Size-dependence of the skin penetration of andrographolide nanosuspensions: In vitro release-ex vivo permeation correlation and visualization of the delivery pathway.

Particle size is a key parameter to determine the capacity of nanoparticles to overcome the skin barrier; however, such effect and the possible mechanism remain only partially understood for nanosuspensions. In this work, we examined the skin delivery performance of andrographolide nanosuspensions (AG-NS) ranging in diameter from 250 nm to 1000 nm and analyzed the role of particle size in influencing their ability of skin penetration. The AG-NS with particle sizes of about 250 nm (AG-NS250), 450 nm (AG-NS450), and 1000 nm (AG-NS1000) were successfully prepared by ultrasonic dispersion method and characterized by transmission electron microscopy. The drug release and penetration via the intact and barrier-removed skin were compared by the Franz cell method, and the related mechanisms were probed using laser scanning confocal microscopy (LSCM) via visualization of penetration routes and histopathological study via observation of structural change of the skin. Our finding revealed that drug retention in the skin or its sub-layers was increased with the reduction of particle size, and the drug permeability through the skin also exhibited an obvious dependence on the particle size from 250 nm to 1000 nm. The linear relationship between the in vitro drug release and ex vivo permeation through the intact skin was well established among different preparations and in each preparation, indicating the skin permeation of the drug was mainly determined by the release process. The LSCM indicated that all these nanosuspensions could deliver the drug into the intercellular lipid space, as well as block the hair follicle in the skin, where a similar size dependence was also observed. The histopathological investigation showed that the formulations could make the stratum corneum of the skin loose and swelling without severe irritation. In conclusion, the reduction of particle size of nanosuspension would facilitate topical drug retention mainly via the modulation of drug release.

Nonporous versus Mesoporous Bioinspired Polydopamine Nanoparticles for Skin Drug Delivery.

The use of polydopamine-based bioinspired nanomaterials has shed new light on advanced drug delivery arising from their efficient surface functionalization. More recently, the polydopamine self-assemblies formed in two different modalities, i.e., nonporous and mesoporous nanoparticles, have begun to attract attention due to their expedient and versatile properties. However, their possibility for use in dermal drug delivery for local therapy, as well as their interaction with the skin, has not yet been demonstrated. Our study aimed to compare and explore the feasibility of the self-assembled nonporous polydopamine nanoparticles (PDA) and mesoporous polydopamine nanoparticles (mPDA) for local skin drug delivery. The formation of the PDA and mPDA structures was confirmed by the UV-vis-NIR absorption spectrum, the Fourier transform infrared spectroscopy, and the nitrogen adsorption/desorption isotherms. Using retinoic acid (RA) as the model drug, their effects on drug loading, release, photostability, skin penetration, and radical scavenging were investigated. Laser scanning confocal microscopy (LSCM) and hematoxylin and eosin (H&E) were introduced to probe their delivery routes and possible interaction with the skin. The results indicated that both PDA and mPDA could reduce the photodegradation of RA, and mPDA showed significantly better radical scavenging activity and drug loading capacity. The ex vivo permeation study revealed that both PDA and mPDA significantly enhanced the delivery of RA into the deep skin layers by comparison with the RA solution, in which follicular and intercellular pathways existed, and alteration in the structure of stratum corneum was observed. In light of drug loading capacity, size controllability, physical stability, as well as radical scavenging activity, mPDA was more preferable due to the improvement of these factors. This work demonstrated the feasibility and promising application of PDA and mPDA nanoparticles for dermal drug delivery, and the comparative concept of these two types of biomaterials can provide implications for their use in other fields.

ZIF-8 integrated with polydopamine coating as a novel nano-platform for skin-specific drug delivery.

Metal-organic frameworks (MOFs) are highly promising as a novel class of drug delivery carriers; however, there are few reports about their application in nanoparticle-based formulations for dermal administration. In this work, we developed a novel kind of nanoparticular system based on zeolitic imidazolate framework-8 (ZIF-8) and polydopamine (PDA) modification for improving the dermal delivery of 5-fluorouracil (5-FU). The structures and properties of the prepared nanoparticles were characterized using a variety of analytical methods. Their ex vivo delivery performance in the skin was investigated using Franz cells, and the underlying mechanisms were studied via confocal laser scanning microscopy (CLSM) and hematoxylin-eosin (HE) experiments which were employed to probe the penetration pathway and the interaction between nanoparticles and the skin. The results revealed that both 5-FU@ZIF-8 and ZIF-8@5-FU@PDA had an enhancement effect on the deposition of 5-FU in the skin, and the surface coating of PDA could further reduce drug permeation across the skin, especially in the case of impaired skin, in comparison with the drug solution. The CLSM study using rhodamine 6G as the fluorescent probe to mimic 5-FU indicated that ZIF-8 and ZIF-8@PDA could deliver their payloads into the skin via two pathways, i.e., intercellular and follicular ones, and the follicular route was shown to be particularly important for ZIF-8@PDA, in which the drug and carrier were co-delivered into the skin as an intact particle. This study provides evidence for using ZIF-8 and PDA modification for skin-specific drug delivery and offers an effective avenue to develop novel nanoplatforms for dermal application to treat skin diseases.

