Extracellular Vesicles and Their Correlation with Inflammatory Factors in an Experimental Model of Steatotic Liver Disease Associated with Metabolic Dysfunction.

Background/Aims: Extracellular vesicles (EVs) are promising as a biomarker of metabolic dysfunction associated steatotic liver disease (MASLD). The objective is to study EVs and their involvement in MASLD concerning the disease's pathogenesis and progression characteristics. Methods: Male adult Sprague Dawley rats were randomly assigned into two experimental models of MASLD: MASLD-16 and MASLD-28, animals received a choline-deficient high-fat diet (CHFD) and Control-16 and Control-28, animals received a standard diet (SD) for 16 and 28 weeks, respectively. Biological samples from these animal models were used, as well as previously registered variables. EVs from hepatic tissue were characterized using confocal microscopy. EVs were isolated through differential ultracentrifugation from serum and characterized using NanoSight. The data from the EVs were correlated with biochemical, molecular, and histopathological parameters. Results: Liver EVs were identified through the flotillin-1 protein. EVs were isolated from the serum of all groups. There was a decrease of EVs concentration in MASLD-28 in comparison with Control-28 (P < 0.001) and a significant increase in EVs concentration in Control-28 compared with Control-16 (P < 0.001). There was a strong correlation between serum EVs concentration with hepatic gene expression of interleukin (Il)6 (r2 = 0.685, P < 0.05), Il1b (r2 = 0.697, P < 0.05) and tumor necrosis factor-alpha (Tnfa; r2 = 0.636, P < 0.05) in MASLD-16. Moreover, there was a strong correlation between serum EVs size and Il10 in MASLD-28 (r2 = 0.762, P < 0.05). Conclusion: The concentration and size of EVs correlated with inflammatory markers, suggesting their involvement in the systemic circulation, cellular communication, and development and progression of MASLD, demonstrating that EVs have the potential to serve as noninvasive biomarkers for MASLD diagnosis and prognosis.

Is imiquimod a promising drug to treat oral mucosa diseases? A scoping review and new perspectives.

Imiquimod (IMQ) is a chemotherapeutic and immunostimulant drug that is applied topically, demonstrating antitumor and antiviral activities. The objective of this review was to compile data on the off-label use of IMQ in oral mucosal diseases. IMQ has exhibited effectiveness in the treatment of various oral mucosal conditions, including oral carcinogenic lesions, neoplasms, HPV-related lesions and autoimmune disorders. Although IMQ holds promise as a potential strategy for addressing oral mucosal lesions, it is important to note that significant side effects have been frequently reported. Nonetheless, it is crucial to develop and test new technological systems, such as the combination of nanotechnology with innovative drug delivery platforms. These advancements aim to minimize side effects and prolong the drug's contact time with the mucosa, preventing its removal by salivary flow.

Effect of nanocapsules containing docosahexaenoic acid in mice with chronic inflammation.

BACKGROUND: Omega 3 fatty acids, such as docosahexaenoic acid (DHA) have been widely consumed as supplements to control chronic inflammation. Nanocapsules containing DHA (MLNC-DHA-a1) were developed and showed excellent stability. Thus, our objective was to evaluate the effect of MLNC-DHA-a1 nanocapsules on biomarkers of chronic inflammation. METHODS: Cells viability was determined by flow cytometry. The uptake of MLNC-DHA-a1 nanocapsules by macrophages and their polarization were determined. In vivo, LDLr(-,-) mice were fed a Western diet to promote chronic inflammation and were treated with MLNC-DHA-a1 nanocapsules, intravenously injected via the caudal vein once a week for 8 weeks. RESULTS: MLNC-DHA-a1 nanocapsules decreased the concentration of TNFα (p = 0.02) in RAW 264.7 cells compared to the non-treated group (NT), with no changes in IL-10 (p = 0.29). The nanocapsules also exhibited an increase in the M2 (F4/80+ CD206) phenotype (p < 0.01) in BMDM cells. In vivo, no difference in body weight was observed among the groups, suggesting that the intervention was well tolerated. However, compared to the CONT group, MLNC-DHA-a1 nanocapsules led to an increase in IL-6 (90.45 ×13.31 pg/mL), IL-1ß (2.76 ×1.34 pg/mL) and IL-10 (149.88 ×2.51 pg/mL) levels in plasma. CONCLUSION: MLNC-DHA-a1 nanocapsules showed the potential to promote in vitro macrophage polarization and were well-tolerated in vivo. However, they also increased systemic pro-inflammatory cytokines. Therefore, considering that this immune response presents a limitation for clinical trials, further studies are needed to identify the specific compound in MLNC-DHA-a1 that triggered the immune response. Addressing this issue is essential, as MLNC-DHA-a1 tissue target nanocapsules could contribute to reducing chronic inflammation.

