Potential Enhancement of Topical Drug Delivery Using Grapefruit-derived Nanoparticles Modified Using TAT Peptide.

Support for the Safe Use of Zinc Oxide Nanoparticle Sunscreens: Lack of Skin Penetration or Cellular Toxicity after Repeated Application in Volunteers

Enhanced skin penetration of P20 phosphopeptide using protein transduction domains

Study of the skin-penetration promoting effect and mechanism of combined system of curcumin liposomes prepared by microfluidic chip and skin penetrating peptides TD-1 for topical treatment of primary melanoma

Summary Laboratory experiments and field trials have shown that oil recovery from carbonate reservoirs can be increased by modifying the injected brine composition in a process termed controlled salinity water-flooding (CSW). However, the mineral- to pore-scale processes responsible for improved recovery during CSW remain ambiguous and there is no method to predict the optimum CSW composition for a given crude oil/brine/rock (COBR) system. The zeta potential is a measure of the electrical potential at mineral-brine and oil-brine interfaces and controls the electrostatic forces acting between these interfaces. Measured values of zeta potential at the mineral-brine interface in carbonate rocks remain scarce, particularly at reservoir conditions of temperature, salinity and wetting state. Moreover, there are no measured zeta potential data for the oil-brine interface at these conditions. Here, we report zeta potential measured using the streaming potential method and intact samples of outcrop and reservoir carbonates. Measured values were obtained in clean, water-wet samples and in the same samples after aging in two different crude oils. Measurements were conducted at laboratory temperature, or at elevated temperatures >70°C. In some samples, CSW was then conducted to determine whether changing the injection brine composition increased recovery. The measured zeta potential in clean samples saturated with synthetic formation brine was consistently positive across all the samples tested, while zeta potential in the same (clean) samples saturated with low salinity brine (dilute seawater) was consistently negative, irrespective of temperature. Consequently, changing the brine composition during CSW from formation brine to low salinity brine in these samples is expected to invert the polarity of the zeta potential. After aging in crude oil and formation brine, the zeta potential consistently became more positive in samples aged in one crude oil, and less positive in samples aged in the other crude oil. This result can be interpreted in terms of the zeta potential at the oil-brine interface: the crude oil yielding a more positive sample zeta potential after aging has a positive zeta potential at its interface with the brine; the crude oil yielding a less positive sample zeta potential after aging has a negative zeta potential at its interface. Injecting low salinity brine yielded improved recovery with the 'negative' oil, but no response with the 'positive' oil, consistent with the hypothesis that improved recovery follows from an increase in the repulsive electrostatic force acting between mineral-brine and oil-brine interfaces.

A new method of using the detonation nanodiamond with positive and negative zeta potential as a spacer for aerogels based on graphene oxide is presented. It is shown that the dosed addition of detonation nanodiamonds' particles to the suspension of graphene oxide hydrosol made it possible to triple the specific surface area of the resulting aerogel compared to graphene oxide aerogel, and this effect is more significant when nanodiamonds with a positive zeta potential are used. It was also shown that aerogels derived from graphene oxide and detonation nanodiamond with a positive zeta potential have a specific morphology with graphene oxide platelets being twisted. This effect is discussed in terms of the change in the average zeta potential of the initial mixtures. Keywords: two-component systems, carbon materials, colloid chemistry.

Synergistic Skin Penetration Enhancer and Nanoemulsion Formulations Promote the Human Epidermal Permeation of Caffeine and Naproxen

Topical application of sebacoyl dinalbuphine ester-loaded nanostructured lipid carriers alleviate pruritus in scratching mouse model

The topical delivery route is proposed as an alternative or adjunctive approach to melanoma treatment, since the target site for melanoma treatment—the epidermal basal layer—is potentially accessible by this route. Microemulsion systems are effective delivery vehicles for enhanced, targeted skin delivery. This work investigated the effect of Rose Bengal (RB) and RB-loaded self-emulsifying microemulsions (SEMEs) on growth inhibition of human melanoma and normal skin cell monolayers, the safety of the excipients incorporated in SEMEs on human cell lines, and the in-vitro human skin penetration of RB delivered in SEMEs and control solution. Cellular toxicity was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the growth inhibitory mechanism of RB was investigated by flow cytometry using PI staining. Unloaded SEMEs caused reduced cellular toxicity compared to the surfactant excipient, Labrasol®. RB-loaded SEMEs increased cell growth inhibition compared to the RB aqueous solution. Flow cytometry revealed apoptotic cells after treatment with RB-loaded SEMEs, indicating that apoptosis may be one of the mechanisms of cell death. Preliminary results of multiphoton microscopy with fluorescence lifetime imaging (MPM-FLIM) analysis showed deeper penetration with greater skin concentrations of RB delivered from SEMEs compared to the RB aqueous solution. This study highlights the enhanced skin penetration and antimelanoma effects of RB loaded in a SEME system.