Light-related activities of metal-based nanoparticles and their implications on dermatological treatment.

Metal-based nanoparticles (MNPs) represent an emerging class of materials that have attracted enormous attention in many fields. By comparison with other biomaterials, MNPs own unique optical properties which make them a potential alternative to conventional therapeutic agents in medical applications. Especially, owing to the easy access to the skin, the use of MNPs based on their optical properties has gained importance for the treatment of a variety of skin diseases. This review provides an insight into the different optical properties of MNPs, including photoprotection, photocatalysis, and photothermal, and highlights their implications in treating skin disorders, with a special emphasis on their use in infection control. Finally, a perspective on the safety concern of MNPs for dermatological use is discussed and analyzed. The information gathered and presented in this review will help the readers have a comprehensive understanding of utilizing the photo-triggered activity of MNPs for the treatment of skin diseases.

Probing Pharmaceutical Strategies to Promote the Skin Delivery of Asiatic Acid from Hydrogels: Enhancement Effects of Organic Amine Counterions, Chemical Enhancers, and Microneedle Pretreatment.

Asiatic acid (AA) is a pentacyclic triterpene isolated from Centella asiatica, holding great promise for treating a variety of skin disorders. However, the dermal application of AA is limited by its poor solubility and permeability. This study aimed to identify a hydrogel formulation for AA and improve its skin penetration by various penetration enhancement methods. Four kinds of hydrogel bases were selected to prepare the AA hydrogel, in which different organic amines and chemical enhancers were incorporated in combination with microneedle pretreatment. The results showed that AA had good release profiles in the presence of hyaluronic acid as the hydrogel base and organic amines as the counter-ions. Diethylamine and Span 80 could promote drug penetration into the skin, and pretreatment with microneedles could further increase the drug permeability. In conclusion, the optimized hyaluronic acid hydrogel has great potential for use in the topical delivery of AA, and its penetration via the skin can be further improved by different pharmaceutical approaches.

Characterization and Quantification of Acrolein-Induced Modifications in Hemoglobin by Mass Spectrometry─Effect of Cigarette Smoking.

Exposure to acrolein, the smallest α, ß-unsaturated aldehyde, in humans originates from cigarette smoking and other environmental sources, food cooking, and endogenous lipid peroxidation and metabolism. The protein modification caused by acrolein is associated with various diseases, including cancer, cardiovascular, and neurodegenerative diseases. In this study, acrolein-modified human hemoglobin was reduced by sodium borohydride. Thus, three types of modifications, that is, Schiff base, Michael addition, and formyl-dehydropiperidion adducts, were converted to the corresponding stable adducts, leading to mass increases of 40.0313, 58.0419, and 96.0575 Da, respectively. These stable acrolein-modified hemoglobin peptides were identified by nanoflow liquid chromatography coupled to a high-resolution nanoelectrospray ionization tandem mass spectrometry. Among the 26 different types and sites of modifications, 15 of them showed a dose-dependent increase with increasing concentrations of acrolein. To investigate the role of acrolein-induced modifications in smoking and oral cancer, the 15 dose-responsive acrolein-modified peptides, together with three ethylated peptides previously identified, were quantified in oral cancer patients, healthy smokers, and healthy nonsmokers. The results reveal that the relative extents of the Michael-type adduct at α-Lys-16, α-His-50, and ß-Lys-59 are significantly higher in smokers (oral cancer and healthy) than in nonsmokers. Areas under the receiver operating characteristic curve of these peptides range from 0.7500 to 0.9375, indicating the ability to discriminate smokers from nonsmokers. Additionally, these acrolein-modified peptides correlate with three ethylated peptides at the N-termini of α- and ß-globin, as well as ß-His-77, and with the number of cigarettes smoked per day. Therefore, measuring the reduced Michael adducts at α-Lys-16, α-His-50, and ß-Lys-59 of hemoglobin from one drop of blood by this sensitive and specific method may reflect the increase of acrolein exposure due to cigarette smoking.