The Anti-Arthritic Activity of Diclofenac Lipid-Core Nanocapsules: Stereological Analysis Showing More Protection of Deep Joint Components.

Diclofenac is the most prescribed nonsteroidal anti-inflammatory drug worldwide and is used to relieve pain and inflammation in inflammatory arthritis. Diclofenac is associated with serious adverse effects, even in regular-dose regimens. Drug delivery systems can overcome this issue by reducing adverse effects and optimizing their efficacy. This study evaluated the activity of lipid-core nanocapsules loaded with diclofenac (DIC-LNCs) in an experimental model of adjuvant-induced arthritis. The diclofenac nanoformulation was obtained via self-assembly. A stereological analysis approach was applied for the morphological quantification of the volume, density, and cellular profile count of the metatarsophalangeal joints of rats. Proinflammatory cytokines and biochemical profiles were also obtained. Our results showed that the diclofenac nanocapsule DIC-LNCs were able to reduce arthritis compared with the control group and the DIC group. DIC-LNCs efficiently reduced proinflammatory cytokines, C-reactive protein, and xanthine oxidase levels. Additionally, DIC-LNCs reduced the loss of synoviocytes and chondrocytes compared with the DIC (p < 0.05) and control groups (p < 0.05). These data suggest that DIC-LNCs have anti-arthritic activity and preserve joint components, making them promising for clinical use.

Characterization and in vivo toxicological evaluation of multi-walled carbon nanotubes: a low-dose repeated intratracheal administration study.

This study characterized and investigated the toxicity of two multi-walled carbon nanotubes (MWCNT) NM-401 and NM-403 at 60 and 180 µg after four repeated intratracheal instillations; follow-up times were 3, 7, 30, and 90 days after the last instillation. NM-401 was needle-like, long, and thick, while NM-403 was entangled, short, and thin. Both MWCNT types induced transient pulmonary and systemic alterations in renal function and oxidative lipid damage markers in recent times. Animals showed general toxicity in the immediate times after exposures, in addition to increased pulmonary LDH release at day 3. In further times, decreased liver and kidney relative weights were noted at higher MWCNT doses. Lung histological damages included pulmonary fibrosis, for both MWCNT types, similarly to asbestos; single liver and kidney histological alterations were present. Repeated instillations led to persistent pulmonary damage at low doses, and possibly the extrapulmonary effects may be associated with the consecutive exposures.

Development of Annexin A1-surface-functionalized metal-complex multi-wall lipid core nanocapsules and effectiveness on experimental colitis.

