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Pharmaceutics
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Drug Delivery of siRNA Therapeutics
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Drug Delivery of siRNA Therapeutics

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

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 66812

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Gaetano Lamberti

E-Mail Website
Guest Editor
Department of Industrial Engineering, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, SA, Italy
Interests: hydrogels; drug delivery; modeling; liposomes; nanoparticles
Special Issues, Collections and Topics in MDPI journals
Dr. Anna Angela Barba

E-Mail Website
Guest Editor
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, Italy
Interests: drug delivery systems; sustainable process; process intensification; micro/nano fabrication techniques; liposomes production; hydrogels
Special Issues, Collections and Topics in MDPI journals

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

Manuscript Submission Information

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Keywords

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

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Published Papers (14 papers)

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Editorial

Jump to: Research, Review

3 pages, 162 KiB  
Editorial
Drug Delivery of siRNA Therapeutics
by Gaetano Lamberti and Anna Angela Barba
Pharmaceutics 2020, 12(2), 178; https://doi.org/10.3390/pharmaceutics12020178 - 20 Feb 2020
Cited by 9 | Viewed by 3617
Abstract
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 [...] Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)

Research

Jump to: Editorial, Review

22 pages, 4587 KiB  
Article
Design of New Polyaspartamide Copolymers for siRNA Delivery in Antiasthmatic Therapy
by Emanuela Fabiola Craparo, Salvatore Emanuele Drago, Nicolò Mauro, Gaetano Giammona and Gennara Cavallaro
Pharmaceutics 2020, 12(2), 89; https://doi.org/10.3390/pharmaceutics12020089 - 22 Jan 2020
Cited by 13 | Viewed by 2634
Abstract
Here, a novel protonable copolymer was realized for the production of polyplexes with a siRNA (inhibitor of STAT6 expression in asthma), with the aim of a pulmonary administration. The polycation was synthesized by derivatization of α,β-poly(N-2-hydroxyethyl)d,l-aspartamide (PHEA) with 1,2-Bis(3-aminopropylamino)ethane [...] Read more.
Here, a novel protonable copolymer was realized for the production of polyplexes with a siRNA (inhibitor of STAT6 expression in asthma), with the aim of a pulmonary administration. The polycation was synthesized by derivatization of α,β-poly(N-2-hydroxyethyl)d,l-aspartamide (PHEA) with 1,2-Bis(3-aminopropylamino)ethane (bAPAE) in proper conditions to obtain a PHEA-g-bAPAE graft copolymer with a derivatization degree in amine (DDbAPAE%) equal to 35 mol%. The copolymer showed a proper buffering behavior, i.e., ranging between pH 5 and 7.4, to potentially give the endosomal escape of the obtained polycations. In effect, an in vitro experiment demonstrated the effect on biological membranes of the copolymer on bronchial epithelial cells (16-HBE) strongly dependent on the pH of the medium, i.e., higher at pH 5. bAPAE-based copolymers were further obtained with an increasing pegylation degree, i.e., equal to 1.9, 2.7, and 4.4 mol%, respectively. All the obtained copolymers were able to complex siRNA at a N/P ratio that decreases as the pegylation degree increases. At the same time, the tendency of polyplexes to aggregate and the capability to interact with mucin also decreases as the pegylation in the copolymer increases. Gene silencing experiments on 16-HBE showed that these copolymers have a significant role in improving the intracellular transport of naked siRNA, where the presence of PEG does not seem to hinder the cellular uptake of polyplexes. The latter obtained at polymer/siRNA weight ratio (R) equal to 10 with PHEA-g-PEG(C)-g-bAPAE also seems to be not susceptible to the presence of mucin, avoiding the polyanionic exchange of complexed siRNA, thus showing adequate behavior to be used as an effective vector for siRNA. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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12 pages, 2080 KiB  
Article
Efficient Delivery of Therapeutic siRNA by Fe3O4 Magnetic Nanoparticles into Oral Cancer Cells
by Lili Jin, Qiuyu Wang, Jiayu Chen, Zixiang Wang, Hongchuan Xin and Dianbao Zhang
Pharmaceutics 2019, 11(11), 615; https://doi.org/10.3390/pharmaceutics11110615 - 17 Nov 2019
Cited by 65 | Viewed by 5869
Abstract
The incidence of oral cancer is increasing due to smoking, drinking, and human papillomavirus (HPV) infection, while the current treatments are not satisfactory. Small interfering RNA (siRNA)-based therapy has brought hope, but an efficient delivery system is still needed. Here, polyethyleneimine (PEI)-modified magnetic [...] Read more.
