Search Results (29)

Skin photoageing remains a topic of considerable concern. Retinol (RT) and retinyl palmitate (RP) have shown preliminary therapeutic efficacy; nevertheless, the high irritation associated with RT and the relatively modest efficacy of RP have constrained their broader application. Consequently, this study explored the effects and biosafety of RT and RP in repairing UV-induced skin ageing through a series of in vitro cell experiments, in vitro hemolysis assays, UV-irradiated mouse models, and molecular simulation techniques. The findings revealed that the interaction between RT and RP achieved complementary and enhanced therapeutic outcomes. Specifically, this combination improved the biosafety profile of retinoid formulations, accelerated cell migration rates, and facilitated the activation of the peroxisome proliferator-activated receptor α (PPARα) pathway. Moreover, the action of RT and RP further mitigated epidermal hyperplasia, mast cell infiltration, and the expression levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumour necrosis factor-α (TNF-α), while stimulating the synthesis of type I collagen. Metabolomics and transcriptomics analyses indicated that RT and RP exerted complementary effects through metabolic pathways, significantly elevating the overall therapeutic efficacy. Network pharmacology and molecular docking studies unveiled that the structural similarity between RT and RP was one of the contributors to their enhancement. In conclusion, this study demonstrated that the combined application of RT and RP exhibited marked effects. Through their mutual action, they not only potentiated each other’s therapeutic effects but also achieved complementary and optimised therapeutic outcomes, thereby substantially enhancing the overall efficacy. Full article

The use of lipid nanocarriers as components of cosmetic formulations may provide an opportunity to fully exploit the beneficial properties of pentapeptide-18 and retinol while reducing the undesirable effects that occur during retinoid therapy. This study aimed to evaluate the effectiveness of semi-solid formulations enriched with retinol and oligopeptide-loaded lipid nanocarriers. Solid lipid nanoparticles were produced using a high-shear homogenization method. The work included physicochemical characterization of the cosmetic products, and evaluation of their stability as well as their efficacy. The resulting semi-solid preparations were determined to be stable regardless of their storage temperature. No effect of the presence of lipid nanoparticles on the shelf-life stability of the cosmetic products was observed. A temperature of 25 °C was considered the recommended storage temperature for the tested semi-solid formulations. Beneficial effects of the cosmetic products were proven (in vivo study on volunteers), i.e., a significant reduction in the level of sebum secretion (anti-acne therapy) and a decrease in the number of facial wrinkles (anti-aging therapy). In addition, the protective properties of the lipid nanoparticles themselves against the skin were confirmed, reducing the irritating effect of retinol that is usually the case with classic retinoid therapies. Full article

Cancer is a major public health problem that ranks as the second leading cause of death. Anti-cancer drug development presents with various hurdles faced throughout the process. Nanoparticle (NP) formulations have emerged as a promising strategy for enhancing drug delivery efficiency, improving stability, and reducing drug toxicity. Previous studies have shown that the adamantyl retinoid ST1926 displays potent anti-tumor activities in several types of tumors, particularly in colorectal cancer (CRC). However, phase I clinical trials in cancer patients using ST1926 are halted due to its low bioavailability. In this manuscript, we developed ST1926-NPs using flash nanoprecipitation with polystyrene-b-poly (ethyleneoxide) as an amphiphilic stabilizer and cholesterol as a co-stabilizer. Dynamic light scattering revealed that the resulting ST1926-NPs Contin diameter was 97 nm, with a polydispersity index of 0.206. Using cell viability, cell cycle analysis, and cell death assays, we showed that ST1926-NP exhibited potent anti-tumor activities in human CRC HCT116 cells. In a CRC xenograft model, mice treated with ST1926-NP exhibited significantly lowered tumor volumes compared to controls at low drug concentrations and enhanced the delivery of ST1926 to the tumors. These findings highlight the potential of ST1926-NPs in attenuating CRC tumor growth, facilitating its further development in clinical settings. Full article