Annexin A1 (AnxA1), a 37KDa protein, is secreted by inflammatory and epithelial cells and displays anti-inflammatory and wound healing activities in intestinal bowel diseases. Herein, we aimed to functionalize recombinant AnxA1 (AnxA1) on multi-wall lipid core nanocapsules (MLNC) and investigate its effectiveness on experimental colitis. MLNC were prepared by covering lipid core nanocapsules (LNC) with chitosan, which coordinates metals to specific protein chemisorption sites. Therefore, MLNC were linked to Zn2+ and AnxA1 was added to form MLNC-AnxA1. LNC, MLNC and MLNC-AnxA1 presented average size of 129, 152 and 163 nm, respectively, and similar polydispersity indexes (0.xx); incorporation of chitosan inverted the negative potential zeta; the coordination efficiency of AnxA1 was 92.22 %, and transmission electron microscope photomicrograph showed MLNC-AnxA1 had a spherical shape. The effectiveness of MLNC-AnxA1 was measured in Dextran Sulfate Sodium (DSS)-induced colitis in male C57BL/6 mice. DSS (2 % solution) was administered from days 1-6; saline, LNC, MLNC, MLNC-AnxA1 or AnxA1 were administered, once a day, by oral or intraperitoneal (i.p.) routes, from days 6-9. Clinical parameters of the disease were measured from day 0-10 and gut tissues were collected for histopathology, immunohistochemistry and flow cytometry analyses. Only i.p. treatment with MLNC-AnxA1 reduced weight loss, diarrhea and disease activity index, and prevented loss of colonic structure integrity; induced the switch of macrophages into M2 phenotype in the lamina propria; recovered the colonic histoarchitecture by decreasing dysplasia of crypts, inflammation and ulcerations; restored the expression of claudin-1 Zonna-occludens-1 tight junctions in the inflamed gut; and induced stem cell proliferation in intestinal crypts. Associated, data highlight the functionalization of MLNC with AnxA1 as a tool to improve the local actions of such protein in the inflamed gut by inducing resolution of inflammation and tissue repair.

Evaluation of an Efficient and Skin-Adherent Semisolid Sunscreen Nanoformulation.

INTRODUCTION: Sunscreens are substances applied on the skin surface to protect the skin from the harmful effects of UV light. Nanoparticles can increase the retention time of the sunscreen on the skin surface and its efficacy, by acting as physical barriers. The present investigation aimed to evaluate the influence of the chitosan coating of benzophenone-3-loaded lipid-core nanocapsules (CH-LCN) on the skin adhesion and photoprotective effect of the sunscreen. METHODS: CH-LNC were obtained by the interfacial deposition of preformed polymer. A suitable semisolid formulation was obtained by using hydroxyethyl cellulose as the gel-forming polymer. Skin adhesion experiments were performed in vitro by applying the formulation on porcine skin and keeping it under water at 32 °C for up to 60 min. Photoprotective effect was analyzed in vitro by the capacity of the formulations to protect a photo unstable substance (resveratrol) from degradation under UV light. RESULTS: CH-LNC presented size of around 150 nm, with low polydispersity, positive zeta potential, due to chitosan, and benzophenone-3 encapsulation efficiency of close to 100% (3 mg/mL). The proposed gel presented suitable consistence and pH for skin application and benzophenone-3 concentration of around 3 mg/g. Although coated and uncoated lipid-core nanocapsules increased benzophenone-3 skin adhesion after 10 min of water immersion, only the nanoparticles coated with chitosan were able to do so after 60 min. The chitosan coating of the nanocapsules increased the photoprotection of the sunscreen under UVA and UVB light after 60 min of exposure, probably due to the film-forming properties of chitosan. CONCLUSION: The chitosan coating of CH-LCN increased the skin adhesion and the photoprotective effect of the sunscreen.

Oral delivery of ambrisentan-loaded lipid-core nanocapsules as a novel approach for the treatment of pulmonary arterial hypertension.

Ambrisentan (AMB) is an orphan drug approved for oral administration that has been developed for the treatment of pulmonary arterial hypertension (PAH), a chronic and progressive pathophysiological state that might result in death if left untreated. Lipid-core nanocapsules (LNCs) are versatile nanoformulations capable of loading lipophilic drugs for topical, vaginal, oral, intravenous, pulmonary, and nasal administration. Our hypothesis was to load AMB into these nanocapsules (LNCamb) and test their effect on slowing or reducing the progression of monocrotaline-induced PAH in a rat model, upon oral administration. LNCamb displayed a unimodal distribution of diameters (around 200 nm), negative zeta potential (-11.5 mV), high encapsulation efficiency (78%), spherical shape, and sustained drug release (50-60% in 24 h). The in vivo pharmacodynamic effect of the LNCamb group was evaluated by observing the echocardiography, hemodynamic, morphometric, and histological data, which showed a significant decrease in PAH in this group, as compared to the control group (AMBsolution). LNCamb showed the benefit of reversing systolic dysfunction and preventing vascular remodeling with greater efficacy than that observed in the control group. The originality and contribution of our work reveal the promising value of this nanoformulation as a novel therapeutic strategy for PAH treatment.

