Impact of Iron-Oxide Containing Formulations Against Visible Light-Induced Skin Pigmentation in Skin of Color Individuals.

Visible light (400-700nm), which contributes to 45% of solar radiation, contributes to skin darkening and worsening of dyschromias, particularly in individuals with Fitzpatrick skin phototypes III and higher. Currently, sunscreens provide limited protection against that spectrum. Due to their capabilities in absorbing, scattering, and reflecting visible light, topical products containing pigments and/or metal oxides can provide additional photoprotection. In this study, the efficacy of two formulations containing iron oxide was evaluated in preventing visible light-induced pigmentation compared with a non-tinted mineral SPF 50+ sunscreen. Expert grading and colorimetry demonstrated that the iron-oxide containing formulations significantly protected against visible light-induced pigmentation compared to untreated skin or mineral SPF 50+ sunscreen in Fitzpatrick IV individuals. These results highlight that iron-oxide containing formulas in a foundation format have dual functions and can provide additional benefits in patients' daily routine by masking existing pigmentation and preventing the development of pigmentation triggered by sunlight exposure, extending protection beyond UV spectrum. J Drugs Dermatol. 2020;19(7): doi:10.36849/JDD.2020.5032 THIS ARTICLE HAD BEEN MADE AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER WITH ANY QUESTIONS.

Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide.

Controlled activation is a critical component in prodrug development. Here we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two 'click and release' systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of the approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix following the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biological and therapeutic effects in vitro and in vivo when compared to controls, which did not result in enrichment. This method is thus a platform for targeted drug delivery that is amenable to conjugation with a variety of molecules and is not limited to cell-surface delivery. Taken together, these two 'click and release' pairs clearly demonstrate the concept of enrichment-triggered drug release and the critical feasibility of treating clinically relevant diseases such as acute liver injury and cancer.

Organic CO Prodrugs Activated by Endogenous ROS.

CO prodrugs with triggered release mechanisms are highly desirable for targeted delivery. Herein described are organic CO prodrugs that are activated by ROS and thus can be used to selectively deliver CO to cells with elevated ROS levels. Such CO prodrugs can serve as powerful tools for targeted delivery to disease sites with elevated ROS levels and to explore the therapeutic applications of CO.

Toward Direct Protein S-Persulfidation: A Prodrug Approach That Directly Delivers Hydrogen Persulfide.

A general strategy of delivering hydrogen persulfide (H2S2) is described herein. Esterase- and phosphatase-sensitive H2S2 prodrugs with tunable release rates have been synthesized. Their utility is validated in examining protein S-persulfidation. With this unique approach of directly delivering H2S2, our findings reaffirmed that S-persulfidation leads to decreased activity of glyceraldehyde 3-phosphate dehydrogenase. This new approach complements available prodrugs/donors that directly deliver a single species, including hydrogen sulfide, perthiol, and COS, and will be very useful as part of the toolbox for delineating the mechanisms of sulfur signaling.

An esterase-activated click and release approach to metal-free CO-prodrugs.

One major challenge in the development of CO as a therapeutic agent is its controllable delivery in a pharmaceutically acceptable form. Herein, we describe for the first time a general chemical strategy to esterase-sensitive organic CO-prodrugs.

Organic CO Prodrugs: Structure-CO-Release Rate Relationship Studies.

Carbon monoxide (CO) is an endogenously produced gasotransmitter in mammals, and may have signaling roles in bacteria as well. It has many recognized therapeutic effects. A significant challenge in this field is the development of pharmaceutically acceptable forms of CO delivery with controllable and tunable release rates. Herein, the structure-release rate studies of the first class of organic CO prodrugs that release CO in aqueous solution at neutral pH is described.

Click and Release: SO2 Prodrugs with Tunable Release Rates.

Employing an intramolecular cycloaddition reaction, we have developed a series of SO2 prodrugs with tunable release rates with half-lives ranging from minutes to days.

Click and Fluoresce: A Bioorthogonally Activated Smart Probe for Wash-Free Fluorescent Labeling of Biomolecules.

Bioorthogonally activated smart probes greatly facilitate the selective labeling of biomolecules in living system. Herein, we described a novel type of smart probes with tunable reaction rates, high fluorescence turn-on ratio, and easy access. The practicality of such probes was demonstrated by selective labeling of lipid and hCAII in Hela cells.

