Search

[Display omitted] The aims of this study were, firstly, to select an optimal lipid solid dispersion of cannabidiol among different lipid excipients (Gelucire® 50/13, 48/16, 44/14 and Labrasol®) and inorganic carriers (colloidal silica, Syloid® XDP and Neusilin® US2) through a screening plan. The enhancement of aqueous solubility of cannabidiol from a free-flowing powder with adequate drug content was obtained by mixing cannabidiol (20%) with Gelucire® 50/13 (40%; Gattefossé, France), both incorporated inside mesopores of mesoporous silica Syloid® XDP (40%; Grace, Germany). Secondly, we have studied the tableting properties of this selected dispersion through a Design of Experiments (DoE) by manufacturing tablets with other excipients with using a compression simulator (Styl'One® Evo, Medelpharm, France). The design of experiments included the percentage of lipid solid dispersion, of glidant, of lubricant and different compression forces. The dissolution efficiency, the drug content, the tensile strength and the ejection force were analyzed. The DoE showed that % of dispersion as well as compression forces were the main influential variables. An exit of lipid materials outside the mesopores of silica due to compression process has been highlighted, reflected by reduced tensile strength. This study showed the possibility of manufacturing tablets with lipid materials even if limitations have been highlighted. Indeed, the dispersion percentage must not exceed 27% and compression forces up to 13 kN are required to produce lipid tablets with optimal properties. [ABSTRACT FROM AUTHOR]

[Display omitted] Preclinical development of deuterated pyrazoloquinolinone ligands, promising drug candidates for various neuropsychiatric disorders, was hindered by unusually low solubility in water and oils. DK-I-60-3 (7-methoxy-d3-2-(4-methoxy-d3-phenyl)-2,5-dihydro-3Hpyrazolo[4,3- c ]quinolin-3-one) is one of such pyrazoloquinolinones, and we recently reported about increased oral bioavailability of its nanocrystal formulation (NC). Lipid nanoparticles (LNP) with a high concentration of lecithin, which enhances loading capacity of the lipid matrix, may give rise to further improvement. After preformulation studies by differential scanning calorimetry and polarized light microscopy, LNP were prepared by the hot high pressure homogenization, and characterized in terms of particle size, morphology, and encapsulation efficacy. The layered structure visible on atomic force micrographs was confirmed by nuclear magnetic resonance. Obtained formulations were desirably stable, with small particle size (<100 nm), and high encapsulation efficacy (>99 %). Lecithin was partially fluid and most probably located in the outer shell of the particle, together with DK-I-60-3. While the hydrophobic part of polysorbate 80 was completely immobilized, its hydrophilic part was free in the aqueous phase. In oral neuropharmacokinetic study in rats, an around 1.5-fold increase of area under the curve with LNP compared to NC was noticed both in brain and plasma. In bioavailability study, F value of LNP (34.7 ± 12.4 %) was 1.4-fold higher than of NC (24.5 ± 7.8 %); however, this difference did not reach statistical significance. Therefore, employment of LNP platform in preclinical formulation of DK-I-60-3 imparted an incremental improvement of its physicochemical as well as pharmacokinetic behavior. [ABSTRACT FROM AUTHOR]

