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18 pages, 8055 KiB

Open AccessArticle

Dually Active Polycation/miRNA Nanoparticles for the Treatment of Fibrosis in Alcohol-Associated Liver Disease

by Chuhan Zhang, Yu Hang, Weimin Tang, Diptesh Sil, Heather C. Jensen-Smith, Robert G. Bennett, Benita L. McVicker and David Oupický

Pharmaceutics 2022, 14(3), 669; https://doi.org/10.3390/pharmaceutics14030669 - 18 Mar 2022

Cited by 6 | Viewed by 2316

Abstract

Alcohol-associated liver disease (AALD) is a major cause of liver disorders worldwide. Current treatment options are limited, especially for AALD-associated fibrosis. Promising approaches include RNA interference for miR-155 overexpression in Kupffer cells (KCs), as well as the use of CXCR4 antagonists that inhibit [...] Read more.

Alcohol-associated liver disease (AALD) is a major cause of liver disorders worldwide. Current treatment options are limited, especially for AALD-associated fibrosis. Promising approaches include RNA interference for miR-155 overexpression in Kupffer cells (KCs), as well as the use of CXCR4 antagonists that inhibit the activation of hepatic stellate cells (HSCs) through the CXCL12/CXCR4 axis. The development of dual-functioning nanoparticles for the effective delivery of antifibrotic RNA together with a CXCR4 inhibitor thus promises to improve the treatment of AALD fibrosis. In this study, cholesterol-modified polymeric CXCR4 inhibitor (Chol-PCX) was synthesized and used to encapsulate anti-miR-155 or non-coding (NC) miRNA in the form of Chol-PCX/miRNA nanoparticles. The results indicate that the nanoparticles induce a significant miR-155 silencing effect both in vitro and in vivo. Treatment with the Chol-PCX/anti-miR-155 particles in a model of moderate alcohol consumption with secondary liver insult resulted in a significant reduction in aminotransferase enzymes as well as collagen content in the liver parenchyma. Overall, our data support the use of Chol-PCX as a carrier for anti-miR-155 for the combined therapeutic inhibition of CXCR4 and miR-155 expression as a way to improve fibrotic damage in the liver. Full article

(This article belongs to the Special Issue Novel Nanoparticles for Targeted Delivery of Therapeutic Nucleic Acids)

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25 pages, 3260 KiB

Open AccessArticle

Aerosol-Mediated Non-Viral Lung Gene Therapy: The Potential of Aminoglycoside-Based Cationic Liposomes

by Tony Le Gall, Mathieu Berchel, Lee Davies, Angélique Mottais, Rosy Ghanem, Alain Fautrel, Deborah Gill, Steve Hyde, Pierre Lehn, Jean-Marie Lehn, Loïc Lemiègre, Thierry Benvegnu, Paul-Alain Jaffrès, Bruno Pitard and Tristan Montier

Pharmaceutics 2022, 14(1), 25; https://doi.org/10.3390/pharmaceutics14010025 - 23 Dec 2021

Cited by 6 | Viewed by 3738

Abstract

Aerosol lung gene therapy using non-viral delivery systems represents a credible therapeutic strategy for chronic respiratory diseases, such as cystic fibrosis (CF). Progress in CF clinical setting using the lipidic formulation GL67A has demonstrated the relevance of such a strategy while emphasizing the [...] Read more.

Aerosol lung gene therapy using non-viral delivery systems represents a credible therapeutic strategy for chronic respiratory diseases, such as cystic fibrosis (CF). Progress in CF clinical setting using the lipidic formulation GL67A has demonstrated the relevance of such a strategy while emphasizing the need for more potent gene transfer agents. In recent years, many novel non-viral gene delivery vehicles were proposed as potential alternatives to GL67 cationic lipid. However, they were usually evaluated using procedures difficult or even impossible to implement in clinical practice. In this study, a clinically-relevant administration protocol via aerosol in murine lungs was used to conduct a comparative study with GL67A. Diverse lipidic compounds were used to prepare a series of formulations inspired by the composition of GL67A. While some of these formulations were ineffective at transfecting murine lungs, others demonstrated modest-to-very-efficient activities and a series of structure-activity relationships were unveiled. Lipidic aminoglycoside derivative-based formulations were found to be at least as efficient as GL67A following aerosol delivery of a luciferase-encoding plasmid DNA. A single aerosol treatment with one such formulation was found to mediate long-term lung transgene expression, exceeding half the animal’s lifetime. This study clearly supports the potential of aminoglycoside-based cationic lipids as potent GL67-alternative scaffolds for further enhanced aerosol non-viral lung gene therapy for diseases such as CF. Full article

