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Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes

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

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 50238

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Special Issue Editors

Dr. Shintaro Fumoto

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Guest Editor

Department of Pharmaceutics, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki-shi, Nagasaki 852-8588, Japan
Interests: lipid nanoparticle; transfection mechanism; tissue optical clearing

Dr. Tsuyoshi Yamamoto

E-Mail Website
Guest Editor

Laboratory of Biofunctional Molecules, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Interests: antisense therapeutics; nucleic acid chemistry; ligand-targeted oligonucleotide delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

To treat intractable and refractory diseases, such as cancers and some kinds of genetic diseases, approaches using oligonucleotides and genes are promising alternative therapeutic modalities. However, as it is necessary to deliver them to the cytosol or nuclei of the target cells after the long, laborious journey in the body, native oligonucleotides and genes, generally unstable in our body, require a drug delivery system. Recently-approved oligonucleotide and gene medicines, including Nusinersen (SPINRAZA®), Patisiran (ONPATTRO®), and Onasemnogene Abeparvovec (ZOLGENSMA®), have their own delivery strategies. The accumulated clinical evidence of these nucleic acid-based drugs suggests the importance of more sophisticated delivery systems. Especially, targeted delivery strategies are meaningful as undesirable bio-distribution would reduce their efficacy and produce severe toxic side effects. Therefore, mechanism-based rational designs will be mandatory to achieve more effective and safe delivery of these drugs. At the same time, we also believe that elucidating the mechanism of transfection will further improve the delivery. This Special Issue will collect research articles and review papers describing targeted delivery of oligonucleotides and genes using chemically-modified oligonucleotides, nanoparticles, exosomes, physical stimuli, environment-responsive carriers, and so on.

Dr. Shintaro Fumoto
Dr. Tsuyoshi Yamamoto
Guest Editors

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Keywords

targeting
oligonucleotide
gene
naked oligonucleotide, chemically modified
nanoparticle
exosome
physical stimulus
environment-responsive delivery system
transfection mechanism

Published Papers (14 papers)

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Research

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16 pages, 2000 KiB

Open AccessArticle

Improvement of mRNA Delivery Efficiency to a T Cell Line by Modulating PEG-Lipid Content and Phospholipid Components of Lipid Nanoparticles

by Hiroki Tanaka, Ryo Miyama, Yu Sakurai, Shinya Tamagawa, Yuta Nakai, Kota Tange, Hiroki Yoshioka and Hidetaka Akita

Pharmaceutics 2021, 13(12), 2097; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13122097 - 06 Dec 2021

Cited by 11 | Viewed by 4743

Abstract

(1) Background: T cells are important target cells, since they exert direct cytotoxic effects on infected/malignant cells, and affect the regulatory functions of other immune cells in a target antigen-specific manner. One of the current approaches for modifying the function of T cells is gene transfection by viral vectors. However, the insertion of the exogenous DNA molecules into the genome is attended by the risk of mutagenesis, especially when a transposon-based gene cassette is used. Based on this scenario, the transient expression of proteins by an in vitro-transcribed messenger RNA (IVT-mRNA) has become a subject of interest. The use of lipid nanoparticles (LNPs) for the transfection of IVT-mRNA is one of the more promising strategies for introducing exogenous genes. In this study, we report on the development of LNPs with transfection efficiencies that are comparable to that for electroporation in a T cell line (Jurkat cells). (2) Methods: Transfection efficiency was improved by optimizing the phospholipids and polyethylene glycol (PEG)-conjugated lipid components. (3) Results: Modification of the lipid composition resulted in the 221-fold increase in luciferase activity compared to a previously optimized formulation. Such a high transfection activity was due to the efficient uptake by clathrin/dynamin-dependent endocytosis and the relatively efficient escape into the cytoplasm at an early stage of endocytosis. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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10 pages, 2478 KiB

Open AccessArticle

Hepatocyte-Specific Co-Delivery of Zinc Ions and Plasmid DNA by Lactosylated Poly(1-vinylimidazole) for Suppression of Insulin Receptor Internalization

by Akito Endo and Shoichiro Asayama

Pharmaceutics 2021, 13(12), 2084; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13122084 - 04 Dec 2021

