Iontophoresis of Biological Macromolecular Drugs

Abstract

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.

Increasing Skeletal Muscle Mass in Mice by Non-Invasive Intramuscular Delivery of Myostatin Inhibitory Peptide by Iontophoresis

“…We focused on ItP as a non-invasive method for the potential intramuscular delivery of MID-35. Previously, we have demonstrated the utility of ItP for the delivery of various macromolecules, such as siRNA, liposomes and antibodies [ 27 ]. siRNA has been delivered into the skin by ItP and induced significant knocking down of the expression of target interleukin 10 mRNA.…”

“…It was suggested that macromolecules such as siRNA and liposomes can penetrate into intercellular spaces cleaved by weak electric currents. Therefore, we concluded that ItP would promote transdermal penetration of macromolecules by cleaving intercellular junctions through activation of cell signaling pathways via Ca 2+ influx [ 27 ].…”

“…We also found that the weak electric current induces unique endocytosis, such as tubular endocytosis, for the uptake of extraneous macromolecules. In addition, weak electric current treatment of culture cells in vitro and rats in vivo increased ceramide levels [ 27 ]. Ceramide is known to form pores in the mitochondrial outer membrane [ 28 ].…”

“…It was found that heat shock protein 90 (Hsp90) α and myristoylated alanine-rich C-kinase substrate (Marcks) were highly phosphorylated after weak electric current treatment. We have also shown that weak electric current induced Rho GTPase activation via Hsp90 and PKC, which could contribute to cellular uptake by actin cytoskeleton remodeling [ 27 ].…”

Permeation Effect Analysis of Drug Using Raman Spectroscopy for Iontophoresis

“…Many studies devote iontophoretic drug delivery to promoting the permeation of different drugs in different pathologic conditions; salbutamol [11] and acyclovir [12] were delivered as iontophoretic drugs in early studies. At present, more kinds of drugs are delivered by iontophoresis for improving treatment effects, such as ocular drugs [13], propranolol [14], biological macromolecular drugs [15], etc. Scars can be treated with iontophoresis, in which cathodal iontophoresis enhances the delivery of sodium fluorescein across the scar skin epidermis by approximately 46 folds, meaning iontophoresis could be utilized to overcome the barrier resistance of the scar skin epidermis and treat scars regionally [16].…”