The development of numerous drugs is often arrested at clinical testing stages, due to their unfavorable biopharmaceutical characteristics. It is the case of fenretinide (4-HPR), a second-generation retinoid, that demonstrated promising in vitro cytotoxic activity against several cancer cell lines. Unfortunately, response rates in early clinical trials with 4-HPR did not confirm the in vitro findings, mainly due to the low bioavailability of the oral capsular formulation that was initially developed. Capsular 4-HPR provided variable and insufficient drug plasma levels attributable to the high hepatic first-pass effect and poor drug water solubility. To improve 4-HPR bioavailability, several approaches have been put forward and tested in preclinical and early-phase clinical trials, demonstrating generally improved plasma levels and minimal systemic toxicities, but also modest antitumor efficacy. The challenge is thus currently still far from being met. To redirect the diminished interest of pharmaceutical companies toward 4-HPR and promote its further clinical development, this manuscript reviewed the attempts made so far by researchers to enhance 4-HPR bioavailability. A comparison of the available data was performed, and future directions were proposed. Full article

Microneedling, also known as percutaneous collagen induction, using microneedling devices and fabricated microneedle patches, has been widely employed in cosmetic applications for acne scar treatment, skin care, hair loss, melasma, skin rejuvenation, and skin cancer. The micro-channels formed by microneedling through the stratum corneum facilitate the delivery of cosmetic agents and stimulate collagen and elastin production by inducing the wound-healing cascade, keeping the skin shiny and wrinkle-free. Several cosmetic agents, such as ascorbic acid, hyaluronic acid, retinoids, niacinamide, and peptides, have been delivered by microneedling. This review aims to highlight the use of microneedling devices and fabricated microneedle patches in facilitating the delivery of cosmetic agents through the skin layers. Moreover, the differences between the microneedling devices, commonly used alone or in combinational treatments with topical formulations, are explored. Furthermore, the safety of microneedling in terms of skin irritation, pain sensation, skin or systemic infection, and chemical and biological materials used in the fabrication of microneedles is discussed. Full article

Physiology disorders of the liver, as it is an important tissue in lipid metabolism, can cause fatty liver disease. The mechanism might be regulated by 17 circadian clock genes and 18 fat metabolism genes, together with a high-fat diet (HFD). Due to their rich nutritional and medicinal value, Chinese soft-shelled turtles (Trionyx sinensis) are very popular among the Chinese people. In the study, we aimed to investigate the influence of an HFD on the daily expression of both the core clock genes and the lipid metabolism genes in the liver tissue of the turtles. The two diets were formulated with 7.98% lipid (the CON group) and 13.86% lipid (the HFD group) to feed 180 juvenile turtles, which were randomly divided into two groups with three replicates per group and 30 turtles in each replicate for six weeks, and the diet experiment was administrated with a photophase regimen of a 24 h light/dark (12L:12D) cycle. At the end of the experiment, the liver tissue samples were collected from nine turtles per group every 3 h (zeitgeber time: ZT 0, 3, 6, 9, 12, 15, 18, 21 and 24) for 24 h to investigate the daily expression and correlation analysis of these genes. The results showed that 11 core clock genes [i.e., circadian locomotor output cycles kaput (Clock), brain and muscle arnt-like protein 1 and 2 (Bmal1/2), timeless (Tim), cryptochrome 1 (Cry2), period2 (Per2), nuclear factor IL-3 gene (Nfil3), nuclear receptor subfamily 1, treatment D, member 1 and 2 (Nr1d1/2) and retinoic acid related orphan receptor α/β/γ β and γ (Rorβ/γ)] exhibited circadian oscillation, but 6 genes did not, including neuronal PAS domain protein 2 (Npas2), Per1, Cry1, basic helix-loop-helix family, member E40 (Bhlhe40), Rorα and D-binding protein (Dbp), and 16 lipid metabolism genes including fatty acid synthase (Fas), diacylglycerol acyltransferase 1 (Dgat1), 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), Low-density lipoprotein receptor-related protein 1-like (Ldlr1), Lipin 1 (Lipin1), Carnitine palmitoyltransferase 1A (Cpt1a), Peroxisome proliferator activation receptor α, β and γ (Pparα/β/γ), Sirtuin 1 (Sirt1), Apoa (Apoa1), Apolipoprotein B (Apob), Pyruvate Dehydrogenase kinase 4 (Pdk4), Acyl-CoA synthase long-chain1 (Acsl1), Liver X receptors α (Lxrα) and Retinoid X receptor, α (Rxra) also demonstrated circadian oscillations, but 2 genes did not, Scd and Acaca, in the liver tissues of the CON group. However, in the HFD group, the circadian rhythms’ expressional patterns were disrupted for the eight core clock genes, Clock, Cry2, Per2, Nfil3, Nr1d1/2 and Rorβ/γ, and the peak expression of Bmal1/2 and Tim showed delayed or advanced phases. Furthermore, four genes (Cry1, Per1, Dbp and Rorα) displayed no diurnal rhythm in the CON group; instead, significant circadian rhythms appeared in the HFD group. Meanwhile, the HFD disrupted the circadian rhythm expressions of seven fat metabolism genes (Fas, Cpt1a, Sirt1, Apoa1, Apob, Pdk4 and Acsl1). Meanwhile, the other nine genes in the HFD group also showed advanced or delayed expression peaks compared to the CON group. Most importantly of all, there were remarkably positive or negative correlations between the core clock genes and the lipid metabolism genes, and their correlation relationships were altered by the HFD. To sum up, circadian rhythm alterations of the core clock genes and the lipid metabolism genes were induced by the high-fat diet (HFD) in the liver tissues of T. sinensis. This result provides experimental and theoretical data for the mass breeding and production of T. sinensis in our country. Full article

