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

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

Deadline for manuscript submissions: 20 October 2024 | Viewed by 6382

Special Issue Editors


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Guest Editor
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
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
Interests: solid-phase synthesis; chemistry of nucleosides, nucleotides, and oligonucleotides; L-sugars; platinum complexes; heterocycles; bioorganic chemistry
Special Issues, Collections and Topics in MDPI journals

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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.

Published Papers (4 papers)

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Research

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16 pages, 2899 KiB  
Article
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
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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, [...] Read more.
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
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25 pages, 5577 KiB  
Article
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
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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 [...] Read more.
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
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Review

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16 pages, 1301 KiB  
Review
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 - 04 Nov 2022
Cited by 9 | Viewed by 1729
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 [...] Read more.
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
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33 pages, 5876 KiB  
Review
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 - 01 Nov 2022
Cited by 9 | Viewed by 2206
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 [...] Read more.
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
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