Special Issue "Drug Delivery of siRNA Therapeutics"

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: 30 September 2019

Special Issue Editors

Guest Editor
Prof. Dr. Gaetano Lamberti

Dipartimento di Ingegneria Industriale, Università degli Studi di Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano (SA)
Website | E-Mail
Interests: controlled drug delivery; mathematical modeling; hydrogels; pharmacokinetics; non-conventional in-vitro testing
Guest Editor
Prof. Dr. Anna Angela Barba

Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano (SA)
Website | E-Mail
Phone: +39 969240
Interests: nanoparticles; liposomes; drug delivery; ultrasound-assisted production processes; microwave-assisted production processes

Special Issue Information

Dear Colleagues,

Small interfering RNA (siRNA) is a class of nucleic acid-based drugs (NABDs) able to block gene expression by interaction with mRNA before its translation, thus being part of the gene therapy field. Their recently discovered mechanism of action (Nobel Prize in Physiology or Medicine 2006 to Andrew Z. Fire and Craig C. Mello “for their discovery of RNA interference – gene silencing by double-stranded RNA”) make siRNAs drugs candidates to combat virtually any disease, since each disease is based on the expression of gene(s) and on the production of (harmful) proteins. The single reason why this approach has not yet “exploded” in terms of countless therapeutics is that the delivery of siRNAs is hindered by several obstacles. siRNAs are large macromolecules that challenging to administer. Once they are in the blood stream they are rapidly degraded by plasma enzymes, they are also negatively charged and therefore cannot easily approach the also-negatively charged cell walls. Therefore, the real challenge is the delivery of these fragile molecules.

This Special Issue of Pharmaceutics is focused on the state-of-the-art for siRNAs delivery, presenting the investigation strategies of research groups with different experiences and skills. The Special Issue will thus be devoted to presenting current connections between experimental and in silico approaches for therapies based on siRNA delivery, accounting for all the most promising techniques based on liposomes, nanoparticles, aptamers, chemical modification of siRNAs, and so on.

Prof. Dr. Gaetano Lamberti
Prof. Dr. Anna Angela Barba
Guest Editors

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Keywords

  • siRNA
  • gene therapy
  • drug delivery systems
  • liposomes
  • nanoparticles
  • aptamers
  • polycations

Published Papers (4 papers)

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Research

Open AccessArticle
Synergistic Anti-Angiogenic Effects Using Peptide-Based Combinatorial Delivery of siRNAs Targeting VEGFA, VEGFR1, and Endoglin Genes
Pharmaceutics 2019, 11(6), 261; https://doi.org/10.3390/pharmaceutics11060261
Received: 26 April 2019 / Revised: 30 May 2019 / Accepted: 3 June 2019 / Published: 6 June 2019
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Abstract
Angiogenesis is a process of new blood vessel formation, which plays a significant role in carcinogenesis and the development of diseases associated with pathological neovascularization. An important role in the regulation of angiogenesis belongs to several key pathways such as VEGF-pathways, TGF-β-pathways, and [...] Read more.
Angiogenesis is a process of new blood vessel formation, which plays a significant role in carcinogenesis and the development of diseases associated with pathological neovascularization. An important role in the regulation of angiogenesis belongs to several key pathways such as VEGF-pathways, TGF-β-pathways, and some others. Introduction of small interfering RNA (siRNA) against genes of pro-angogenic factors is a promising strategy for the therapeutic suppression of angiogenesis. These siRNA molecules need to be specifically delivered into endothelial cells, and non-viral carriers modified with cellular receptor ligands can be proposed as perspective delivery systems for anti-angiogenic therapy purposes. Here we used modular peptide carrier L1, containing a ligand for the CXCR4 receptor, for the delivery of siRNAs targeting expression of VEGFA, VEGFR1 and endoglin genes. Transfection properties of siRNA/L1 polyplexes were studied in CXCR4-positive breast cancer cells MDA-MB-231 and endothelial cells EA.Hy926. We have demonstrated the efficient down-regulation of endothelial cells migration and proliferation by anti-VEGFA, anti-VEGFR1, and anti-endoglin siRNA-induced silencing. It was found that the efficiency of anti-angiogenic treatment can be synergistically improved via the combinatorial delivery of anti-VEGFA and anti-VEGFR1 siRNAs. Thus, this approach can be useful for the development of therapeutic angiogenesis inhibition. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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Graphical abstract