Development of bozepinib-loaded nanocapsules for nose-to-brain delivery: preclinical evaluation in glioblastoma.

Aim: To develop and characterize bozepinib-loaded lipid-core nanocapsules (BZP-LNC+) as a potential treatment for glioblastoma (GBM). Methods: Characterization of nanocapsules was performed by diameter, polydispersity index, Zeta potential, pH and encapsulation efficiency. GBM cell viability, cell cycle and Annexin/PI were evaluated after BZP-LNC+ treatment. Synergism between BZP-LNC+ and temozolomide (TMZ) was performed by CompuSyn software and confirmed in vitro and in vivo. Results: BZP-LNC+ showed adequate particle sizes, positive Zeta potential, narrow size distribution and high encapsulation efficiency. BZP-LNC+ reduces GBM growth by inducing apoptosis. BZP-LNC+ and TMZ showed synergistic effect in vitro and reduced the in vivo glioma growth by approximately 81%. Conclusion: The present study provides proof-of-principle insights for the combination of these drugs for GBM treatment.

Organic Nanocarriers for Bevacizumab Delivery: An Overview of Development, Characterization and Applications.

Bevacizumab (BCZ) is a recombinant humanized monoclonal antibody against the vascular endothelial growth factor, which is involved in the angiogenesis process. Pathologic angiogenesis is observed in several diseases including ophthalmic disorders and cancer. The multiple administrations of BCZ can cause adverse effects. In this way, the development of controlled release systems for BCZ delivery can promote the modification of drug pharmacokinetics and, consequently, decrease the dose, toxicity, and cost due to improved efficacy. This review highlights BCZ formulated in organic nanoparticles providing an overview of the physicochemical characterization and in vitro and in vivo biological evaluations. Moreover, the main advantages and limitations of the different approaches are discussed. Despite difficulties in working with antibodies, those nanocarriers provided advantages in BCZ protection against degradation guaranteeing bioactivity maintenance.

Nanoformulation Shows Cytotoxicity against Glioblastoma Cell Lines and Antiangiogenic Activity in Chicken Chorioallantoic Membrane.

Glioblastoma (GB) is a histological and genetically heterogeneous brain tumor that is highly proliferative and vascularized. The prognosis is poor with currently available treatment. In this study, we evaluated the cytotoxicity and antiangiogenic activity of doxorubicin-loaded-chitosan-coated-arginylglycylaspartic acid-functionalized-poly(ε-caprolactone)-alpha bisabolol-LNC (AB-DOX-LNC-L-C-RGD). The nanoformulation was prepared by self-assembling followed by interfacial reactions, physicochemically characterized and evaluated in vitro against GB cell lines (U87MG and U138MG) and in vivo using the chicken chorioallantoic membrane assay (CAM). Spherical shape nanocapsules had a hydrodynamic mean diameter of 138 nm, zeta potential of +13.4 mV, doxorubicin encapsulation of 65%, and RGD conjugation of 92%. After 24 h of treatment (U87MG and U138MG), the median inhibition concentrations (IC50) were 520 and 490 nmol L-1 doxorubicin-equivalent concentrations, respectively. The treatment induced antiproliferative activity with S-phase cell-cycle arrest and apoptosis in the GB cells. Furthermore, after 48 h of exposure, evaluation of antiangiogenic activity (CAM) showed that the relative vessel growth following treatment with the nanocapsules was 5.4 times lower than that with the control treatment. The results support the therapeutic potential of the nanoformulation against GB and, thereby, pave the way for future preclinical studies.

Folic acid-doxorubicin polymeric nanocapsules: A promising formulation for the treatment of triple-negative breast cancer.