Cited by 2 | Viewed by 1329

Abstract

The lactosylated poly(1-vinylimidazole) (PVIm-Lac) with various lactosylated degrees has been synthesized for the co-delivery of zinc ions (Zn) and plasmid DNA (pDNA). The Zn/DNA/PVIm-Lac complex formation has achieved the specific delivery of zinc ions to HepG2 cells. Especially, the resulting hepatocyte-specific delivery of zinc ions has increased the number of insulin receptors on the cell surface. Consequently, the Zn/DNA/PVIm-Lac complexes have suppressed insulin receptor internalization on the surface of the HepG2 cells, expecting to offer unique therapy to inhibit hepatic insulin clearance. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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11 pages, 1841 KiB

Open AccessArticle

Delivery of pDNA to the Lung by Lipopolyplexes Using N-Lauroylsarcosine and Effect on the Pulmonary Fibrosis

by Tomoaki Kurosaki, Hiroki Kanda, Junya Hashizume, Kayoko Sato, Hitomi Harasawa, Tadahiro Nakamura, Hitoshi Sasaki and Yukinobu Kodama

Pharmaceutics 2021, 13(11), 1983; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13111983 - 22 Nov 2021

Cited by 4 | Viewed by 1821

Abstract

In a previous study, we constructed a lung-targeting lipopolyplex containing polyethyleneimine (PEI), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), and N-lauroylsarcosine (LS). The lipopolyplex exhibited an extremely high gene expression in the lung after intravenous administration. Here, we optimized the lipopolyplex and used it to deliver a TGF-β1 shRNA to treat refractory pulmonary fibrosis. We constructed several lipopolyplexes with pDNA, various cationic polymers, cationic lipids, and LS to select the most effective formulation. Then, the pDNA encoding shRNA against mouse TGF-β1 was encapsulated in the lipopolyplex and injected into mice with bleomycin-induced pulmonary fibrosis. After optimizing the lipopolyplex, dendrigraft poly-L-lysine (DGL) and DOTMA were selected as the appropriate cationic polymer and lipid, respectively. The lipopolyplex was constructed with a pDNA, DGL, DOTMA, and LS charge ratio of 1:2:2:4 showed the highest gene expression. After intravenous administration of the lipopolyplex, the highest gene expression was observed in the lung. In the in vitro experiment, the lipopolyplex delivered pDNA into the cells via endocytosis. As a result, the lipopolyplex containing pDNA encoding TGF-β1 shRNA significantly decreased hydroxyproline in the pulmonary fibrosis model mice. We have successfully inhibited pulmonary fibrosis using a novel lung-targeting lipopolyplex. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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16 pages, 5431 KiB

Open AccessArticle

Hybrid-Type SELEX for the Selection of Artificial Nucleic Acid Aptamers Exhibiting Cell Internalization Activity

by Hiro Uemachi, Yuuya Kasahara, Keisuke Tanaka, Takumi Okuda, Yoshihiro Yoneda and Satoshi Obika

Pharmaceutics 2021, 13(6), 888; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13060888 - 15 Jun 2021

Cited by 8 | Viewed by 3371

Abstract

Nucleic acid aptamers have attracted considerable attention as next-generation pharmaceutical agents and delivery vehicles for small molecule drugs and therapeutic oligonucleotides. Chemical modification is an effective approach for improving the functionality of aptamers. However, the process of selecting appropriately modified aptamers is laborious because of many possible modification patterns. Here, we describe a hybrid-type systematic evolution of ligands by exponential enrichment (SELEX) approach for the generation of the artificial nucleic acid aptamers effective against human TROP2, a cell surface protein identified by drug discovery as a promising target for cancer therapy. Capillary electrophoresis SELEX was used for the pre-screening of multiple modified nucleic acid libraries and enrichment of TROP2 binding aptamers in the first step, followed by functional screening using cell-SELEX in the second step for the generation of cell-internalizing aptamers. One representative aptamer, Tac-B1, had a nanomolar-level affinity to human TROP2 and exhibited elevated capacity for internalization by cells. Because of the growing interest in the application of aptamers for drug delivery, our hybrid selection approach has great potential for the generation of functional artificial nucleic acid aptamers with ideal modification patterns in vitro. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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16 pages, 2011 KiB