The incidence of oral cancer is increasing due to smoking, drinking, and human papillomavirus (HPV) infection, while the current treatments are not satisfactory. Small interfering RNA (siRNA)-based therapy has brought hope, but an efficient delivery system is still needed. Here, polyethyleneimine (PEI)-modified magnetic Fe3O4 nanoparticles were prepared for the delivery of therapeutic siRNAs targeting B-cell lymphoma-2 (BCL2) and Baculoviral IAP repeat-containing 5 (BIRC5) into Ca9-22 oral cancer cells. The cationic nanoparticles were characterized by transmission electronic microscopy (TEM), scanning electronic microscopy (SEM), dynamic light scattering (DLS), and vibrating sample magnetometer (VSM). By gel retardation assay, the nanoparticles were found to block siRNA in a concentration-dependent manner. The cellular uptake of the nanoparticle/siRNA complexes under a magnetic field was visualized by Perl’s Prussian blue staining and FAM labeling. High gene silencing efficiencies were determined by quantitative real-time PCR and western blotting. Furthermore, the nanoparticle-delivered siRNAs targeting BCL2 and BIRC5 were found to remarkably inhibit the viability and migration of Ca9-22 cells, by cell counting kit-8 assay and transwell assay. In this study, we have developed a novel siRNA-based therapeutic strategy targeting BCL2 and BIRC5 for oral cancer. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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18 pages, 3677 KiB  
Article
Polymeric Nanoparticles Based on Tyrosine-Modified, Low Molecular Weight Polyethylenimines for siRNA Delivery
by Alexander Ewe, Sandra Noske, Michael Karimov and Achim Aigner
Pharmaceutics 2019, 11(11), 600; https://doi.org/10.3390/pharmaceutics11110600 - 12 Nov 2019
Cited by 26 | Viewed by 3373
Abstract
A major hurdle for exploring RNA interference (RNAi) in a therapeutic setting is still the issue of in vivo delivery of small RNA molecules (siRNAs). The chemical modification of polyethylenimines (PEIs) offers a particularly attractive avenue towards the development of more efficient non-viral [...] Read more.
A major hurdle for exploring RNA interference (RNAi) in a therapeutic setting is still the issue of in vivo delivery of small RNA molecules (siRNAs). The chemical modification of polyethylenimines (PEIs) offers a particularly attractive avenue towards the development of more efficient non-viral delivery systems. Here, we explore tyrosine-modified polyethylenimines with low or very low molecular weight (P2Y, P5Y, P10Y) for siRNA delivery. In comparison to their respective parent PEI, they reveal considerably increased knockdown efficacies and very low cytotoxicity upon tyrosine modification, as determined in different reporter and wildtype cell lines. The delivery of siRNAs targeting the anti-apoptotic oncogene survivin or the serine/threonine-protein kinase PLK1 (polo-like kinase 1; PLK-1) oncogene reveals strong inhibitory effects in vitro. In a therapeutic in vivo setting, profound anti-tumor effects in a prostate carcinoma xenograft mouse model are observed upon systemic application of complexes for survivin or PLK1 knockdown, in the absence of in vivo toxicity. We thus demonstrate the tyrosine-modification of (very) low molecular weight PEIs for generating efficient nanocarriers for siRNA delivery in vitro and in vivo, present data on their physicochemical and biological properties, and show their efficacy as siRNA therapeutic in vivo, in the absence of adverse effects. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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15 pages, 2150 KiB  
Article
Intracellular Delivery of siRNAs Targeting AKT and ERBB2 Genes Enhances Chemosensitization of Breast Cancer Cells in a Culture and Animal Model
by Tahereh Fatemian, Hamid Reza Moghimi and Ezharul Hoque Chowdhury
Pharmaceutics 2019, 11(9), 458; https://doi.org/10.3390/pharmaceutics11090458 - 3 Sep 2019
Cited by 5 | Viewed by 3699
Abstract
Pharmacotherapy as the mainstay in the management of breast cancer suffers from various drawbacks, including non-targeted biodistribution, narrow therapeutic and safety windows, and also resistance to treatment. Thus, alleviation of the constraints from the pharmacodynamic and pharmacokinetic profile of classical anti-cancer drugs could [...] Read more.
Pharmacotherapy as the mainstay in the management of breast cancer suffers from various drawbacks, including non-targeted biodistribution, narrow therapeutic and safety windows, and also resistance to treatment. Thus, alleviation of the constraints from the pharmacodynamic and pharmacokinetic profile of classical anti-cancer drugs could lead to improvements in efficacy and patient survival in malignancies. Moreover, modifications in the genetic pathophysiology of cancer via administration of small nucleic acids might pave the way towards higher response rates to chemotherapeutics. Inorganic pH-dependent carbonate apatite (CA) nanoparticles were utilized in this study to efficiently deliver various classes of therapeutics into cancer cells. Co-delivery of drugs and genetic materials was successfully attained through a carbonate apatite delivery device. On 4T1 cells, siRNAs against AKT and ERBB2 plus paclitaxel or docetaxel resulted in the largest increase in anti-cancer effects compared to CA/paclitaxel or CA/docetaxel. Therefore, these ingredients were selected for further in vivo investigations. Animals receiving injections of CA/paclitaxel or CA/docetaxel loaded with siRNAs against AKT and ERBB2 possessed significantly smaller tumors compared to CA/drug-treated mice. Interestingly, synergistic interactions in target protein knock down with combinations of CA/AKT/paclitaxel, CA/ERBB2/docetaxel were documented via western blotting. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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19 pages, 2695 KiB  
Article
Synergistic Anti-Angiogenic Effects Using Peptide-Based Combinatorial Delivery of siRNAs Targeting VEGFA, VEGFR1, and Endoglin Genes
by Anna A. Egorova, Sofia V. Shtykalova, Marianna A. Maretina, Dmitry I. Sokolov, Sergei A. Selkov, Vladislav S. Baranov and Anton V. Kiselev
Pharmaceutics 2019, 11(6), 261; https://doi.org/10.3390/pharmaceutics11060261 - 6 Jun 2019
Cited by 16 | Viewed by 3677
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