Click and Release: A Chemical Strategy toward Developing Gasotransmitter Prodrugs by Using an Intramolecular Diels-Alder Reaction.

Prodrug strategies have been proven to be a very effective way of addressing delivery problems. Much of the chemistry in prodrug development relies on the ability to mask an appropriate functional group, which can be removed under appropriate conditions. However, developing organic prodrugs of gasotransmitters represent unique challenges. This is especially true with carbon monoxide, which does not have an easy "handle" for bioreversible derivatization. By taking advantage of an intramolecular Diels-Alder reaction, we have developed a prodrug strategy for preparations of organic CO prodrugs that are stable during synthesis and storage, and yet readily release CO with tunable release rates under near physiological conditions. The effectiveness of the CO prodrug system in delivering a sufficient quantity of CO for possible therapeutic applications has been studied using a cell culture anti-inflammatory assay and a colitis animal model. These studies fully demonstrate the proof of concept, and lay a strong foundation for further medicinal chemistry work in developing organic CO prodrugs.

Esterase-Sensitive Prodrugs with Tunable Release Rates and Direct Generation of Hydrogen Sulfide.

Prodrugs that release hydrogen sulfide upon esterase-mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H2 S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H2 S donors. Additionally, such prodrugs can easily be conjugated to another non-steroidal anti-inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H2 S prodrugs, the anti-inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS-induced TNF-α production in RAW 264.7 cells. This type of H2 S prodrugs shows great potential as both research tools and therapeutic agents.

Hydrogen sulfide prodrugs-a review.

Hydrogen sulfide (H2S) is recognized as one of three gasotransmitters together with nitric oxide (NO) and carbon monoxide (CO). As a signaling molecule, H2S plays an important role in physiology and shows great potential in pharmaceutical applications. Along this line, there is a need for the development of H2S prodrugs for various reasons. In this review, we summarize different H2S prodrugs, their chemical properties, and some of their potential therapeutic applications.

Selection of cholesterol esterase aptamers using a dual-partitioning approach.

Non-systematic evolution of ligands by exponential enrichment and other capillary-based methods have grown in popularity for selection of aptamers since they provide a fast and efficient partitioning method when compared to classical techniques. Despite promising developments in these techniques, a major obstacle needs to be overcome for capillary-based selections to be widely accepted. Due to the small injection volumes associated with CE, only a small proportion of the nucleic acid library can be partitioned at any one time. In this paper, we propose a new two-step method for the selection of aptamers which firstly incorporates a nitrocellulose membrane filter followed by CE. This technique allows for nonbinding sequences to be eliminated, reducing the library size before subsequent capillary-based partitioning, while still reducing the time taken for aptamers to be selected. We demonstrated this technique on the selection of aptamers for cholesterol esterase and the highest binding truncated aptamer CES 4T displayed a K(D) of 203 ± 14 nM. In addition, an increase in the number of sequences partitioned was estimated using spectrophotometry and capillary injection volumes. The results suggested that for successful selection a two-step approach is needed. This hybrid technique could be used to select aptamers that bind to targets both in solution and immobilized onto a stationary phase, allowing the aptamers to be used in different binding environments.

Post-synthesis DNA modifications using a trans-cyclooctene click handle.

Post-synthesis DNA modification is a very useful method for DNA functionalization. This is achieved by using a modified NTP, which has a handle for further modifications, replacing the corresponding natural NTP in polymerase-catalyzed DNA synthesis. Subsequently, the handle can be used for further functionalization after PCR, preferably through a very fast reaction. Herein we describe polymerase-mediated incorporation of trans-cyclooctene modified thymidine triphosphate (TCO-TTP). Subsequently, the trans-cyclooctene group was reacted with a tetrazine tethered to other functional groups through a very fast click reaction. The utility of this DNA functionalization method was demonstrated with the incorporation of a boronic acid group and a fluorophore. The same approach was also successfully used in modifying a known aptamer for fluorescent labelling applications.

A click-and-release approach to CO prodrugs.

Carbon monoxide belongs to the family of signaling molecules and has been shown to possess therapeutic effects. Similar to NO, safe delivery of CO is a key issue in developing CO-based therapeutics. Herein we report a "click and release" CO-prodrug approach, which allows the release of CO under physiological conditions without the need for light irradiation. The system releases CO in a triggered and controllable manner and possesses the potential of tunable release rates.