Open AccessArticle

Highly Potent GalNAc-Conjugated Tiny LNA Anti-miRNA-122 Antisense Oligonucleotides

by Tsuyoshi Yamamoto, Yahiro Mukai, Fumito Wada, Chisato Terada, Yukina Kayaba, Kaho Oh, Asako Yamayoshi, Satoshi Obika and Mariko Harada–Shiba

Pharmaceutics 2021, 13(6), 817; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13060817 - 31 May 2021

Cited by 12 | Viewed by 4942

Abstract

The development of clinically relevant anti-microRNA antisense oligonucleotides (anti-miRNA ASOs) remains a major challenge. One promising configuration of anti-miRNA ASOs called “tiny LNA (tiny Locked Nucleic Acid)” is an unusually small (~8-mer), highly chemically modified anti-miRNA ASO with high activity and specificity. Within this platform, we achieved a great enhancement of the in vivo activity of miRNA-122-targeting tiny LNA by developing a series of N-acetylgalactosamine (GalNAc)-conjugated tiny LNAs. Specifically, the median effective dose (ED50) of the most potent construct, tL-5G3, was estimated to be ~12 nmol/kg, which is ~300–500 times more potent than the original unconjugated tiny LNA. Through in vivo/ex vivo imaging studies, we have confirmed that the major advantage of GalNAc over tiny LNAs can be ascribed to the improvement of their originally poor pharmacokinetics. We also showed that the GalNAc ligand should be introduced into its 5′ terminus rather than its 3′ end via a biolabile phosphodiester bond. This result suggests that tiny LNA can unexpectedly be recognized by endogenous nucleases and is required to be digested to liberate the parent tiny LNA at an appropriate time in the body. We believe that our strategy will pave the way for the clinical application of miRNA-targeting small ASO therapy. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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18 pages, 2258 KiB

Open AccessArticle

Delivery of Oligonucleotides Using a Self-Degradable Lipid-Like Material

by Hiroki Tanaka, Nae Takata, Yu Sakurai, Tokuyuki Yoshida, Takao Inoue, Shinya Tamagawa, Yuta Nakai, Kota Tange, Hiroki Yoshioka, Masatoshi Maeki, Manabu Tokeshi and Hidetaka Akita

Pharmaceutics 2021, 13(4), 544; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13040544 - 13 Apr 2021

Cited by 24 | Viewed by 6765

Abstract

The world-first success of lipid nanoparticle (LNP)-based siRNA therapeutics (ONPATTRO^®) promises to accelerate developments in siRNA therapeutics/gene therapy using LNP-type drug delivery systems (DDS). In this study, we explore the optimal composition of an LNP containing a self-degradable material (ssPalmO-Phe) for the delivery of oligonucleotides. siRNA or antisense oligonucleotides (ASO) were encapsulated in LNP with different lipid compositions. The hepatic knockdown efficiency of the target genes and liver toxicity were evaluated. The optimal compositions for the siRNA were different from those for ASO, and different from those for mRNA that were reported in a previous study. Extracellular stability, endosomal escape and cellular uptake appear to be the key processes for the successful delivery of mRNA, siRNA and ASO, respectively. Moreover, the compositions of the LNPs likely contribute to their toxicity. The lipid composition of the LNP needs to be optimized depending on the type of nucleic acids under consideration if the applications of LNPs are to be further expanded. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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14 pages, 2997 KiB

Open AccessArticle

Suppression of Peritoneal Fibrosis by Sonoporation of Hepatocyte Growth Factor Gene-Encoding Plasmid DNA in Mice

by Koyo Nishimura, Koki Ogawa, Maho Kawaguchi, Shintaro Fumoto, Hidefumi Mukai and Shigeru Kawakami

Pharmaceutics 2021, 13(1), 115; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13010115 - 18 Jan 2021

