-araAMP showed relative antiviral potencies of 1.0, 1.1, and 1.2, respectively. In comparison, GCyDAc-complexes of araA, araAMP, and p-araAMP were 2.5, 1.3, and 1.2 times more effective than non-complexed araA in suppressing viral DNA production. The antiviral potencies of these complexes were minimally supportive of the hypothesis that ASGPr-targeted, CyD-based charge-association complexation of nucleosides and nucleotides could effectively enhance antiviral efficacy. GCyDAc was non-toxic to mammalian cells in cell culture, as determined using the MTS proliferation assay. Full article

(This article belongs to the Special Issue Nucleic-Acid-Based Strategies and Nanotechnology Applications for Targeted Therapy)

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25 pages, 5577 KiB

Open AccessArticle

Cationic Calix[4]arene Vectors to Efficiently Deliver AntimiRNA Peptide Nucleic Acids (PNAs) and miRNA Mimics

by Jessica Gasparello, Chiara Papi, Matteo Zurlo, Stefano Volpi, Roberto Gambari, Roberto Corradini, Alessandro Casnati, Francesco Sansone and Alessia Finotti

Pharmaceutics 2023, 15(8), 2121; https://doi.org/10.3390/pharmaceutics15082121 - 10 Aug 2023

Cited by 4 | Viewed by 1806

Abstract

One of the most appealing approaches for regulating gene expression, named the “microRNA therapeutic” method, is based on the regulation of the activity of microRNAs (miRNAs), the intracellular levels of which are dysregulated in many diseases, including cancer. This can be achieved by miRNA inhibition with antimiRNA molecules in the case of overexpressed microRNAs, or by using miRNA-mimics to restore downregulated microRNAs that are associated with the target disease. The development of new efficient, low-toxic, and targeted vectors of such molecules represents a key topic in the field of the pharmacological modulation of microRNAs. We compared the delivery efficiency of a small library of cationic calix[4]arene vectors complexed with fluorescent antimiRNA molecules (Peptide Nucleic Acids, PNAs), pre-miRNA (microRNA precursors), and mature microRNAs, in glioma- and colon-cancer cellular models. The transfection was assayed by cytofluorimetry, cell imaging assays, and RT-qPCR. The calix[4]arene-based vectors were shown to be powerful tools to facilitate the uptake of both neutral (PNAs) and negatively charged (pre-miRNAs and mature microRNAs) molecules showing low toxicity in transfected cells and ability to compete with commercially available vectors in terms of delivery efficiency. These results could be of great interest to validate microRNA therapeutics approaches for future application in personalized treatment and precision medicine. Full article

(This article belongs to the Special Issue Nucleic-Acid-Based Strategies and Nanotechnology Applications for Targeted Therapy)

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Review

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57 pages, 1992 KiB

Open AccessReview

The 20th Anniversary of Pegaptanib (MacugenTM), the First Approved Aptamer Medicine: History, Recent Advances and Future Prospects of Aptamers in Therapy

by Miklós Bege, Rasha Ghanem Kattoub and Anikó Borbás

Pharmaceutics 2025, 17(3), 394; https://doi.org/10.3390/pharmaceutics17030394 - 20 Mar 2025

Viewed by 712

Abstract

In addition to classic small-molecule drugs and modern protein-based biologics, an intriguing class of medicines is the therapeutic oligonucleotides. Most approved drugs in this category are antisense oligomers or those acting via RNA interference, both of which use base hybridization. Aptamers, also known as chemical antibodies form a smaller, yet equally interesting group of oligonucleotides that can recognize a wide range of molecular targets. Despite their high potential, only two aptamers have been approved to date, pegaptanib (MacugenTM) and avacincaptad pegol (IzervayTM), both for the treatment of age-related macular degeneration (AMD). Targeting vascular endothelial growth factor (VEGF), which plays an important role in the pathogenesis of many eye diseases, pegaptanib emerged as the first anti-VEGF agent and was used in various indications, further inspiring the development of other anti-VEGF therapies. In this review, we summarize the history of the first approved aptamer medicine, pegaptanib. We describe its chemistry and track its development from the earliest stages to the preclinical phase, clinical trials, and eventual regulatory approval. Additionally, we evaluate its position among other therapeutic agents and provide a comprehensive overview of pegaptanib’s efficacy, safety, and cost-effectiveness, comparing these aspects with those of monoclonal antibodies with similar indications, bevacizumab and ranibizumab. Full article

(This article belongs to the Special Issue Nucleic-Acid-Based Strategies and Nanotechnology Applications for Targeted Therapy)