Elucidating the particle size effect of andrographolide suspensions on their IVIVC performance in oral absorption.

The study aimed to explore the size effect on the in vitro-in vivo correlation (IVIVC) in the oral absorption of andrographolide nanosuspensions (Ag-NS). Ag-NS with controllable particle sizes were prepared by ultrasonic dispersion method, and the formulation and process parameters were optimized through single factor experiments using mean particle size, polydispersity index, and stability as evaluation indicators. The morphology of Ag-NS was observed by scanning electron microscopy (SEM), and the crystalline state of the nanosuspensions was characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The dissolution tests were carried out with the paddle method in two different mediums simulating the pH conditions in intestinal fluid (pH 6.8) and gastric fluid (pH 1.2), respectively. The pharmacokinetic behaviors were investigated in rats after oral administration, and a deconvolution approach was introduced to determine the correlation between in vitro dissolution and in vivo absorption (IVIVC). The formulation with the use of lecithin and PEG-800 as stabilizers showed its potential in the size-controllable preparation of Ag-NS. Via altering the ultrasonication amplitude and time, three Ag-NS suspensions with three particle sizes, i.e., Ag-NS 250 (249.8 ± 1.3 nm), Ag-NS 450 (485.2 ± 3.7 nm), Ag-NS 1000 (1015 ± 36.1 nm) were prepared. Their morphological and crystal characteristics were not changed during the size reduction process, but both of their in vitro dissolution and in vivo absorption were improved. Relatively better IVIVC performance was observed with the in vitro dissolution data at pH 6.8 (r > 0.9). With the reduction of particle size, the in vivo absorption fraction was more closed to the level of the in vitro dissolution. In conclusion, the decrease in particle size would improve the dissolution and absorption of Ag-NS, and also affect their IVIVC performance. The study would facilitate the design and quality control of Ag-NS in terms of particle size and dissolution specifications.

The role of internal and external stimuli in the rational design of skin-specific drug delivery systems.

The concept of skin-specific drug delivery with a spatio-temporal control has just recently received concerns in dermatology. Inspired by the progress in smart materials and their perspective application in medicine science, development of stimuli responsive drug delivery systems with skin-specificity has become possible, which has led to a new era in the localized treatment of skin diseases. This review highlights both the internal and external stimuli that have been employed in this field, with a focus on their implication on the rational design of pharmaceutical formulations, especially those nanoscale drug carriers that are able to provide release of payloads with a precise spatio-temporal control in response to specific stimuli. Also, the strategy of dual stimuli responsive drug delivery systems will be discussed for further improvement of the efficacy of skin drug delivery. The prominent examples of the established approaches are described as comprehensive and current as possible. The review is expected to provide some inspiration for utilizing different stimuli for realizing the site-specific and on-demand drug delivery to the skin.

Analysis of Oxidative and Advanced Oxidative Modifications in Hemoglobin of Oral Cancer Patients by Mass Spectrometry.

We are exposed to endogenous reactive oxygen species (ROS) produced during normal aerobic metabolism and by the innate immune systems. Excessive production of ROS is critically important in disease onset and progression. Post-translational oxidative modifications of hemoglobin have been used as a surrogate biomarker for monitoring the oxidative stress in vivo. In this study, the Fenton reaction was used as a model to produce ROS and react with human hemoglobin. After trypsin digestion, the types and sites of modifications were characterized by a nanoflow LC-nanoelectrospray ionization high-resolution mass spectrometer. Besides oxidation at certain sites of Met, His, and Tyr, conversion of histidine to aspartate and hydroxyaspartate was identified at four sites. Furthermore, advanced oxidation of histidine to hydroxyaspartate was identified at two sites. Elevated oxidative stress is tightly associated with oral cancer. The relative extent of modification at the identified sites was quantified relative to the native peptide present in the digest as the reference peptide in hemoglobin from 18 oral cancer patients and 15 healthy control subjects. The results revealed that the extents of oxidation at ß-His-77 and ß-Asp-99 of globin were significantly elevated in oral cancer patients compared to healthy subjects, while the extents of conversion of histidine residues at α-His-20, α-His-50, and ß-His-2 to aspartate were significantly decreased. Furthermore, the advanced oxidation of histidine to hydroxyaspartate at α-His-50 and ß-His-2 is also significantly higher in oral cancer patients than in healthy subjects (p < 0.05). To our knowledge, this advanced oxidation of histidine to hydroxyaspartate is a new post-translational protein modification, and it is found in human hemoglobin isolated from blood. This advanced oxidative modification in hemoglobin might be a potential biomarker to assess oxidative stress in oral cancer patients.