22 pages, 6705 KiB  
Article
Effect of Cationic Lipid Type in Folate-PEG-Modified Cationic Liposomes on Folate Receptor-Mediated siRNA Transfection in Tumor Cells
by Yoshiyuki Hattori, Satono Shimizu, Kei-ichi Ozaki and Hiraku Onishi
Pharmaceutics 2019, 11(4), 181; https://doi.org/10.3390/pharmaceutics11040181 - 15 Apr 2019
Cited by 28 | Viewed by 5717
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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19 pages, 6419 KiB  
Article
Targeted Co-Delivery of siRNA and Methotrexate for Tumor Therapy via Mixed Micelles
by Fei Hao, Robert J. Lee, Chunmiao Yang, Lihuang Zhong, Yating Sun, Shiyan Dong, Ziyuan Cheng, Lirong Teng, Qingfan Meng, Jiahui Lu, Jing Xie and Lesheng Teng
Pharmaceutics 2019, 11(2), 92; https://doi.org/10.3390/pharmaceutics11020092 - 21 Feb 2019
Cited by 19 | Viewed by 4477
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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16 pages, 1977 KiB  
Article
Light-Triggered Cellular Delivery of Oligonucleotides
by Leena-Stiina Kontturi, Joep van den Dikkenberg, Arto Urtti, Wim E. Hennink and Enrico Mastrobattista
Pharmaceutics 2019, 11(2), 90; https://doi.org/10.3390/pharmaceutics11020090 - 21 Feb 2019
Cited by 18 | Viewed by 6991
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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Review

