Delivery Of Hydrophilic Macromolecules Research Articles

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

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 gp10025-33 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.

Enhancement of nose-to-brain delivery of hydrophilic macromolecules with stearate- or polyethylene glycol-modified arginine-rich peptide

Recently, nose-to-brain delivery is a highly versatile route, which, in combination with novel drugs being developed for treating intractable CNS diseases, is a promising approach for the treatment of disorders. Furthermore, nano-sized drug carriers may improve nose-to-brain drug delivery by their capability to increase the transmucosal penetration of the drugs across nasal mucosal tissue barrier. However, there is still not enough information regarding mechanism of absorption pathway from nasal cavity to brain using nanocarriers. In this study, to investigate the nose-to-brain transport pathway using nanocarriers, the distribution in whole brain, nasal mucosa, and trigeminal nerve after intranasal administration of two kinds of nanocarriers which have hydrophobic or hydrophilic moiety. We used CHHRRRRHHC peptide (CH2R4H2C) as basic peptide carriers, and modified with stearic acid (STR) as a hydrophobic moiety (STR-CH2R4H2C) or polyethylene glycol (PEG)-based block copolymer (PEG-PCL) as hydrophilic moiety (PEG-PCL-CH2R4H2C). The nose-to-brain drug delivery can be improved by using STR-CH2R4H2C and PEG-PCL-CH2R4H2C as carriers. Specifically, hydrophobic STR-CH2R4H2C is more suitable for the transport of drugs targeting the forebrain, while PEG-PCL-modified CH2R4H2C is more suitable for transporting drugs targeting the hindbrain or whole brain tissue. In conclusion, the results of this study support the possibility that drug delivery pathways can be controlled depending on the properties of different carrier complexes.

Transdermal delivery of fluorescein isothiocyanate-dextrans using the combination of microneedles and low-frequency sonophoresis

This study aimed to evaluate the patient-friendly methods that are used in the delivery of hydrophilic macromolecules into deep skin layers, in particular, the combination of microneedles patch (MNs patch) and low-frequency sonophoresis (SN). The hydrophilic macromolecule drug fluorescein isothiocyanate (FITC)-dextrans (FD-4: MW 4.4 kDa) was used as the model drug in our experimental design. In this study, excised porcine skin was used to investigate and optimize the key parameters that determine effective MNs- and SN-facilitated FD-4 delivery. In vitro skin permeation experiments revealed that the combination of MNs patch with SN had a superior enhancing effect of skin permeation for FD-4 compared to MNs alone, SN alone or untreated skin, respectively. The optimal parameters for the combination of MNs and SN included the following: 10 N insertion force of MNs, 4 W/cm2 SN intensity, 6 mm radiation diameter of the SN probe, 2 min application time, and the continuous mode duty cycle of SN. In addition, vertical sections of skin, clearly observed under a confocal microscope, confirmed that the combination of MNs and SN enhanced permeation of FD-4 into the deep skin layers. These studies suggest that the combination of MNs and SN techniques could have great potential in the delivery of hydrophilic macromolecules into deep skin.

Effects of ultrasound and sodium lauryl sulfate on the transdermal delivery of hydrophilic permeants: Comparative in vitro studies with full-thickness and split-thickness pig and human skin

The simultaneous application of ultrasound and the surfactant sodium lauryl sulfate (referred to as US/SLS) to skin enhances transdermal drug delivery (TDD) in a synergistic mechanical and chemical manner. Since full-thickness skin (FTS) and split-thickness skin (STS) differ in mechanical strength, US/SLS treatment may have different effects on their transdermal transport pathways. Therefore, we evaluated STS as an alternative to the well-established US/SLS-treated FTS model for TDD studies of hydrophilic permeants. We utilized the aqueous porous pathway model to compare the effects of US/SLS treatment on the skin permeability and the pore radius of pig and human FTS and STS over a range of skin electrical resistivity values. Our findings indicate that the US/SLS-treated pig skin models exhibit similar permeabilities and pore radii, but the human skin models do not. Furthermore, the US/SLS-enhanced delivery of gold nanoparticles and quantum dots (two model hydrophilic macromolecules) is greater through pig STS than through pig FTS, due to the presence of less dermis that acts as an artificial barrier to macromolecules. In spite of greater variability in correlations between STS permeability and resistivity, our findings strongly suggest the use of 700 μm-thick pig STS to investigate the in vitro US/SLS-enhanced delivery of hydrophilic macromolecules.