Cell-penetrating peptides (CPPs) consist of 5-30 amino acids with intracellular transduction abilities and diverse physicochemical properties, origins, and sequences. Although recent developments in bioinformatics have facilitated the prediction of CPP candidates with the potential for transduction into cells, the mechanisms by which CPPs penetrate cells and various tissues have not yet been elucidated at the molecular interaction level. Recently, the skin-penetrating ability of CPPs has gained wide attention and emerged as a simple and effective strategy for the delivery of macromolecules into the skin. Studies on the skin structure have suggested that the penetration potential of CPPs is based on the molecular interactions and characteristics of the lipid lamellar structure between corneocytes in the stratum corneum. This review provides a brief overview of the general properties, transduction mechanisms, applications, and safety issues of CPPs, focusing on CPPs with transdermal properties, that are currently being used to develop therapeutics and cosmetics.

C/EBP-homologous protein (CHOP) is a ubiquitously expressed stress-inducible transcription factor robustly induced by maladaptive endoplasmic reticulum (ER) stresses in a wide variety of cells. Here, we examined a novel function of Sigma 1 receptor (Sigmar1) in regulating CHOP expression under ER stress in cardiomyocytes. We also defined Sigmar1-dependent activation of the adaptive ER-stress pathway in regulating CHOP expression. We used adenovirus-mediated Sigmar1 overexpression as well as Sigmar1 knockdown by siRNA in neonatal rat ventricular cardiomyocytes (NRCs); to induce ER stress, cardiomyocytes were treated with tunicamycin. Sigmar1-siRNA knockdown significantly increased the expression of CHOP and significantly induced cellular toxicity by sustained activation of ER stress in cardiomyocytes. Sigmar1 overexpression decreased the expression of CHOP and significantly decreased cellular toxicity in cells. Using biochemical and immunocytochemical experiments, we also defined the specific ER-stress pathway associated with Sigmar1-dependent regulation of CHOP expression and cellular toxicity. We found that Sigmar1 overexpression significantly increased inositol requiring kinase 1α (IRE1α) phosphorylation and increased spliced X-box-binding proteins (XBP1s) expression as well as nuclear localization. In contrast, Sigmar1 knockdown significantly decreased IRE1α phosphorylation and decreased XBP1s expression as well as nuclear transport. Taken together, these results indicate that Sigmar1-dependent activation of IRE1α-XBP1s ER-stress response pathways are associated with inhibition of CHOP expression and suppression of cellular toxicity. Hence, Sigmar1 is an essential component of the adaptive ER-stress response pathways eliciting cellular protection in cardiomyocytes.

Cell-penetrating peptides (CPPs) have an ability of internalisation to inner cells through plasma membrane. The plasma membrane and lipid bilayer in experiments contain negatively charged lipids. HIV-1 Tat peptide, which is one of the CPPs, has many arginines with positive charge, and strongly interacts with negatively charged lipids. We investigate the difference between neutral lipids, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and negatively charged lipids, 1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (DOPG), by all-atom molecular dynamics simulations. We found that the speed of binding of Tat to lipid membrane for DOPC is more than 10 times faster than the speed for DOPG. The Tat peptides bind to the lipid membrane by attractive interaction between arginine in Tat and phosphates in lipids. Comparing the number of phosphates binding to arginine, DOPG gives a larger number than DOPC. The differences indicate the importance of negatively charged lipids for the investigation of the property of CPPs.

A number of cell-penetrating peptides (CPPs) have been reported, but their transduction efficiencies are too low to be used as intracellular carriers for therapeutic purposes. We conducted a comprehensive search to find novel CPPs using an in vitro virus (IVV) library, which presented random peptides consisting of 15 amino acids (diversity of the library was >10(12)). We found 9 kinds of novel CPPs with an intracellular translocation efficiency higher than that of the TAT peptide (YGRKKKRRQRRR). Interestingly, one of the novel CPPs, No. 14 (KLWMRWYSPTTRRYG), showed a dramatic improvement in translocation activity relative to the TAT peptide in CHO cells (>10-fold efficiency in 50 microM). As the intracellular translocation efficiency of No. 14 was increased by substitution Arg for Lys1 (14-1), we carried out alanine scanning on the basis of 14-1 to determine important amino acids for the intracellular translocation. The Ala substitution analysis showed that both Arg and Trp residues were important for the cell-penetrating activity and that their contribution was in the order Trp3<Arg12<Arg1<Arg5, Arg13<Trp6. Moreover, it was possible to substitute two Trp with other bulky amino acids such as Ile or Tyr. In this study, we showed that novel CPPs could be acquired by screening random peptides and modifying some amino acids could increase their cell-penetrating activity.