Cited by 8 | Viewed by 2267

Abstract

Gene therapy is expected to be used for the treatment of peritoneal fibrosis, which is a serious problem associated with long-term peritoneal dialysis. Hepatocyte growth factor (HGF) is a well-known anti-fibrotic gene. We developed an ultrasound and nanobubble-mediated (sonoporation) gene transfection system, which selectively targets peritoneal tissues. Thus, we attempted to treat peritoneal fibrosis by sonoporation-based human HGF (hHGF) gene transfection in mice. To prepare a model of peritoneal fibrosis, mice were intraperitoneally injected with chlorhexidine digluconate. We evaluated the preventive and curative effects of sonoporation-based hHGF transfection by analyzing the following factors: hydroxyproline level, peritoneum thickness, and the peritoneal equilibration test. The transgene expression characteristics of sonoporation were also evaluated using multicolor deep imaging. In early-stage fibrosis in mice, transgene expression by sonoporation was observed in the submesothelial layer. Sonoporation-based hHGF transfection showed not only a preventive effect but also a curative effect for early-stage peritoneal fibrosis. Sonoporation-based hHGF transfection may be suitable for the treatment of peritoneal fibrosis regarding the transfection characteristics of transgene expression in the peritoneum under fibrosis. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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11 pages, 1839 KiB

Open AccessArticle

Structure-Activity Relationship of Mono-Ion Complexes for Plasmid DNA Delivery by Muscular Injection

by Amika Mori, Yuki Kobayashi, Kei Nirasawa, Yoichi Negishi and Shoichiro Asayama

Pharmaceutics 2021, 13(1), 78; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13010078 - 08 Jan 2021

Cited by 2 | Viewed by 1509

Abstract

The structure-activity relationship of mono-ion complexes (MICs) for plasmid DNA (pDNA) delivery by muscular injection is demonstrated. MICs were formed between pDNA and monocationic poly(ethylene glycol) (PEG) macromolecules. As monocationic PEGs, the ω-amide-pentylimidazolium (APe-Im) end-modified PEGs with a stable amide (Am) and hydrolytic ester (Es) bond, that is, APe-Im-Am-PEG and APe-Im-Es-PEG, respectively, are synthesized. The difference between the APe-Im-Am-PEG and APe-Im-Es-PEG was only a spacer structure between a terminal cation and a PEG chain. The resulting pDNA MICs with APe-Im-Am-PEG at a charge ratio (+/−) of 32 or 64 were more stable than those with APe-Im-Es-PEG in the presence of serum proteins. The highest gene expression by muscular injection was achieved using the APe-Im-Am-PEG/pDNA MIC at a charge ratio (+/−) of 32 with a smaller particle diameter of approximately 50 nm, as compared to that charge ratio of 64. Consequently, the pDNA MIC with the monocationic PEG with a stable amide spacer, as compared to a hydrolytic ester spacer, is considered to be suitable for the highest gene expression by muscular injection. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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13 pages, 30235 KiB

Open AccessArticle

Microbial Antigen-Presenting Extracellular Vesicles Derived from Genetically Modified Tumor Cells Promote Antitumor Activity of Dendritic Cells

by Tomoko Ito, Kikuya Sugiura, Aya Hasegawa, Wakana Ouchi, Takayuki Yoshimoto, Izuru Mizoguchi, Toshio Inaba, Katsuyuki Hamada, Masazumi Eriguchi and Yoshiyuki Koyama

Pharmaceutics 2021, 13(1), 57; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13010057 - 04 Jan 2021