Breast cancer is the most common cancers among women and is one of the main causes of morbidity and mortality in this population. In this study, we aimed to conjugate doxorubicin (DOX), a drug widely used in cancer chemotherapy, and folic acid (FA), a ligand targeted for cancer therapy, to lipid-core nanocapsules (LNC), and evaluate the efficacy of the nanoformulation against triple-negative breast cancer (TNBC) MDA-MB-231 cells that overexpress folate receptors (FRs). We performed cell viability assays, quantitative real-time PCR (qRT-PCR), cell migration assay, and clonogenic assay, as well as measured the levels of nitric oxide (NO) generated and cellular uptake. The results showed that the nanoformulation reduced cell viability. The results of qRT-PCR analysis revealed that the nanoformulation induced apoptosis of MDA-MB-231 cells. The mRNA expression levels of Cat and MnSod were increased when the nanoformulation was compared to the doxorubicin solution. Furthermore, the nanoformulation significantly decreased the migration of breast cancer cells in vitro and inhibited colony formation. Additionally, the expression of iNOS in MDA-MB-231 cells was higher when the nanoformulation was used compared to the doxorubicin solution. Cellular uptake was observed after incubating the MDA-MB-231 cells with the fluorescent-labeled nanoformulation. In conclusion, we developed a promising nanoformulation for the treatment of TNBC. Further studies are necessary to demonstrate the in vivo efficacy of this formulation.

Resveratrol-Loaded Lipid-Core Nanocapsules Modulate Acute Lung Inflammation and Oxidative Imbalance Induced by LPS in Mice.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are inflammatory and oxidative imbalance lung conditions with no successful pharmacological therapy and a high mortality rate. Resveratrol (RSV) is a plant-derived stilbene that presents anti-inflammatory and antioxidant effects. However, its therapeutic application remains limited due to its poor bioavailability, which can be solved by the use of nanocarriers. Previously, we demonstrated that nanoencapsulated RSV (RSV-LNC) pre-treatment, performed 4 h before lipopolysaccharide (LPS) stimulation in mice, increased its anti-inflammatory properties. In this study, we evaluated the anti-inflammatory and antioxidant effects, and lung distribution of RSV-LNCs administered therapeutically (6 h post LPS exposure) in a lung injury mouse model. The results showed that RSV-LNCs posttreatment improved lung function and diminished pulmonary inflammation. Moreover, RSV-LNC treatment enhanced the antioxidant catalase level together with a decrease in the oxidative biomarker in mouse lungs, which was accompanied by an increase in pulmonary Nrf2 antioxidant expression. Finally, the presence of RSV in lung tissue was significantly detected when mice received RSV-LNCs but not when they received RSV in its free form. Together, our results confirm that RSV nanoencapsulation promotes an increase in RSV bioavailability, enhancing its therapeutic effects in an LPS-induced lung injury model.

scFv-Anti-LDL(-)-Metal-Complex Multi-Wall Functionalized-Nanocapsules as a Promising Tool for the Prevention of Atherosclerosis Progression.

Atherosclerosis can be originated from the accumulation of modified cholesterol-rich lipoproteins in the arterial wall. The electronegative LDL, LDL(-), plays an important role in the pathogenesis of atherosclerosis once this cholesterol-rich lipoprotein can be internalized by macrophages, contributing to the formation of foam cells, and provoking an immune-inflammatory response. Herein, we engineered a nanoformulation containing highly pure surface-functionalized nanocapsules using a single-chain fragment variable (scFv) reactive to LDL(-) as a ligand and assessed whether it can affect the LDL(-) uptake by primary macrophages and the progression of atherosclerotic lesions in Ldlr -/- mice. The engineered and optimized scFv-anti-LDL(-)-MCMN-Zn nanoformulation is internalized by human and murine macrophages in vitro by different endocytosis mechanisms. Moreover, macrophages exhibited lower LDL(-) uptake and reduced mRNA and protein levels of IL1B and MCP1 induced by LDL(-) when treated with this new nanoformulation. In a mouse model of atherosclerosis employing Ldlr -/- mice, intravenous administration of scFv-anti-LDL(-)-MCMN-Zn nanoformulation inhibited atherosclerosis progression without affecting vascular permeability or inducing leukocytes-endothelium interactions. Together, these findings suggest that a scFv-anti-LDL(-)-MCMN-Zn nanoformulation holds promise to be used in future preventive and therapeutic strategies for atherosclerosis.