One of the recent hot topics in peptide-related chemical biology research is the potential of cell-penetrating peptides (CPPs). Owing to their ability to deliver exogenous molecules into cells easily and effectively, their flexible design that allows transporters to comprise various chemical structures and functions, and their potential in chemical and cell biology studies and clinical applications, CPPs have been attracting enormous interest among researchers in related fields. Consequently, publications on CPPs have increased significantly. Although there are many types of CPPs with different physicochemical properties and applications, arginine-rich CPPs, which include the human immunodeficiency virus type 1 (HIV-1) TAT peptide and oligoarginines, are among the most extensively employed and studied. Previous studies demonstrated the importance of the guanidino group in arginine, which confers flexibility in transporter design. Therefore, in addition to peptides, various transporters rich in guanidino groups, which do not necessarily share specific chemical and three-dimensional structures, have been developed. Typically, cell-penetrating transporters have 6-12 guanidino groups. Since the pKa of the guanidino group in arginine is approximately 12.5, these molecules are highly basic and hydrophilic. Our group is interested in why these cationic molecules can penetrate cells. Understanding their mechanism of action should lead to the rational design of intracellular delivery systems that have high efficacy. Additionally, novel cellular uptake mechanisms may be elucidated during the course of these studies. Therefore, our group is trying to understand the basic aspects underlying the ability of these peptides to penetrate cells. Regarding the delivery of biopharmaceuticals including proteins and nucleic acids, achieving efficient and effective delivery to target organs and cells is one of the biggest challenges. Furthermore, when the target sites of these drug molecules are within cells, effective cell penetration becomes another obstacle. Cells are surrounded by a membrane that separates the inside of the cell from its outside. This barrier function is critical for keeping cellular contents inside cells, and without this, cells cannot function. Therefore, understanding the mechanism of action of CPPs is necessary to overcome these obstacles and will allow us not only to improve CPP-mediated delivery but also to create other types of intracellular delivery systems. In this Account, we summarize the current knowledge on the mechanisms of internalization of arginine-rich CPPs, from the viewpoints of both direct cell-membrane penetration (i.e., physicochemical aspects) and endocytic uptake (i.e., physiological aspects), and discuss the implications of this knowledge. We also discussed loosening of lipid packing as a factor to promote direct cell-membrane penetration.

The skin functions as a formidable barrier, particularly the stratum corneum, effectively restricting the penetration of most substances, including therapeutic agents. To circumvent this barrier, skin penetration enhancers (SPEs) are frequently employed to transiently increase skin permeability, facilitating drug absorption without causing irritation or damage. Despite advancements in dermal formulation development, a deeper understanding of the fundamental science underpinning drug delivery via SPEs remains essential. This review delivers a critical update on conventional SPEs, exploring their mechanisms in promoting drug permeation across the skin. In addition to offering an overview of percutaneous drug delivery, we examine the prevailing theories on how SPEs enhance drug transport. Furthermore, we address the intricate interplay between SPEs, drugs and the skin, providing valuable insights into how the molecular properties and permeation behaviours of SPEs influence their efficacy. This comprehensive review aims to support the ongoing development of optimised drug delivery systems for dermal applications by elucidating the complexities and challenges involved in using SPEs effectively.

Protein therapeutics are emerging as essential technologies due to their functional and chemical properties. However, their application is currently limited to delivery by oral and injection methods-the former being inefficient and the latter invasive and potentially tissue damaging. Researchers are, therefore, exploring noninvasive delivery systems for proteins through the skin, including transdermal and topical delivery. The large molecular size of proteins presents a key challenge for skin penetration, hindering their ability to penetrate the dense skin lamellar structure. This review focuses on using nanoparticles as carriers to increase protein stability and enhance skin penetration. The use of noninvasive or minimally invasive enhancers for controlling and improving penetration depth is also examined. Furthermore, the physical properties of nanoparticles that affect delivery are evaluated, aiming to propose ways to advance transdermal and topical delivery methods in the future.