Highly sensitive and quantitative human thrombospondin-1 detection by an M55 aptasensor and clinical validation in patients with atherosclerotic disease.

Aptamer-based biosensors (aptasensor) are powerful tools for rapid and sensitive biomarker detection. In this study, we report a DNA aptamer probe evolved from cell-SELEX that can recognize thrombospondin-1 protein in human plasma samples. The KD value of the aptamer M55 binding to thrombospondin-1 was determined as 0.5 ± 0.2 µM with an R(2) of 0.9144. A horseradish peroxidase-linked short oligo was complementarily bound onto the 3' end of the aptamer sequence to facilitate the 'smart' design of an M55-aptasensor for quantifying thrombospondin-1 protein in plasma samples. The limit of detection was 6.96 fM. Thrombospondin-1 is a glycoprotein with multiple biological functions, including inflammation, platelet aggregation and endothelial cell apoptosis, and is involved in the pathology of atherosclerosis. In total, 118 plasma subjects were analyzed by using the aptasensor measurement with 1 µL sample volume and 5 min incubation time. The thrombospondin-1 concentrations in ST-Elevation Myocardial Infarction patients with severe atherosclerotic plaque burden were statistically significantly higher than in the healthy volunteers without atherosclerosis conditions, suggesting that thromboposnidn-1 is a potential plasma biomarker for atherosclerosis progression.

A two-step stimulus-response cell-SELEX method to generate a DNA aptamer to recognize inflamed human aortic endothelial cells as a potential in vivo molecular probe for atherosclerosis plaque detection.

Aptamers are single-stranded oligonucleotides that are capable of binding wide classes of targets with high affinity and specificity. Their unique three-dimensional structures present numerous possibilities for recognizing virtually any class of target molecules, making them a promising alternative to antibodies used as molecular probes in biomedical analysis and clinical diagnosis. In recent years, cell-systematic evolution of ligands by exponential enrichment (SELEX) has been used extensively to select aptamers for various cell targets. However, aptamers that have evolved from cell-SELEX to distinguish the "stimulus-response cell" have not previously been reported. Moreover, a number of cumbersome and time-consuming steps involved in conventional cell-SELEX reduce the efficiency and efficacy of the aptamer selection. Here, we report a "two-step" methodology of cell-SELEX that successfully selected DNA aptamers specifically against "inflamed" endothelial cells. This has been termed as stimulus-response cell-SELEX (SRC-SELEX). The SRC-SELEX enables the selection of aptamers to distinguish the cells activated by stimulus of healthy cells or cells isolated from diseased tissue. We report a promising aptamer, N55, selected by SRC-SELEX, which can bind specifically to inflamed endothelial cells both in cell culture and atherosclerotic plaque tissue. This aptamer probe was demonstrated as a potential molecular probe for magnetic resonance imaging to target inflamed endothelial cells and atherosclerotic plaque detection.

Selection of bovine catalase aptamers using non-SELEX.

In this research, we used the non-SELEX method to successfully select an aptamer that binds to the protein target (bovine catalase) with a K(D) value in the low micro molar range. The time window was determined for the target and aptamer library by optimizing the buffer conditions using 3 × Tris-glycine-potassium phosphate (TGK) buffer as the run buffer and 1× TGK as the selection buffer to give the biggest complex peak. Fractions were collected by multistep nonequilibrium capillary electrophoresis of equilibrium mixtures (NECEEM)-based partitioning for three rounds of selection. The fractions from each round were enriched using PCR and the progress of selection was monitored using bulk affinity analysis. Fraction 2 was determined to have the optimal bulk affinity (0.75 µM) and this enriched library was cloned and sequenced giving four aptamer sequences. These sequences were verified using affinity capillary electrophoresis (CAT 1 0.237 µM) and fluorescence intensity measurements (CAT 1 0.430 µM). The specificity of the aptamer was also determined by fluorescence intensity measurements. The results showed that the aptamer with the highest binding affinity showed at least a 100-fold decrease in affinity toward four other proteins (i.e. lysozyme, trypsinogen, chymotrypsinogen A, and myoglobin) tested and this confirmed that the aptamer exhibited a distinct specificity toward bovine catalase. This aptamer will be useful in biosensing, Western blot, and biomarker identification.