New nanotechnological formulation based on amiodarone-loaded lipid core nanocapsules displays anticryptococcal effect.

Cryptococcus neoformans is the etiological agent of cryptococcal meningoencephalitis. The recommended available treatment has low efficiency, with high toxicity and resistance as recurrent problems. In the search of new treatment protocols, the proposal of new pharmacological approaches is considered an innovative strategy, mainly nanotechnological systems considering fungal diseases. The antiarrhythmic drug amiodarone has demonstrated antifungal activity against a range of fungi, including C. neoformans. Here, considering the importance of calcium storage mediated by transporters on cryptococcal virulence, we evaluated the use of the calcium channel blocker amiodarone as an alternative therapy for cryptococcosis. C. neoformans displayed high sensitivity to amiodarone, which was also synergistic with fluconazole. Amiodarone treatment influenced some virulence factors, interrupting the calcium-calcineurin signaling pathway. Experiments with murine cryptococcosis models revealed that amiodarone treatment increased the fungal burden in the lungs, while its combination with fluconazole did not improve treatment compared to fluconazole alone. In addition, we have developed different innovative nanotechnological formulations, one of which combining two drugs with different mechanisms of action. Lipid-core nanocapsules (LNC) loaded with amiodarone (LNCAMD), fluconazole (LNCFLU) and both (LNCAMD+FLU) were produced to achieve a better efficacy in vivo. In an intranasal model of treatment, all the LNC formulations had an antifungal effect. In an intraperitoneal treatment, LNCAMD showed an enhanced anticryptococcal effect compared to the free drug, whereas LNCFLU or LNCAMD+FLU displayed no differences from the free drugs. In this way, nanotechnology using amiodarone formulations could be an effective therapy for cryptococcal infections.

Folic Acid-Doxorubicin-Double-Functionalized-Lipid-Core Nanocapsules: Synthesis, Chemical Structure Elucidation, and Cytotoxicity Evaluation on Ovarian (OVCAR-3) and Bladder (T24) Cancer Cell Lines.

PURPOSE: Folic acid-doxorubicin-double-functionalized-lipid-core nanocapsules (LNC-CS-L-Zn+2-DOX-FA) were prepared, characterized, and evaluated in vitro against ovarian and bladder cancer cell lines (OVCAR-3 and T24). METHODS: LNC-CS-L-Zn+2-DOX-FA was prepared by self-assembly and interfacial reactions, and characterized using liquid chromatography, particle sizing, transmission electron microscopy, and infrared spectroscopy. Cell viability and cellular uptake were studied using MTT assay and confocal microscopy. RESULTS: The presence of lecithin allows the formation of nanocapsules with a lower tendency of agglomeration, narrower size distributions, and smaller diameters due to an increase in hydrogen bonds at the surface. LNC-L-CS-Zn+2-DOX-FA, containing 98.00 ± 2.34 µg mL-1 of DOX and 105.00 ± 2.05 µg mL-1 of FA, had a mean diameter of 123 ± 4 nm and zeta potential of +12.0 ± 1.3 mV. After treatment with LNC-L-CS-Zn+2-DOX-FA (15 µmol L-1 of DOX), T24 cells had inhibition rates above 80% (24 h) and 90% (48 h), whereas OVCAR-3 cells showed inhibition rates of 68% (24 h) and 93% (48 h), showing higher cytotoxicity than DOX.HCl. The fluorescent-labeled formulation showed a higher capacity of internalization in OVCAR-3 compared to T24 cancer cells. CONCLUSION: Lecithin favored the increase of hydrogen bonds at the surface, leading to a lower tendency of agglomeration for nanocapsules. LNC-CS-L-Zn+2-DOX-FA is a promising therapeutic agent against tumor-overexpressing folate receptors.

Innovative hydrogel containing polymeric nanocapsules loaded with phloretin: Enhanced skin penetration and adhesion.