Retinoid-based drugs, while effective, are associated with systemic toxicity. Topical alternatives offer a safer option, and tazarotene, a third-generation synthetic retinoid, holds promise. This study investigates tazarotene’s transdermal delivery potential, focusing on its application for joint-related conditions. The aim of this study was to investigate the suitability of tazarotene as a candidate for transdermal delivery into joints. In vitro permeation studies, using porcine skin, assessed tazarotene’s transdermal drug delivery from solution and gel formulations. A tape-stripping analysis determined stratum corneum retention and a pilot study using porcine joints assessed tazarotene’s ability to reach articular cartilage. Ultra Performance Liquid Chromatography coupled with a mass detector method was used to quantify tazarotene and tazarotenic acid permeation. The results validate that tazarotene can permeate porcine skin and accumulate in articular cartilage in detectable amounts. The detection of tazarotene and tazarotenic acid in both the in vitro permeation studies and the pilot study on porcine joints validate the drug’s potential therapeutic use for hand osteoarthritis. This study lays the groundwork for future research, contributing insights into tazarotene’s potential for transdermal drug delivery and guiding further exploration in topical retinoid applications. Full article

Topical retinoid treatment is considered a standard therapeutic approach for chrono and photo skin aging. Retinol (vitamin A) is the precursor of endogenous retinoids. A prospective, 12-week, randomized, parallel-group trial comparing the combination of vitamins’ oral supplementation (one capsule daily, 50.000 UI vitamin A and 50 mg vitamin E) and a 0.02% retinoic acid topical gel formulation (RG) applied in the evening (Group B) in comparison with the topical RG treatment alone (Group A) was conducted. A total of 60 subjects (men and women, aged >50 years, mean age 60 ± 8 years) with moderate-severe facial skin aging (Glogau score > 2) were enrolled after their written informed consent. Thirty participants were randomly assigned to Group A and 30 to Group B. The primary endpoint was the clinical evaluation of a Skin Aging Global Score (SAGS), at baseline, and after 6 and 12 weeks. A VISIA^® (Canfield Scientific, Parsippany, NJ, USA)face sculptor analysis was performed in a subgroup of 20 subjects. Skin tolerability was evaluated in both groups at weeks 6 and 12. In comparison with the baseline, SAGS scores in both groups were reduced by 13% (Group A) and by 14% (Group B) after 6 weeks and by 22% (Group A) and by 27% (Group B) at week 12. At the end of the study, SAGS score absolute reduction in Group B was significantly greater (p < 0.01) in comparison with the absolute reduction in Group A. Both treatment regimens were well tolerated. The combination of medium-high doses of oral retinol supplementation (Vitamin A) and topical retinoic acid gel showed superior efficacy in terms of clinical improvement in comparison with the topical treatment alone in subjects with moderate/severe skin aging. Full article