[Display omitted] Non-melanoma skin cancer is one of the most common malignancies reported with high number of morbidities, demanding an advanced treatment option with superior chemotherapeutic effects. Due to high degree of drug resistance, conventional therapy fails to meet the desired therapeutic efficacy. To break the bottleneck, nanoparticles have been used as next generation vehicles that facilitate the efficient interaction with the cancer cells. Here, we developed combined therapy of 5-fluorouracil (5-FU) and cannabidiol (CBD)-loaded nanostructured lipid carrier gel (FU-CBD-NLCs gel). The NLCs were optimized using central composite design that showed an average particle size of 206 nm and a zeta potential of −34 mV. In addition, in vitro and ex vivo drug permeations studies demonstrated the effective delivery of both drugs in the skin layers via lipid structured nanocarriers. Also, the prepared FU-CBD-NLCs showed promising effect in-vitro cell studies including MTT assays, wound healing and cell cycle as compared to the conventional formulation. Moreover, dermatokinetic studies shows there was superior deposition of drugs at epidermal and the dermal layer when treated with FU-CBD-NLCs. In the end, overall study offered a novel combinatorial chemotherapy that could be an option for the treatment of non-melanoma skin cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] Small interfering RNA (siRNA) mediating specific gene silencing provides a promising strategy for anti-inflammatory therapy. However, the development of potent carriers for anti-inflammatory siRNA to macrophages remains challenging. With the aim of realizing potent delivery of siRNA to macrophages, we engineered ionizable lipid nanoparticles (LNPs) with the key component of synthetic lipid-like materials. By varying the amine molecules in the structure of synthetic lipid-like materials, a potent LNP (1O 14 -LNP) was identified, which exhibited efficient transfection of macrophages by facilitating efficient internalization and endosomal escape. The 1O 14 -LNP successfully delivered anti-inflammatory siRNA against interleukin-1β (siIL-1β) with more than 90% downregulation of IL-1β expression in LPS-activated macrophages. From in vivo studies, systemic administrated 1O 14 -LNP/siRNA mainly distributed in liver and efficiently captured by hepatic macrophages without notable sign of toxicity. Furthermore, LPS/ d -GalN-induced acute liver injury model treated with 1O 14 -LNP/siIL-1β resulted in significant suppression of IL-1β expression and amelioration of liver tissue damage. These results demonstrate that the engineered ionizable LNP provides a powerful tool for siRNA delivery to macrophages and that the strategy of silencing of pro-inflammatory cytokines holds great potential for treating inflammatory diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] After two decades of research in the field of nanomedicine, nanoscale delivery systems for biologicals are becoming clinically relevant tools. Microfluidic-based fabrication processes are replacing conventional techniques based on precipitation, emulsion, and homogenization. Here, the focus is on solid lipid nanoparticles (SLNs) for the encapsulation and delivery of lysozyme (LZ) as a model biologic. A thorough analysis was conducted to compare conventional versus microfluidic-based production techniques, using a 3D-printed device. The efficiency of the microfluidic technique in producing LZ-loaded SLNs (LZ SLNs) was demonstrated: LZ SLNs were found to have a lower size (158.05 ± 4.86 nm vs 180.21 ± 7.46 nm) and higher encapsulation efficacy (70.15 ± 1.65 % vs 53.58 ± 1.13 %) as compared to particles obtained with conventional methods. Cryo-EM studies highlighted a peculiar turtle-like structure on the surface of LZ SLNs. In vitro studies demonstrated that LZ SLNs were suitable to achieve a sustained release over time (7 days). Enzymatic activity of LZ entrapped into SLNs was challenged on Micrococcus lysodeikticus cultures, confirming the stability and potency of the biologic. This systematic analysis demonstrates that microfluidic production of SLNs can be efficiently used for encapsulation and delivery of complex biological molecules. [ABSTRACT FROM AUTHOR]

[Display omitted] • LDV peptide amphiphiles were synthesized for self-assembly into lipid-based micelles. • Micelles, liposomes and solid lipid nanoparticles of similar composition were synthesized and compared for their physicochemical characteristics, in vitro stability and in vivo efficacy. • Solid lipid nanoparticles demonstrated enhanced in vitro stability and anti-tumor efficacy compared to micelles and liposomes. The purpose of this work was to compare the in vitro and in vivo characteristics of LDV-targeted lipid-based micelles, liposomes and solid lipid nanoparticles (SLN) to provide further insights into their therapeutic potential for clinical development. Micelles, liposomes and SLN were prepared using LDV peptide amphiphiles and palmitic acid-derived lipids using solvent evaporation, thin-film hydration and microfluidic mixing respectively. Nanocarriers were characterized for their physicochemical properties, paclitaxel loading efficiency, in vitro release behavior, stability in biological media as well as in vivo antitumor efficacy in melanoma xenograft model. TEM and DLS results confirmed the presence of paclitaxel-loaded nanosized micelles (6 to 12 nm), liposomes (123.31 ± 5.87 nm) and SLN (80.53 ± 5.37 nm). SLN demonstrated the slowest paclitaxel release rate and the highest stability in biological media compared to micelles and liposomes. Paclitaxel-loaded SLN demonstrated a statistically significant delay in tumor growth compared to mice treated with paclitaxel-loaded liposomes and paclitaxel-loaded micelles (p < 0.05). The results obtained in this study indicate the potential of SLN as drug delivery vehicles for anticancer therapy. [ABSTRACT FROM AUTHOR]