Open AccessArticle
Effect of Cationic Lipid Type in Folate-PEG-Modified Cationic Liposomes on Folate Receptor-Mediated siRNA Transfection in Tumor Cells
Pharmaceutics 2019, 11(4), 181; https://doi.org/10.3390/pharmaceutics11040181
Received: 12 March 2019 / Revised: 6 April 2019 / Accepted: 12 April 2019 / Published: 15 April 2019
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Abstract
In this study, we examined the effect of cationic lipid type in folate (FA)-polyethylene glycol (PEG)-modified cationic liposomes on gene-silencing effects in tumor cells using cationic liposomes/siRNA complexes (siRNA lipoplexes). We used three types of cationic cholesterol derivatives, cholesteryl (3-((2-hydroxyethyl)amino)propyl)carbamate hydroiodide (HAPC-Chol), N [...] Read more.
In this study, we examined the effect of cationic lipid type in folate (FA)-polyethylene glycol (PEG)-modified cationic liposomes on gene-silencing effects in tumor cells using cationic liposomes/siRNA complexes (siRNA lipoplexes). We used three types of cationic cholesterol derivatives, cholesteryl (3-((2-hydroxyethyl)amino)propyl)carbamate hydroiodide (HAPC-Chol), N-(2-(2-hydroxyethylamino)ethyl)cholesteryl-3-carboxamide (OH-Chol), and cholesteryl (2-((2-hydroxyethyl)amino)ethyl)carbamate (OH-C-Chol), and we prepared three types of FA-PEG-modified siRNA lipoplexes. The modification of cationic liposomes with 1–2 mol % PEG-lipid abolished the gene-silencing effect in human nasopharyngeal tumor KB cells, which overexpress the FA receptor (FR). In contrast, FA-PEG-modification of cationic liposomes restored gene-silencing activity regardless of the cationic lipid type in cationic liposomes. However, the optimal amount of PEG-lipid and FA-PEG-lipid in cationic liposomes for selective gene silencing and cellular uptake were different among the three types of cationic liposomes. Furthermore, in vitro transfection of polo-like kinase 1 (PLK1) siRNA by FA-PEG-modified liposomes exhibited strong cytotoxicity in KB cells, compared with PEG-modified liposomes; however, in in vivo therapy, intratumoral injection of PEG-modified PLK1 siRNA lipoplexes inhibited tumor growth of KB xenografts, as well as that of FA-PEG-modified PLK1 siRNA lipoplexes. From these results, the optimal formulation of PEG- and FA-PEG-modified liposomes for FR-selective gene silencing might be different between in vitro and in vivo transfection. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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Graphical abstract

Open AccessArticle
Targeted Co-Delivery of siRNA and Methotrexate for Tumor Therapy via Mixed Micelles
Pharmaceutics 2019, 11(2), 92; https://doi.org/10.3390/pharmaceutics11020092
Received: 24 December 2018 / Revised: 1 February 2019 / Accepted: 14 February 2019 / Published: 21 February 2019
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Abstract
A combination of chemotherapeutic drugs and siRNA is emerging as a new modality for cancer therapy. A safe and effective carrier platform is needed for combination drug delivery. Here, a functionalized mixed micelle-based delivery system was developed for targeted co-delivery of methotrexate (MTX) [...] Read more.
A combination of chemotherapeutic drugs and siRNA is emerging as a new modality for cancer therapy. A safe and effective carrier platform is needed for combination drug delivery. Here, a functionalized mixed micelle-based delivery system was developed for targeted co-delivery of methotrexate (MTX) and survivin siRNA. Linolenic acid (LA) was separately conjugated to branched polyethlenimine (b-PEI) and methoxy-polyethyleneglycol (mPEG). MTX was then conjugated to LA-modified b-PEI (MTX-bPEI-LA) to form a functionalized polymer-drug conjugate. Functionalized mixed micelles (M-MTX) were obtained by the self-assembly of MTX-bPEI-LA and LA-modified mPEG (mPEG-LA). M-MTX had a narrow particle size distribution and could successfully condense siRNA at an N/P ratio of 16/1. M-MTX/siRNA was selectively taken up by HeLa cells overexpressing the folate receptor (FR) and facilitated the release of the siRNA into the cytoplasm. In vitro, M-MTX/siRNA produced a synergy between MTX and survivin siRNA and markedly suppressed survivin protein expression. In tumor-bearing mice, M-MTX/Cy5-siRNA showed an elevated tumor uptake. In addition, M-MTX/siRNA inhibited tumor growth. Immunohistochemistry and a western blot analysis showed a significant target gene downregulation. In conclusion, M-MTX/siRNA was highly effective as a delivery system and may serve as a model for the targeted co-delivery of therapeutic agents. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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Figure 1

Open AccessArticle
Light-Triggered Cellular Delivery of Oligonucleotides
Pharmaceutics 2019, 11(2), 90; https://doi.org/10.3390/pharmaceutics11020090
Received: 9 January 2019 / Revised: 1 February 2019 / Accepted: 14 February 2019 / Published: 21 February 2019
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Abstract
The major challenge in the therapeutic applicability of oligonucleotide-based drugs is the development of efficient and safe delivery systems. The carriers should be non-toxic and stable in vivo, but interact with the target cells and release the loaded oligonucleotides intracellularly. We approached this [...] Read more.
The major challenge in the therapeutic applicability of oligonucleotide-based drugs is the development of efficient and safe delivery systems. The carriers should be non-toxic and stable in vivo, but interact with the target cells and release the loaded oligonucleotides intracellularly. We approached this challenge by developing a light-triggered liposomal delivery system for oligonucleotides based on a non-cationic and thermosensitive liposome with indocyanine green (ICG) as photosensitizer. The liposomes had efficient release properties, as 90% of the encapsulated oligonucleotides were released after 1-minute light exposure. Cell studies using an enhanced green fluorescent protein (EGFP)-based splicing assay with HeLa cells showed light-activated transfection with up to 70%–80% efficacy. Moreover, free ICG and oligonucleotides in solution transfected cells upon light induction with similar efficacy as the liposomal system. The light-triggered delivery induced moderate cytotoxicity (25%–35% reduction in cell viability) 1–2 days after transfection, but the cell growth returned to control levels in 4 days. In conclusion, the ICG-based light-triggered delivery is a promising method for oligonucleotides, and it can be used as a platform for further optimization and development. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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Graphical abstract

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