Iontophoresis-mediated direct delivery of nucleic acid therapeutics, without use of carriers, to internal organs via non-blood circulatory pathways

Hasan, Mahadi; Fukuta, Tatsuya; Inoue, Shinya; Mori, H; Kagawa, Masaaki; Kogure, Kentaro

doi:10.1016/j.jconrel.2022.01.052

Cited by 10 publications

(18 citation statements)

References 37 publications

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“…IP was conducted according to our previous report with some modifications. 19) In brief, after anesthetizing the mice with chloral hydrate (400 mg/kg mouse) dissolved in phosphate buffered saline (PBS) intraperitoneally, their dorsal skin was shaved for IP application. Then, moistened nonwoven fabric (0.5 cm 2 ) containing FITC-labeled oligonucleotide (10 µg/50 µL) was attached to the shaved dorsal skin, and another wetted nonwoven fabric (0.5 cm 2 ) containing PBS (50 µL) was placed 1 cm away.…”

Section: Methodsmentioning

confidence: 99%

“…2,[15][16][17] Accordingly, our work focused on using iontophoretic transdermal technology, in which a weak electric current (0.3-0.5 mA/cm 2 ) is applied for non-invasive delivery of hydrophilic macromolecules via the skin. [15][16][17][18][19] Iontophoresis (IP) relies on various mechanisms, including electrorepulsion, electroosmosis and recently, intercellular cleavage of both tight and gap junctions. [15][16][17][18][19] In the present study, we utilize two unique features related to IP: the first is the ability to deliver hydrophilic macromolecules via the stratum corneum of the skin; and the second is the potential to improve cellular uptake of negatively-charged macromolecules, as reported previously for small interfering RNA (siRNA).…”

Section: Introductionmentioning

confidence: 99%

“…[15][16][17][18][19] Iontophoresis (IP) relies on various mechanisms, including electrorepulsion, electroosmosis and recently, intercellular cleavage of both tight and gap junctions. [15][16][17][18][19] In the present study, we utilize two unique features related to IP: the first is the ability to deliver hydrophilic macromolecules via the stratum corneum of the skin; and the second is the potential to improve cellular uptake of negatively-charged macromolecules, as reported previously for small interfering RNA (siRNA). 20,21) However, In fact, IP and electroporation are used previously for the delivery of charged compounds like DNA, RNA and peptides.…”

Section: Introductionmentioning

confidence: 99%

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Use of Iontophoresis Technology for Transdermal Delivery of a Minimal mRNA Vaccine as a Potential Melanoma Therapeutic

Husseini

Abe

Hara

et al. 2023

Biological & Pharmaceutical Bulletin

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mRNA vaccines have attracted considerable attention as a result of the 2019 coronavirus pandemic; however, challenges remain regarding use of mRNA vaccines, including insufficient delivery owing to the high molecular weights and high negative charges associated with mRNA. These characteristics of mRNA vaccines impair intracellular uptake and subsequent protein translation. In the current study, we prepared a minimal mRNA vaccine encoding a tumor associated antigen human gp100 25-33 peptide (KVPRNQDWL), as a potential treatment for melanoma. Minimal mRNA vaccines have recently shown promise at improving the translational process, and can be prepared via a simple production method. Moreover, we previously reported the successful use of iontophoresis (IP) technology in the delivery of hydrophilic macromolecules into skin layers, as well as intracellular delivery of small interfering RNA (siRNA). We hypothesized that combining IP technology with a newly synthesized minimal mRNA vaccine can improve both transdermal and intracellular delivery of mRNA. Following IP-induced delivery of a mRNA vaccine, an immune response is elicited resulting in activation of skin resident immune cells. As expected, combining both technologies led to potent stimulation of the immune system, which was observed via potent tumor inhibition in mice bearing melanoma. Additionally, there was an elevation in mRNA expression levels of various cytokines, mainly interferon (IFN)-γ, as well as infiltration of cytotoxic CD8 T cells in the tumor tissue, which are responsible for tumor clearance. This is the first report demonstrating the application of IP for delivery of a minimal mRNA vaccine as a potential melanoma therapeutic.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Use of Iontophoresis Technology for Transdermal Delivery of a Minimal mRNA Vaccine as a Potential Melanoma Therapeutic