Jump to: Editorial, Research

16 pages, 649 KiB  
Review
Aptamers as Delivery Agents of siRNA and Chimeric Formulations for the Treatment of Cancer
by Ana Paula Dinis Ano Bom, Patrícia Cristina da Costa Neves, Carlos Eduardo Bonacossa de Almeida, Dilson Silva and Sotiris Missailidis
Pharmaceutics 2019, 11(12), 684; https://doi.org/10.3390/pharmaceutics11120684 - 16 Dec 2019
Cited by 15 | Viewed by 5074
Abstract
Both aptamers and siRNA technologies have now reached maturity, and both have been validated with a product in the market. However, although pegaptanib reached the market some time ago, there has been a slow process for new aptamers to follow. Today, some 40 [...] Read more.
Both aptamers and siRNA technologies have now reached maturity, and both have been validated with a product in the market. However, although pegaptanib reached the market some time ago, there has been a slow process for new aptamers to follow. Today, some 40 aptamers are in the market, but many in combination with siRNAs, in the form of specific delivery agents. This combination offers the potential to explore the high affinity and specificity of aptamers, the silencing power of siRNA, and, at times, the cytotoxicity of chemotherapy molecules in powerful combinations that promise to delivery new and potent therapies. In this review, we report new developments in the field, following up from our previous work, more specifically on the use of aptamers as delivery agents of siRNA in nanoparticle formulations, alone or in combination with chemotherapy, for the treatment of cancer. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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Graphical abstract

31 pages, 3805 KiB  
Review
Strategies for Delivery of siRNAs to Ovarian Cancer Cells
by Rossella Farra, Matea Maruna, Francesca Perrone, Mario Grassi, Fabio Benedetti, Marianna Maddaloni, Maguie El Boustani, Salvo Parisi, Flavio Rizzolio, Giancarlo Forte, Fabrizio Zanconati, Maja Cemazar, Urska Kamensek, Barbara Dapas and Gabriele Grassi
Pharmaceutics 2019, 11(10), 547; https://doi.org/10.3390/pharmaceutics11100547 - 22 Oct 2019
Cited by 19 | Viewed by 4554
Abstract
The unmet need for novel therapeutic options for ovarian cancer (OC) deserves further investigation. Among the different novel drugs, small interfering RNAs (siRNAs) are particularly attractive because of their specificity of action and efficacy, as documented in many experimental setups. However, the fragility [...] Read more.
The unmet need for novel therapeutic options for ovarian cancer (OC) deserves further investigation. Among the different novel drugs, small interfering RNAs (siRNAs) are particularly attractive because of their specificity of action and efficacy, as documented in many experimental setups. However, the fragility of these molecules in the biological environment necessitates the use of delivery materials able to protect them and possibly target them to the cancer cells. Among the different delivery materials, those based on polymers and lipids are considered very interesting because of their biocompatibility and ability to carry/deliver siRNAs. Despite these features, polymers and lipids need to be engineered to optimize their delivery properties for OC. In this review, we concentrated on the description of the therapeutic potential of siRNAs and polymer-/lipid-based delivery systems for OC. After a brief description of OC and siRNA features, we summarized the strategies employed to minimize siRNA delivery problems, the targeting strategies to OC, and the preclinical models available. Finally, we discussed the most interesting works published in the last three years about polymer-/lipid-based materials for siRNA delivery. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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26 pages, 1751 KiB  
Review
Lipid Delivery Systems for Nucleic-Acid-Based-Drugs: From Production to Clinical Applications
by Anna Angela Barba, Sabrina Bochicchio, Annalisa Dalmoro and Gaetano Lamberti
Pharmaceutics 2019, 11(8), 360; https://doi.org/10.3390/pharmaceutics11080360 - 24 Jul 2019
Cited by 103 | Viewed by 7528
Abstract
In the last years the rapid development of Nucleic Acid Based Drugs (NABDs) to be used in gene therapy has had a great impact in the medical field, holding enormous promise, becoming “the latest generation medicine” with the first ever siRNA-lipid based formulation [...] Read more.
In the last years the rapid development of Nucleic Acid Based Drugs (NABDs) to be used in gene therapy has had a great impact in the medical field, holding enormous promise, becoming “the latest generation medicine” with the first ever siRNA-lipid based formulation approved by the United States Food and Drug Administration (FDA) for human use, and currently on the market under the trade name Onpattro™. The growth of such powerful biologic therapeutics has gone hand in hand with the progress in delivery systems technology, which is absolutely required to improve their safety and effectiveness. Lipid carrier systems, particularly liposomes, have been proven to be the most suitable vehicles meeting NABDs requirements in the medical healthcare framework, limiting their toxicity, and ensuring their delivery and expression into the target tissues. In this review, after a description of the several kinds of liposomes structures and formulations used for in vitro or in vivo NABDs delivery, the broad range of siRNA-liposomes production techniques are discussed in the light of the latest technological progresses. Then, the current status of siRNA-lipid delivery systems in clinical trials is addressed, offering an updated overview on the clinical goals and the next challenges of this new class of therapeutics which will soon replace traditional drugs. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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26 pages, 6961 KiB  
Review
Evolution from Covalent to Self-Assembled PAMAM-Based Dendrimers as Nanovectors for siRNA Delivery in Cancer by Coupled In Silico-Experimental Studies. Part I: Covalent siRNA Nanocarriers
by Domenico Marson, Erik Laurini, Suzana Aulic, Maurizio Fermeglia and Sabrina Pricl
Pharmaceutics 2019, 11(7), 351; https://doi.org/10.3390/pharmaceutics11070351 - 18 Jul 2019
Cited by 15 | Viewed by 3984
Abstract
Small interfering RNAs (siRNAs) represent a new approach towards the inhibition of gene expression; as such, they have rapidly emerged as promising therapeutics for a plethora of important human pathologies including cancer, cardiovascular diseases, and other disorders of a genetic etiology. However, the [...] Read more.
Small interfering RNAs (siRNAs) represent a new approach towards the inhibition of gene expression; as such, they have rapidly emerged as promising therapeutics for a plethora of important human pathologies including cancer, cardiovascular diseases, and other disorders of a genetic etiology. However, the clinical translation of RNA interference (RNAi) requires safe and efficient vectors for siRNA delivery into cells. Dendrimers are attractive nanovectors to serve this purpose, as they present a unique, well-defined architecture and exhibit cooperative and multivalent effects at the nanoscale. This short review presents a brief introduction to RNAi-based therapeutics, the advantages offered by dendrimers as siRNA nanocarriers, and the remarkable results we achieved with bio-inspired, structurally flexible covalent dendrimers. In the companion paper, we next report our recent efforts in designing, characterizing and testing a series of self-assembled amphiphilic dendrimers and their related structural alterations to achieve unprecedented efficient siRNA delivery both in vitro and in vivo. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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Graphical abstract