Cited by 10 | Viewed by 2181

Abstract

Tumor-derived extracellular vesicles (EVs), as tumor vaccines, carry tumor-associated antigens (TAAs), and were expected to transfer TAAs to antigen-presenting cells. However, treatment with tumor-derived EVs exhibited no obvious antitumor effect on the established tumors, likely due to their immuno-suppressive functions, and also to the poor immunogenicity of TAAs. In order to improve the immune stimulating properties, EVs expressing a highly immunogenic bacterial antigen, 6 kDa early secretory antigenic target (ESAT-6), from Mycobacterium tuberculosis were prepared by genetically modifying the parent tumor cells with a plasmid coding for ESAT-6. Cultured B16 tumor cells were transfected with a ternary complex system consisting of pDNA, polyethylenimine (PEI), and chondroitin sulfate. The cells that were transfected with the ternary complex secreted EVs with a higher number of ESAT-6 epitopes than those transfected by a conventional DNA/PEI binary complex, due to the low cytotoxicity, and durable high expression efficiency of the ternary complex systems. The EVs presenting the ESAT-6 epitope (ESAT-EV) were collected and explored as immune modulatory agents. Dendritic cells (DCs) were differentiated from mouse bone marrow cells and incubated with ESAT-EV. After incubating with the EVs for one day, the DCs expressed a significantly higher level of DC maturation marker, CD86. The DCs treated with ESAT-EV showed a significantly improved antitumor activity in tumor-bearing mice. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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12 pages, 7554 KiB

Open AccessArticle

Development of Antibody–Oligonucleotide Complexes for Targeting Exosomal MicroRNA

by Asako Yamayoshi, Shota Oyama, Yusuke Kishimoto, Ryo Konishi, Tsuyoshi Yamamoto, Akio Kobori, Hiroshi Harada, Eishi Ashihara, Hiroshi Sugiyama and Akira Murakami

Pharmaceutics 2020, 12(6), 545; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12060545 - 12 Jun 2020

Cited by 15 | Viewed by 4709

Abstract

MicroRNAs in exosomes (exosomal miRNAs) are considered as significant targets for cancer therapy. Anti-miR oligonucleotides are often used for the functional inhibition of miRNAs; however, there are no studies regarding the regulation of exosomal miRNA functions. In this study, we attempted to develop a novel drug delivery system using anti-exosome antibody–anti-miR oligonucleotide complexes (ExomiR-Tracker) to hijack exosomes to carry anti-miR oligonucleotides inside exosome-recipient cells. We found that ExomiR-Tracker bound to the exosomes, and then the complexes were introduced into the recipient cells. We also found that anti-miR oligonucleotides introduced into the recipient cells can exhibit inhibitory effects on exosomal miRNA functions in vitro and in vivo. We believe that our strategy would be a promising one for targeting exosomal miRNAs. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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18 pages, 3912 KiB

Open AccessArticle

Nano-Polyplexes Mediated Transfection of Runx2-shRNA Mitigates the Osteodifferentiation of Human Valvular Interstitial Cells

by Geanina Voicu, Daniela Rebleanu, Cristina Ana Constantinescu, Elena Valeria Fuior, Letitia Ciortan, Ionel Droc, Cristina Mariana Uritu, Mariana Pinteala, Ileana Manduteanu, Maya Simionescu and Manuela Calin

Pharmaceutics 2020, 12(6), 507; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12060507 - 02 Jun 2020

Cited by 9 | Viewed by 2438

Abstract

Calcific aortic valve disease (CAVD) is a progressive disorder that increases in prevalence with age. An important role in aortic valve calcification is played by valvular interstitial cells (VIC), that with age or in pathological conditions acquire an osteoblast-like phenotype that advances the disease. Therefore, pharmacological interventions aiming to stop or reverse the osteoblastic transition of VIC may represent a therapeutic option for CAVD. In this study, we aimed at developing a nanotherapeutic strategy able to prevent the phenotypic switch of human aortic VIC into osteoblast-like cells. We hypothesize that nanocarriers designed for silencing the Runt-related transcription factor 2 (Runx2) will stop the progress or reverse the osteodifferentiation of human VIC, induced by high glucose concentrations and pro-osteogenic factors. We report here the potential of fullerene (C60)-polyethyleneimine (PEI)/short hairpin (sh)RNA-Runx2 nano-polyplexes to efficiently down-regulate Runx2 mRNA and protein expression leading subsequently to a significant reduction in the expression of osteogenic proteins (i.e., ALP, BSP, OSP and BMP4) in osteoblast-committed VIC. The data suggest that the silencing of Runx2 could represent a novel strategy to impede the osteoblastic phenotypic shift of VIC and the ensuing progress of CAVD. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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Review