Husseini

Abe

Hara

et al. 2023

Biological & Pharmaceutical Bulletin

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“…Although IP is a noninvasive transdermal drug delivery technology, a recent study reported the application of IP to the liver [ 100 ]. Liver fibrosis and steatosis gradually develop into liver cirrhosis, a leading cause of mortality and morbidity worldwide.…”

Section: Recent Advances In the Ip-mediated Transdermal Delivery Of B...mentioning

confidence: 99%

Iontophoresis of Biological Macromolecular Drugs

2022

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Over the last few decades, biological macromolecular drugs (e.g., peptides, proteins, and nucleic acids) have become a significant therapeutic modality for the treatment of various diseases. These drugs are considered superior to small-molecule drugs because of their high specificity and favorable safety profiles. However, such drugs are limited by their low oral bioavailability and short half-lives. Biological macromolecular drugs are typically administrated via invasive methods, e.g., intravenous or subcutaneous injections, which can be painful and induce needle phobia. Noninvasive transdermal delivery is an alternative administration route for the local and systemic delivery of biological macromolecular drugs. However, a challenge with the noninvasive transdermal delivery of biological macromolecular drugs is the outermost layer of the skin, known as the stratum corneum, which is a physical barrier that restricts the entry of extraneous macromolecules. Iontophoresis (IP) relies on the application of a low level of electricity for transdermal drug delivery, in order to facilitate the skin permeation of hydrophilic and charged molecules. The IP of several biological macromolecular drugs has recently been investigated. Herein, we review the IP-mediated noninvasive transdermal delivery of biological macromolecular drugs, their routes of skin permeation, their underlying mechanisms, and their advance applications.

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“…9,10,12,14) Designing prophylactic cancer vaccines is a major challenge, in part due to the need to select safe and immunogenic tumor antigens that are considered appropriate for use. 9,15,16) Human gp100 [25][26][27][28][29][30][31][32][33] antigen peptide (KVPRNQDWL) is a tumor associated antigen (TAA) that is significantly expressed in melanoma, as well as in normal melanocytes. [17][18][19] Despite its expression in normal melanocytes, it is the most commonly used antigen in the development of melanoma vaccines.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Iontophoretic-Delivered Polyplex Vaccine on Melanoma Regression

Husseini

Fukuta

Ozono

et al. 2023

Biological & Pharmaceutical Bulletin

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Although the strategy in cancer vaccination is to provide a therapeutic effect against an established tumor, there is an urgent need to develop prophylactic vaccines for non-viral cancers. In this study, we prepared polyplex nanoparticles through electrostatic interactions between a positively-charged modified tumor associated antigen, namely human derived melanoma gp100 25-33 peptide (KVPRNQDWL-RRRR), and a negatively charged cytosine-phosphate-guanosine motif (CpG-ODN) adjuvant. We previously demonstrated successful transdermal delivery of various hydrophilic macromolecules by iontophoresis (IP) using weak electricity. Herein, we investigated the effectiveness of IP in the transdermal delivery of a prophylactic polyplex vaccine. IP was successful in establishing a homogenous distribution of the vaccine throughout skin. Efficacy of the vaccine was demonstrated against melanoma growth. A significant tumor regression effect was observed, which was confirmed by elevated mRNA expression levels of various cytokines, mainly interferon (IFN)-γ, as well as infiltration of cytotoxic CD8 T cells. Additionally, we evaluated the therapeutic effect of the vaccine and we found a significant reduction in tumor burden. Stimulation of systemic immunity was confirmed by upregulation of IFN-γ. This is the first report to demonstrate the use of IP in the transdermal delivery of a prophylactic melanoma vaccine.

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Iontophoresis-mediated direct delivery of nucleic acid therapeutics, without use of carriers, to internal organs via non-blood circulatory pathways

Cited by 10 publications

References 37 publications

Use of Iontophoresis Technology for Transdermal Delivery of a Minimal mRNA Vaccine as a Potential Melanoma Therapeutic

Use of Iontophoresis Technology for Transdermal Delivery of a Minimal mRNA Vaccine as a Potential Melanoma Therapeutic

Iontophoresis of Biological Macromolecular Drugs

The Effect of Iontophoretic-Delivered Polyplex Vaccine on Melanoma Regression

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