Dermatological applications of phloretin are restricted by its poor aqueous solubility. Nanotechnology has been proposed as strategy to increase the apparent drug solubility in aqueous media. This study aimed to develop, characterize, and evaluate the antitumoral effects and safety of polymeric nanocapsules containing phloretin (NCPhl). Further, to incorporate NC-Phl in an innovative semi-solid formulation (HG-NCPhl) to evaluate its performance using porcine skin model. NC-Phl was prepared and the effects in MRC5, HACAT, and SK-mel28 cells were evaluated. Hydrogels were prepared with Lecigel ® and characterized for their nanotechnological properties, adhesion (in vitro washability), and penetration/permeation studies in porcine skin. NC-Phl had a cytotoxic effect against Sk-Mel-28 cells and the population doubling time was increased upon treatment with NC-Phl for longer culture periods; notably when cells were treated for 72 h and then followed for 7 days after the treatment was removed (p < 0.05). HG-NC-Phl was considered adhesive and had a higher capacity to penetrate all skin layers compared with HG-Phl (p < 0.05). The innovative hydrogel HGNC-Phl promoted a drug-reservoir in the stratum corneum and higher penetration of the flavonoid into the epidermis. Therefore, this approach can be considered as a platform to establish versatile dermatological solutions for both cosmeceutics and melanoma therapy.

Dermatopharmacokinetic and pharmacodynamic evaluation of a novel nanostructured formulation containing capsaicinoids for treating neuropathic pain.

The in vivo skin penetration by dermal microdialysis and the pharmacological efficacy of a chitosan hydrogel containing capsaicinoids-loaded nanocapsules (CHNCCaps) was evaluated in this study. Such gel has previously been proven to control capsaicinoids release and decrease the drugs side effects in humans. The nanocapsules containing capsaicinoids had an average size around 150 nm, with a low polydispersity index, positive zeta potential, and high encapsulation efficiency of the drugs. The CHNCCaps showed intact nanocapsules, a slightly acid pH value, and a pseudoplastic behavior suitable for topical application. Microdialysis experiments showed a 1.6-fold increase in the concentration of capsaicinoids in the dermis (after 12 h of its application) when CHNCCaps was administered compared to a chitosan hydrogel containing capsaicinoids in hydroethanolic solution (CHETCaps) and the commercial cream. The CHNCCaps showed antiallodynic and antihyperalgesic effects from 6 h to 96 h after treatment initiation, whereas CHETCaps and the commercial cream showed antiallodynic and antihyperalgesic effects only at 48 h and 96 h after treatment initiation, respectively. CHNCCaps and the commercial cream maintained antihyperalgesic activity for 6 days after treatment interruption. For mechanical allodynia, the antinociceptive effect was maintained for 48 h after treatment interruption only with CHNCCaps. In conclusion, CHNCCaps is a promising formulation for treating peripheral neuropathic pain.

Dermatological applications of the flavonoid phloretin.

Botanical molecules are known to have the ability to counteract ultraviolet radiation-induced skin damage. The interest in the development of natural compound-based products for the prevention of solar ultraviolet radiation-induced skin photoaging, melasma, and photocarcinogenesis has been increasing. Recently, the flavonoid phloretin has attracted the attention of researchers in the dermatological field for application in cosmetics and therapeutics. In addition to its antioxidant activity, phloretin has been shown to have properties such as anti-aging and depigmenting effects. In this study, we review the dermatological treatments with phloretin for conditions such as melasma, photoaging, acne, and melanoma. Phloretin has been shown to inhibit elastase and matrix metalloproteinase-1 activity, to reduce cellular tyrosinase activity and melanin content, and induce apoptosis in B16 mouse melanoma 4A5 cells. An in vivo study showed that phloretin, applied topically to the dorsal skin of mice, suppressed the 12-O-tetradecanoylphorbol 13-acetate-induced expression of COX-2, a critical molecular target of many chemopreventive, as well as anti-inflammatory agents. Phloretin can penetrate the skin; nevertheless, its penetration profile in different skin layers has not yet been evaluated. Despite its health benefits, phloretin application has been limited because of its photoinstability and poor aqueous solubility, among other limitations. Therefore, we reviewed the recent advances in pharmaceutical applications such as the use of nanotechnology, in order to improve the cutaneous availability of phloretin. In this review, we also focus on the oral application, product development challenges, and recent progress and future research directions on phloretin.