Carotenoids are natural products regulated by the food sector, currently used as feed dyes and as antioxidants in dietary supplements and composing functional foods for human consumption. Of the nearly one thousand carotenoids described to date, only retinoids, derived from beta carotene, have the status of a drug and are regulated by the pharmaceutical sector. In this review, we address a novel field: the transformation of xanthophylls, particularly the highly marketed astaxanthin and the practically unknown bacterioruberin, in therapeutic agents by altering their pharmacokinetics, biodistribution, and pharmacodynamics through their formulation as nanomedicines. The antioxidant activity of xanthophylls is mediated by routes different from those of the classical oral anti-inflammatory drugs such as corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs): remarkably, xanthophylls lack therapeutic activity but also lack toxicity. Formulated as nanomedicines, xanthophylls gain therapeutic activity by mechanisms other than increased bioavailability. Loaded into ad hoc tailored nanoparticles to protect their structure throughout storage and during gastrointestinal transit or skin penetration, xanthophylls can be targeted and delivered to selected inflamed cell groups, achieving a massive intracellular concentration after endocytosis of small doses of formulation. Most first reports showing the activities of oral and topical anti-inflammatory xanthophyll-based nanomedicines against chronic diseases such as inflammatory bowel disease, psoriasis, atopic dermatitis, and dry eye disease emerged between 2020 and 2023. Here we discuss in detail their preclinical performance, mostly targeted vesicular and polymeric nanoparticles, on cellular models and in vivo. The results, although preliminary, are auspicious enough to speculate upon their potential use for oral or topical administration in the treatment of chronic inflammatory diseases. Full article

Chronic obstructive pulmonary disease (COPD) results in obstructive ventilatory impairment caused by emphysema, and current treatment is limited to symptomatic therapy or lung transplantation. Therefore, the development of new treatments to repair alveolar destruction is especially urgent. Our previous study revealed that 1.0 mg/kg of synthetic retinoid Am80 had a repair effect on collapsed alveoli in a mouse model of elastase-induced emphysema. From these results, however, the clinical dose calculated in accordance with FDA guidance is estimated to be 5.0 mg/60 kg, and it is desirable to further reduce the dose to allow the formulation of a powder inhaler for clinical application. To efficiently deliver Am80 to the retinoic acid receptor in the cell nucleus, which is the site of action, we focused on SS-cleavable proton-activated lipid-like material O-Phentyl-P4C2COATSOME^®SS-OP, hereinafter referred to as “SS-OP”). In this study, we investigated the cellular uptake and intracellular drug delivery process of Am80-encapsulated SS-OP nanoparticles to elucidate the mechanism of Am80 by nanoparticulation. Am80-encapsulated SS-OP nanoparticles were taken up into the cells via ApoE, and then Am80 was efficiently delivered into the nucleus via RARα. These results indicated the usefulness of SS-OP nanoparticles as drug delivery system carriers of Am80 for COPD treatment. Full article

Neuroblastoma (NB) is a severe form of tumor occurring mainly in young children and originating from nerve cells found in the abdomen or next to the spine. NB needs more effective and safer treatments, as the chance of survival against the aggressive form of this disease are very small. Moreover, when current treatments are successful, they are often responsible for unpleasant health problems which compromise the future and life of surviving children. As reported, cationic macromolecules have previously been found to be active against bacteria as membrane disruptors by interacting with the negative constituents of the surface of cancer cells, analogously inducing depolarization and permeabilization, provoking lethal damage to the cytoplasmic membrane, and cause loss of cytoplasmic content and consequently, cell death. Here, aiming to develop new curative options for counteracting NB cells, pyrazole-loaded cationic nanoparticles (NPs) (BBB4-G4K and CB1H-P7 NPs), recently reported as antibacterial agents, were assayed against IMR 32 and SHSY 5Y NB cell lines. Particularly, while BBB4-G4K NPs demonstrated low cytotoxicity against both NB cell lines, CB1H-P7 NPs were remarkably cytotoxic against both IMR 32 and SHSY 5Y cells (IC₅₀ = 0.43–0.54 µM), causing both early-stage (66–85%) and late-stage apoptosis (52–65%). Interestingly, in the nano-formulation of CB1H using P7 NPs, the anticancer effects of CB1H and P7 were increased by 54–57 and 2.5–4-times, respectively against IMR 32 cells, and by 53–61 and 1.3–2 times against SHSY 5Y cells. Additionally, based on the IC₅₀ values, CB1H-P7 was also 1-12-fold more potent than fenretinide, an experimental retinoid derivative in a phase III clinical trial, with remarkable antineoplastic and chemopreventive properties. Collectively, due to these results and their good selectivity for cancer cells (selectivity indices = 2.8–3.3), CB1H-P7 NPs represent an excellent template material for developing new treatment options against NB. Full article