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27 pages, 7079 KiB

Open AccessReview

Amphiphilic Oligonucleotide Derivatives—Promising Tools for Therapeutics

by Irina A. Bauer and Elena V. Dmitrienko

Pharmaceutics 2024, 16(11), 1447; https://doi.org/10.3390/pharmaceutics16111447 - 12 Nov 2024

Viewed by 1096

Abstract

Recent advances in genetics and nucleic acid chemistry have created fundamentally new tools, both for practical applications in therapy and diagnostics and for fundamental genome editing tasks. Nucleic acid-based therapeutic agents offer a distinct advantage of selectively targeting the underlying cause of the disease. Nevertheless, despite the success achieved thus far, there remain unresolved issues regarding the improvement of the pharmacokinetic properties of therapeutic nucleic acids while preserving their biological activity. In order to address these challenges, there is a growing focus on the study of safe and effective delivery methods utilising modified nucleic acid analogues and their lipid bioconjugates. The present review article provides an overview of the current state of the art in the use of chemically modified nucleic acid derivatives for therapeutic applications, with a particular focus on oligonucleotides conjugated to lipid moieties. A systematic analysis has been conducted to investigate the ability of amphiphilic oligonucleotides to self-assemble into micelle-like structures, as well as the influence of non-covalent interactions of such derivatives with serum albumin on their biodistribution and therapeutic effects. Full article

(This article belongs to the Special Issue Nucleic-Acid-Based Strategies and Nanotechnology Applications for Targeted Therapy)

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16 pages, 1301 KiB

Open AccessReview

Exploring the Relationship between G-Quadruplex Nucleic Acids and Plants: From Plant G-Quadruplex Function to Phytochemical G4 Ligands with Pharmaceutic Potential

by Andrea P. Falanga, Monica Terracciano, Giorgia Oliviero, Giovanni N. Roviello and Nicola Borbone

Pharmaceutics 2022, 14(11), 2377; https://doi.org/10.3390/pharmaceutics14112377 - 4 Nov 2022

Cited by 16 | Viewed by 2844

Abstract

G-quadruplex (G4) oligonucleotides are higher-order DNA and RNA secondary structures of enormous relevance due to their implication in several biological processes and pathological states in different organisms. Strategies aiming at modulating human G4 structures and their interrelated functions are first-line approaches in modern research aiming at finding new potential anticancer treatments or G4-based aptamers for various biomedical and biotechnological applications. Plants offer a cornucopia of phytocompounds that, in many cases, are effective in binding and modulating the thermal stability of G4s and, on the other hand, contain almost unexplored G4 motifs in their genome that could inspire new biotechnological strategies. Herein, we describe some G4 structures found in plants, summarizing the existing knowledge of their functions and biological role. Moreover, we review some of the most promising G4 ligands isolated from vegetal sources and report on the known relationships between such phytochemicals and G4-mediated biological processes that make them potential leads in the pharmaceutical sector. Full article

(This article belongs to the Special Issue Nucleic-Acid-Based Strategies and Nanotechnology Applications for Targeted Therapy)

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33 pages, 5876 KiB

Open AccessReview

Insights into the Small Molecule Targeting of Biologically Relevant G-Quadruplexes: An Overview of NMR and Crystal Structures

by Andrea Criscuolo, Ettore Napolitano, Claudia Riccardi, Domenica Musumeci, Chiara Platella and Daniela Montesarchio

Pharmaceutics 2022, 14(11), 2361; https://doi.org/10.3390/pharmaceutics14112361 - 1 Nov 2022

Cited by 17 | Viewed by 3409

Abstract

G-quadruplexes turned out to be important targets for the development of novel targeted anticancer/antiviral therapies. More than 3000 G-quadruplex small-molecule ligands have been described, with most of them exerting anticancer/antiviral activity by inducing telomeric damage and/or altering oncogene or viral gene expression in cancer cells and viruses, respectively. For some ligands, in-depth NMR and/or crystallographic studies were performed, providing detailed knowledge on their interactions with diverse G-quadruplex targets. Here, the PDB-deposited NMR and crystal structures of the complexes between telomeric, oncogenic or viral G-quadruplexes and small-molecule ligands, of both organic and metal-organic nature, have been summarized and described based on the G-quadruplex target, from telomeric DNA and RNA G-quadruplexes to DNA oncogenic G-quadruplexes, and finally to RNA viral G-quadruplexes. An overview of the structural details of these complexes is here provided to guide the design of novel ligands targeting more efficiently and selectively cancer- and virus-related G-quadruplex structures. Full article

(This article belongs to the Special Issue Nucleic-Acid-Based Strategies and Nanotechnology Applications for Targeted Therapy)

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