26 pages, 10418 KiB  
Review
Evolution from Covalent to Self-Assembled PAMAM-Based Dendrimers as Nanovectors for siRNA Delivery in Cancer by Coupled in Silico-Experimental Studies. Part II: Self-Assembled siRNA Nanocarriers
by Erik Laurini, Domenico Marson, Suzana Aulic, Maurizio Fermeglia and Sabrina Pricl
Pharmaceutics 2019, 11(7), 324; https://doi.org/10.3390/pharmaceutics11070324 - 10 Jul 2019
Cited by 9 | Viewed by 3199
Abstract
In part I of this review, the authors showed how poly(amidoamine) (PAMAM)-based dendrimers can be considered as promising delivering platforms for siRNA therapeutics. This is by virtue of their precise and unique multivalent molecular architecture, characterized by uniform branching units and a plethora [...] Read more.
In part I of this review, the authors showed how poly(amidoamine) (PAMAM)-based dendrimers can be considered as promising delivering platforms for siRNA therapeutics. This is by virtue of their precise and unique multivalent molecular architecture, characterized by uniform branching units and a plethora of surface groups amenable to effective siRNA binding and delivery to e.g., cancer cells. However, the successful clinical translation of dendrimer-based nanovectors requires considerable amounts of good manufacturing practice (GMP) compounds in order to conform to the guidelines recommended by the relevant authorizing agencies. Large-scale GMP-standard high-generation dendrimer production is technically very challenging. Therefore, in this second part of the review, the authors present the development of PAMAM-based amphiphilic dendrons, that are able to auto-organize themselves into nanosized micelles which ultimately outperform their covalent dendrimer counterparts in in vitro and in vivo gene silencing. Full article
(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)
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