(This article belongs to the Special Issue Novel Nanoparticles for Targeted Delivery of Therapeutic Nucleic Acids)

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16 pages, 2495 KiB

Open AccessArticle

Peptide-Functionalized Dendrimer Nanocarriers for Targeted Microdystrophin Gene Delivery

by Jessica Hersh, José Manuel Condor Capcha, Camila Iansen Irion, Guerline Lambert, Mauricio Noguera, Mohit Singh, Avinash Kaur, Emre Dikici, Joaquín J. Jiménez, Lina A. Shehadeh, Sylvia Daunert and Sapna K. Deo

Pharmaceutics 2021, 13(12), 2159; https://doi.org/10.3390/pharmaceutics13122159 - 15 Dec 2021

Cited by 7 | Viewed by 3530

Abstract

Gene therapy is a good alternative for determined congenital disorders; however, there are numerous limitations for gene delivery in vivo including targeted cellular uptake, intracellular trafficking, and transport through the nuclear membrane. Here, a modified G5 polyamidoamine (G5 PAMAM) dendrimer–DNA complex was developed, [...] Read more.

Gene therapy is a good alternative for determined congenital disorders; however, there are numerous limitations for gene delivery in vivo including targeted cellular uptake, intracellular trafficking, and transport through the nuclear membrane. Here, a modified G5 polyamidoamine (G5 PAMAM) dendrimer–DNA complex was developed, which will allow cell-specific targeting to skeletal muscle cells and transport the DNA through the intracellular machinery and the nuclear membrane. The G5 PAMAM nanocarrier was modified with a skeletal muscle-targeting peptide (SMTP), a DLC8-binding peptide (DBP) for intracellular transport, and a nuclear localization signaling peptide (NLS) for nuclear uptake, and polyplexed with plasmid DNA containing the GFP-tagged microdystrophin (µDys) gene. The delivery of µDys has been considered as a therapeutic modality for patients suffering from a debilitating Duchenne muscular dystrophy (DMD) disorder. The nanocarrier–peptide–DNA polyplexes were prepared with different charge ratios and characterized for stability, size, surface charge, and cytotoxicity. Using the optimized nanocarrier polyplexes, the transfection efficiency in vitro was determined by demonstrating the expression of the GFP and the µDys protein using fluorescence and Western blotting studies, respectively. Protein expression in vivo was determined by injecting an optimal nanocarrier polyplex formulation to Duchenne model mice, mdx^4Cv. Ultimately, these nanocarrier polyplexes will allow targeted delivery of the microdystrophin gene to skeletal muscle cells and result in improved muscle function in Duchenne muscular dystrophy patients. Full article

(This article belongs to the Special Issue Novel Nanoparticles for Targeted Delivery of Therapeutic Nucleic Acids)

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18 pages, 8486 KiB

Open AccessArticle

Novel Fluorinated Spermine and Small Molecule PEI to Deliver Anti-PD-L1 and Anti-VEGF siRNA for Highly Efficient Tumor Therapy

by Yihui Zhang, Zihan Yuan, Yi Jin, Wenkai Zhang and Wei-En Yuan

Pharmaceutics 2021, 13(12), 2058; https://doi.org/10.3390/pharmaceutics13122058 - 02 Dec 2021

Cited by 5 | Viewed by 2067

Abstract

Small interfering RNA (siRNA) can specifically silence disease gene expression. This project investigated the overexpression of programmed death receptor ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) on the surface of tumor cells. However, the main obstacle to the development of gene [...] Read more.