Jump to: Research

18 pages, 1933 KiB

Open AccessReview

Antisense Oligonucleotide-Based Therapy of Viral Infections

by Woan-Yuh Tarn, Yun Cheng, Shih-Han Ko and Li-Min Huang

Pharmaceutics 2021, 13(12), 2015; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13122015 - 26 Nov 2021

Cited by 24 | Viewed by 6644

Abstract

Nucleic acid-based therapeutics have demonstrated their efficacy in the treatment of various diseases and vaccine development. Antisense oligonucleotide (ASO) technology exploits a single-strand short oligonucleotide to either cause target RNA degradation or sterically block the binding of cellular factors or machineries to the target RNA. Chemical modification or bioconjugation of ASOs can enhance both its pharmacokinetic and pharmacodynamic performance, and it enables customization for a specific clinical purpose. ASO-based therapies have been used for treatment of genetic disorders, cancer and viral infections. In particular, ASOs can be rapidly developed for newly emerging virus and their reemerging variants. This review discusses ASO modifications and delivery options as well as the design of antiviral ASOs. A better understanding of the viral life cycle and virus-host interactions as well as advances in oligonucleotide technology will benefit the development of ASO-based antiviral therapies. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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30 pages, 3716 KiB

Open AccessReview

Twenty Years of Research on Cyclodextrin Conjugates with PAMAM Dendrimers

by Hidetoshi Arima

Pharmaceutics 2021, 13(5), 697; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13050697 - 11 May 2021

Cited by 8 | Viewed by 2894

Abstract

Recently, the number of gene and oligonucleotide drugs are increasing. Of various drug delivery systems (DDSs) for gene and oligonucleotide drugs, few examples of the clinical application of polymer as drug carriers are known, despite development of the novel polymers has been progressing. Cyclodextrin (CD) conjugates with starburst polyamidoamine (PAMAM) dendrimer (CDEs), as a new type of polymer-based carriers, were first published in 2001. After that, galactose-, lactose-, mannose-, fucose-, folate-, and polyethyleneglycol (PEG)-appended CDEs have been prepared for passive and active targeting for gene, oligonucleotide, and low-molecular-weight drugs. PEG-appended CDE formed polypsuedorotaxanes with α-CD and γ-CD, which are useful for a sustained release system of gene and oligonucleotide drugs. Interestingly, CDEs were found to have anti-inflammatory effects and anti-amyloid effects themselves, which have potential as active pharmaceutical ingredients. Most recently, CDE is reported to be a useful Cas9-RNA ribonucleoproteins (Cas9 RNP) carrier that induces genome editing in the neuron and brain. In this review, the history and progression of CDEs are overviewed. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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35 pages, 2877 KiB

Open AccessReview

Understanding In Vivo Fate of Nucleic Acid and Gene Medicines for the Rational Design of Drugs

by Shintaro Fumoto, Tsuyoshi Yamamoto, Kazuya Okami, Yuina Maemura, Chisato Terada, Asako Yamayoshi and Koyo Nishida

Pharmaceutics 2021, 13(2), 159; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13020159 - 26 Jan 2021

Cited by 11 | Viewed by 3510

Abstract

Nucleic acid and genetic medicines are increasingly being developed, owing to their potential to treat a variety of intractable diseases. A comprehensive understanding of the in vivo fate of these agents is vital for the rational design, discovery, and fast and straightforward development of the drugs. In case of intravascular administration of nucleic acids and genetic medicines, interaction with blood components, especially plasma proteins, is unavoidable. However, on the flip side, such interaction can be utilized wisely to manipulate the pharmacokinetics of the agents. In other words, plasma protein binding can help in suppressing the elimination of nucleic acids from the blood stream and deliver naked oligonucleotides and gene carriers into target cells. To control the distribution of these agents in the body, the ligand conjugation method is widely applied. It is also important to understand intracellular localization. In this context, endocytosis pathway, endosomal escape, and nuclear transport should be considered and discussed. Encapsulated nucleic acids and genes must be dissociated from the carriers to exert their activity. In this review, we summarize the in vivo fate of nucleic acid and gene medicines and provide guidelines for the rational design of drugs. Full article

(This article belongs to the Special Issue Rational and Mechanism-Based Approach to Targeted Delivery of Oligonucleotides and Genes)

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