Fenretinide (4-HPR), a retinoid derivative, has shown high antitumor activity, a low toxicological profile, and no induction of resistance. Despite these favorable features, the variability in oral absorption due to its low solubility combined with the high hepatic first pass effect strongly reduce clinical outcomes. To overcome the solubility and dissolution challenges of poorly water-soluble 4-HPR, we prepared a solid dispersion of the drug (4-HPR-P5) using a hydrophilic copolymer (P5) previously synthesized by our team as the solubilizing agent. The molecularly dispersed drug was obtained by antisolvent co-precipitation, an easy and up-scalable technique. A higher drug apparent solubility (1134-fold increase) and a markedly faster dissolution were obtained. In water, the colloidal dispersion showed a mean hydrodynamic diameter of 249 nm and positive zeta potential (+41.3 mV), confirming the suitability of the formulation for intravenous administration. The solid nanoparticles were also characterized by a high drug payload (37%), as was also evidenced by a chemometric-assisted Fourier transform infrared spectroscopy (FTIR) investigation. The 4-HPR-P5 exhibited antiproliferative activity, with IC50 values of 1.25 and 1.93 µM on IMR-32 and SH-SY5Y neuroblastoma cells, respectively. Our data confirmed that the 4-HPR-P5 formulation developed herein was able to increase drug apparent aqueous solubility and provide an extended release over time, thus suggesting that it represents an efficient approach to improve 4-HPR bioavailability. Full article

Retinoids are considered the mainstay treatment for moderate to severe acne. Adapalene, a third-generation retinoid, has physiochemical properties which hinder the effective delivery of the drug to the skin. Therefore, the current study aimed to develop and evaluate adapalene liposomal loaded gel (ADA-LP gel) for the effective management of acne to improve tolerability and delivery to targeted sites as compared to the conventional dosage form of the drug. A novel spontaneous phase transition method (SPT) was used to formulate liposomes. Liposomal formulation (ADA-LP) was prepared and optimized based on particle size, zeta potential, and PDI. Optimized formulation was further characterized by different techniques and loaded into Carbopol gel. In vitro drug release, ex vivo permeation, and in vivo studies were performed using the prepared adapalene-loaded liposomal-based gel. The in vivo study was done employing the testosterone-induced acne model in mice. The optimized formulation had a size of 181 nm, PDI 0.145, and a zeta potential of −35 mV, indicating that the formulation was stable. Encapsulation efficiency was 89.69 ± 0.5%. ADA-LPs were loaded into the gel. Prepared ADA-LP showed a 79 ± 0.02% release of drug in a sustained manner, within 24 h. The ex vivo permeability study showed a total of 43 ± 0.06 µg/cm² of drug able to permeate through the skin within 24 h. Moreover, only 28.27 ± 0.04% was retained on the epidermis. The developed ADA-LP gel showed significant improvement in the acne lesions in mice with no visible scars and inflammation on the skin. Therefore, ADA-LP-based gel could be a promising carrier system for the safe and effective delivery of Adapalene. Full article

Dermatological conditions, such as acne, photoaging, psoriasis, and wounds, have been treated topically with all-trans retinoic acid (ATRA) for many years owing to its anti-inflammatory activity, comedolytic effect, and ability to increase collagen production. However, common side effects of ATRA known as the retinoid reaction can occur. These side effects are countered by ATRA encapsulation in solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLCs), and liposomes. Liposomes used to encapsulate ATRA include niosomes, ethosomes, and transfersomes. Side effects involving inflammatory reactions, such as irritation, redness, and erythema, were diminished using these approaches. The use of such carriers enhanced the efficacy of ATRA by enhancing its permeation into skin. These formulations have been compared in terms of improving the activity of ATRA and the ability to relieve the side effects. Further research into different delivery systems for ATRA using various formulations will improve the future of topical ATRA delivery. Full article

Ethyl cellulose (EC)-based microparticles, with and without the incorporation of polyethylene glycol (PEG) as a second encapsulating agent, were prepared using the spray-drying process for the encapsulation of retinoic acid (RA). The production of a suitable controlled delivery system for this retinoid will promote its antitumor efficiency against acute promyelocytic leukemia (APL) due to the possibility of increasing the bioavailability of RA. Product yield ranged from 12 to 28% in all the microparticle formulations, including unloaded microparticles and RA-loaded microparticles. Microparticles with a mean diameter between 0.090 ± 0.002 and 0.54 ± 0.02 µm (number size distribution) and with an irregular form and rough surface were obtained. Furthermore, regarding RA-loaded microparticles, both polymer-based formulations exhibited an encapsulation efficiency of around 100%. A rapid and complete RA release was reached in 40 min from EC− and EC + PEG-based microparticles. Full article