Small interfering RNA (siRNA) can specifically silence disease gene expression. This project investigated the overexpression of programmed death receptor ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) on the surface of tumor cells. However, the main obstacle to the development of gene therapy drugs is the lack of an efficient delivery vector, which should be able to overcome multiple delivery barriers and protect siRNA to enter the target cells. Therefore, a novel fluorine-modified endogenous molecular carrier TFSPEI was constructed by linking fluorinated groups with hydrophobic and hydrophilic characteristics on the surface of PEI and spermine. The results showed that lower toxicity, higher endocytosis, and silencing efficiency were achieved. We found that the inhibition of VEGF targets can indirectly activate the immune response to promote the tumor-killing and invasion effects of T cells. The combined delivery of anti-VEGF siRNA and anti-PD-L1 siRNA could inhibit the expression of corresponding proteins, restore the anti-tumor function of T cells and inhibit the growth of neovascularization, and obtained significant anti-tumor effects. Therefore, this safe and efficient fluorinated spermine and small molecule PEI-based anti-PD-L1 and anti-VEGF siRNA delivery system is expected to provide a new strategy for gene therapy of tumors. Full article

(This article belongs to the Special Issue Novel Nanoparticles for Targeted Delivery of Therapeutic Nucleic Acids)

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16 pages, 8498 KiB

Open AccessArticle

Novel PEGylated Lipid Nanoparticles Have a High Encapsulation Efficiency and Effectively Deliver MRTF-B siRNA in Conjunctival Fibroblasts

by Amisha Sanghani, Konstantinos N. Kafetzis, Yusuke Sato, Salsabil Elboraie, Julia Fajardo-Sanchez, Hideyoshi Harashima, Aristides D. Tagalakis and Cynthia Yu-Wai-Man

Pharmaceutics 2021, 13(3), 382; https://doi.org/10.3390/pharmaceutics13030382 - 13 Mar 2021

Cited by 17 | Viewed by 4780

Abstract

The master regulator of the fibrosis cascade is the myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway, making it a key target for anti-fibrotic therapeutics. In the past, inhibitors and small interfering RNAs (siRNAs) targeting the MRTF-B gene have been deployed to counter fibrosis [...] Read more.

The master regulator of the fibrosis cascade is the myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway, making it a key target for anti-fibrotic therapeutics. In the past, inhibitors and small interfering RNAs (siRNAs) targeting the MRTF-B gene have been deployed to counter fibrosis in the eye, with the latter showing promising results. However, the biggest challenge in implementing siRNA therapeutics is the method of delivery. In this study, we utilised the novel, pH-sensitive, cationic lipid CL4H6, which has previously demonstrated potent targeting of hepatocytes and endosomal escape, to safely and efficiently deliver an MRTF-B siRNA into human conjunctival fibroblasts. We prepared two lipid nanoparticle (LNP) formulations, incorporating targeting cleavable peptide cY in one of them, and measured their physicochemical properties and silencing effect in human conjunctival fibroblasts. Both proved to be non-cytotoxic at a concentration of 50 nM and effectively silenced the MRTF-B gene in vitro, with the targeting cleavable peptide not affecting the silencing efficiency [LNP with cY: 62.1% and 81.5% versus LNP without cY: 77.7% and 80.2%, at siRNA concentrations of 50 nM (p = 0.06) and 100 nM (p = 0.09), respectively]. On the other hand, the addition of the targeting cleavable peptide significantly increased the encapsulation efficiency of the LNPs from 92.5% to 99.3% (p = 0.0005). In a 3D fibroblast-populated collagen matrix model, both LNP formulations significantly decreased fibroblast contraction after a single transfection. We conclude that the novel PEGylated CL4H6-MRTF-B siRNA-loaded LNPs represent a promising therapeutic approach to prevent conjunctival fibrosis after glaucoma filtration surgery. Full article

(This article belongs to the Special Issue Novel Nanoparticles for Targeted Delivery of Therapeutic Nucleic Acids)

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24 pages, 7137 KiB

Open AccessArticle

Layered Double Hydroxide as a Potent Non-viral Vector for Nucleic Acid Delivery Using Gene-Activated Scaffolds for Tissue Regeneration Applications

by Lara S. Costard, Domhnall C. Kelly, Rachael N. Power, Christopher Hobbs, Sonia Jaskaniec, Valeria Nicolosi, Brenton L. Cavanagh, Caroline M. Curtin and Fergal J. O’Brien

Pharmaceutics 2020, 12(12), 1219; https://doi.org/10.3390/pharmaceutics12121219 - 16 Dec 2020

Cited by 25 | Viewed by 4240

Abstract

Nonviral vectors offer a safe alternative to viral vectors for gene therapy applications, albeit typically exhibiting lower transfection efficiencies. As a result, there remains a significant need for the development of a nonviral delivery system with low cytotoxicity and high transfection efficacy as [...] Read more.

Nonviral vectors offer a safe alternative to viral vectors for gene therapy applications, albeit typically exhibiting lower transfection efficiencies. As a result, there remains a significant need for the development of a nonviral delivery system with low cytotoxicity and high transfection efficacy as a tool for safe and transient gene delivery. This study assesses MgAl-NO₃ layered double hydroxide (LDH) as a nonviral vector to deliver nucleic acids (pDNA, miRNA and siRNA) to mesenchymal stromal cells (MSCs) in 2D culture and using a 3D tissue engineering scaffold approach. Nanoparticles were formulated by complexing LDH with pDNA, microRNA (miRNA) mimics and inhibitors, and siRNA at varying mass ratios of LDH:nucleic acid. In 2D monolayer, pDNA delivery demonstrated significant cytotoxicity issues, and low cellular transfection was deemed to be a result of the poor physicochemical properties of the LDH–pDNA nanoparticles. However, the lower mass ratios required to successfully complex with miRNA and siRNA cargo allowed for efficient delivery to MSCs. Furthermore, incorporation of LDH–miRNA nanoparticles into collagen-nanohydroxyapatite scaffolds resulted in successful overexpression of miRNA in MSCs, demonstrating the development of an efficacious miRNA delivery platform for gene therapy applications in regenerative medicine. Full article

(This article belongs to the Special Issue Novel Nanoparticles for Targeted Delivery of Therapeutic Nucleic Acids)

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Review

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21 pages, 1128 KiB

Open AccessReview

Delivery of RNAs to Specific Organs by Lipid Nanoparticles for Gene Therapy

by Kelly Godbout and Jacques P. Tremblay

Pharmaceutics 2022, 14(10), 2129; https://doi.org/10.3390/pharmaceutics14102129 - 07 Oct 2022

Cited by 15 | Viewed by 7930

Abstract

Gene therapy holds great promise in the treatment of genetic diseases. It is now possible to make DNA modifications using the CRISPR system. However, a major problem remains: the delivery of these CRISPR-derived technologies to specific organs. Lipid nanoparticles (LNPs) have emerged as [...] Read more.

Gene therapy holds great promise in the treatment of genetic diseases. It is now possible to make DNA modifications using the CRISPR system. However, a major problem remains: the delivery of these CRISPR-derived technologies to specific organs. Lipid nanoparticles (LNPs) have emerged as a very promising delivery method. However, when delivering LNPs intravenously, most of the cargo is trapped by the liver. Alternatively, injecting them directly into organs, such as the brain, requires more invasive procedures. Therefore, developing more specific LNPs is crucial for their future clinical use. Modifying the composition of the lipids in the LNPs allows more specific deliveries of the LNPs to some organs. In this review, we have identified the most effective compositions and proportions of lipids for LNPs to target specific organs, such as the brain, lungs, muscles, heart, liver, spleen, and bones. Full article

(This article belongs to the Special Issue Novel Nanoparticles for Targeted Delivery of Therapeutic Nucleic Acids)

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23 pages, 1955 KiB

Open AccessReview

Nanoparticle-Based RNAi Therapeutics Targeting Cancer Stem Cells: Update and Prospective

by Yongquan Tang, Yan Chen, Zhe Zhang, Bo Tang, Zongguang Zhou and Haining Chen

Pharmaceutics 2021, 13(12), 2116; https://doi.org/10.3390/pharmaceutics13122116 - 08 Dec 2021

Cited by 15 | Viewed by 3584

Abstract

Cancer stem cells (CSCs) are characterized by intrinsic self-renewal and tumorigenic properties, and play important roles in tumor initiation, progression, and resistance to diverse forms of anticancer therapy. Accordingly, targeting signaling pathways that are critical for CSC maintenance and biofunctions, including the Wnt, [...] Read more.

Cancer stem cells (CSCs) are characterized by intrinsic self-renewal and tumorigenic properties, and play important roles in tumor initiation, progression, and resistance to diverse forms of anticancer therapy. Accordingly, targeting signaling pathways that are critical for CSC maintenance and biofunctions, including the Wnt, Notch, Hippo, and Hedgehog signaling cascades, remains a promising therapeutic strategy in multiple cancer types. Furthermore, advances in various cancer omics approaches have largely increased our knowledge of the molecular basis of CSCs, and provided numerous novel targets for anticancer therapy. However, the majority of recently identified targets remain ‘undruggable’ through small-molecule agents, whereas the implications of exogenous RNA interference (RNAi, including siRNA and miRNA) may make it possible to translate our knowledge into therapeutics in a timely manner. With the recent advances of nanomedicine, in vivo delivery of RNAi using elaborate nanoparticles can potently overcome the intrinsic limitations of RNAi alone, as it is rapidly degraded and has unpredictable off-target side effects. Herein, we present an update on the development of RNAi-delivering nanoplatforms in CSC-targeted anticancer therapy and discuss their potential implications in clinical trials. Full article

(This article belongs to the Special Issue Novel Nanoparticles for Targeted Delivery of Therapeutic Nucleic Acids)

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27 pages, 3142 KiB

Open AccessReview

New Applications of Lipid and Polymer-Based Nanoparticles for Nucleic Acids Delivery

by Adelina-Gabriela Niculescu, Alexandra Cătălina Bîrcă and Alexandru Mihai Grumezescu

Pharmaceutics 2021, 13(12), 2053; https://doi.org/10.3390/pharmaceutics13122053 - 01 Dec 2021

Cited by 12 | Viewed by 3659

Abstract

Nucleic acids represent a promising lead for engineering the immune system. However, naked DNA, mRNA, siRNA, and other nucleic acids are prone to enzymatic degradation and face challenges crossing the cell membrane. Therefore, increasing research has been recently focused on developing novel delivery [...] Read more.

Nucleic acids represent a promising lead for engineering the immune system. However, naked DNA, mRNA, siRNA, and other nucleic acids are prone to enzymatic degradation and face challenges crossing the cell membrane. Therefore, increasing research has been recently focused on developing novel delivery systems that are able to overcome these drawbacks. Particular attention has been drawn to designing lipid and polymer-based nanoparticles that protect nucleic acids and ensure their targeted delivery, controlled release, and enhanced cellular uptake. In this respect, this review aims to present the recent advances in the field, highlighting the possibility of using these nanosystems for therapeutic and prophylactic purposes towards combatting a broad range of infectious, chronic, and genetic disorders. Full article

(This article belongs to the Special Issue Novel Nanoparticles for Targeted Delivery of Therapeutic Nucleic Acids)

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33 pages, 2450 KiB

Open AccessReview

Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB

by Seigo Kimura and Hideyoshi Harashima

Pharmaceutics 2020, 12(12), 1216; https://doi.org/10.3390/pharmaceutics12121216 - 15 Dec 2020

Cited by 39 | Viewed by 5148

Abstract

The era of the aging society has arrived, and this is accompanied by an increase in the absolute numbers of patients with neurological disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Such neurological disorders are serious costly diseases that have a [...] Read more.

The era of the aging society has arrived, and this is accompanied by an increase in the absolute numbers of patients with neurological disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Such neurological disorders are serious costly diseases that have a significant impact on society, both globally and socially. Gene therapy has great promise for the treatment of neurological disorders, but only a few gene therapy drugs are currently available. Delivery to the brain is the biggest hurdle in developing new drugs for the central nervous system (CNS) diseases and this is especially true in the case of gene delivery. Nanotechnologies such as viral and non-viral vectors allow efficient brain-targeted gene delivery systems to be created. The purpose of this review is to provide a comprehensive review of the current status of the development of successful drug delivery to the CNS for the treatment of CNS-related disorders especially by gene therapy. We mainly address three aspects of this situation: (1) blood-brain barrier (BBB) functions; (2) adeno-associated viral (AAV) vectors, currently the most advanced gene delivery vector; (3) non-viral brain targeting by non-invasive methods. Full article

(This article belongs to the Special Issue Novel Nanoparticles for Targeted Delivery of Therapeutic Nucleic Acids)

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