[Display omitted] l -Glutathione (GSH) has exceptional antioxidant activities against UVA irradiation-induced oxidative stress and is used widely for combatting skin ageing. However, topical administration of GSH is challenging due to its inability to penetrate the stratum corneum (SC). This study aims to evaluate the solid lipid nanoparticles (SLNs) carrier system for improving the skin penetration and stability of GSH. The GSH-loaded SLNs (GSH-SLNs) were prepared by the double emulsion technique and were optimized by a full factorial design. The optimized GSH-SLNs formulation had a mean particle size of 305 ± 0.6 nm and a zeta potential of + 20.1 ± 9.5 mV, suitable for topical delivery. The ex-vivo penetration study using human skin demonstrated a 3.7-fold improvement of GSH penetration across SC with GSH-SLNs when compared with aqueous GSH. GSH-SLNs prolonged antioxidant activity on UVA irradiated fibroblast cells when compared to GSH solution, preventing UVA-induced cell death and promoting cell growth for times over 48 h. This research has illustrated that as a carrier system, SLNs were able to enhance the physicochemical stability, skin penetration, and drug deposition in the viable epidermis and dermis layers of the skin for GSH, while also maintaining the ability to protect human skin fibroblast cells against oxidative stress caused by UVA irradiation. This delivery system shows future promise as a topical delivery platform for the topical delivery of GSH and other chemically similar bioactive compounds for improving skin health. [ABSTRACT FROM AUTHOR]

To develop a combinatorial artificial-neural-network design-of-experiment (ANN-DOE) model, the effect of ionizable lipid, an ionizable lipid-to-cholesterol ratio, N/P ratio, flow rate ratio (FRR), and total flow rate (TFR) on the outcome responses of mRNA-LNP vaccine were evaluated using a definitive screening design (DSD) and machine learning (ML) algorithms. Particle size (PS), PDI, zeta potential (ZP), and encapsulation efficiency (EE) of mRNA-LNP were optimized within a defined constraint (PS 40-100 nm, PDI ≤ 0.30, ZP≥(±)0.30 mV, EE ≥ 70 %), fed to ML algorithms (XGBoost, bootstrap forest, support vector machines, k-nearest neighbors, generalized regression-Lasso, ANN) and prediction was compared to ANN-DOE model. Increased FRR decreased the PS and increased ZP, while increased TFR increased PDI and ZP. Similarly, DOTAP and DOTMA produced higher ZP and EE. Particularly, a cationic ionizable lipid with an N/P ratio ≥ 6 provided a higher EE. ANN showed better predictive ability (R 2  = 0.7269-0.9946), while XGBoost demonstrated better RASE (0.2833-2.9817). The ANN-DOE model outperformed both optimized ML models by R 2  = 1.21 % and RASE = 43.51 % (PS prediction), R 2  = 0.23 % and RASE = 3.47 % (PDI prediction), R 2  = 5.73 % and RASE = 27.95 % (ZP prediction), and R 2  = 0.87 % and RASE = 36.95 % (EE prediction), respectively, which demonstrated that ANN-DOE model was superior in predicting the bioprocess compared to independent models., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Exparel is a bupivacaine multivesicular liposomes (MVLs) formulation developed based on the DepoFoam technology. The complex composition and the unique structure of MVLs pose challenges to the development and assessment of generic versions. In the present work, we developed a panel of analytical methods to characterize Exparel with respect to particle size, drug and lipid content, residual solvents, and pH. In addition, an accelerated in vitro drug release assay was developed using a rotator-facilitated, sample-and-separate experimental setup. The proposed method could achieve over 80% of bupivacaine release within 24 h, which could potentially be used for formulation comparison and quality control purposes. The batch-to-batch variability of Exparel was examined by the established analytical methods. Four different batches of Exparel showed good batch-to-batch consistency in drug content, particle size, pH, and in vitro drug release kinetics. However, slight variation in lipid contents were observed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anna Schwendeman reports financial support was provided by US Food and Drug Administration. Minzhi Yu reports financial support was provided by American Heart Association. Anna Schwendeman reports a relationship with EVOQ Therapeutics that includes: board membership, consulting or advisory, equity or stocks, and funding grants., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cholesterol (CHOL) is essential for developing lipid nanoparticles (LNPs) for gene delivery because it enhances membrane fusion and improves the delivery efficiency of gene cargos. An attractive pDNA carrier, corosolic acid (CA)-modified lipid nanoparticles (CLNPs), was developed by replacing CHOL in LNPs to deliver pDNA at various ratios of nitrogen groups to phosphate groups (N/P). The resultant CLNPs with a higher CHOL/CA ratio exhibited similar mean particle size, zeta potential, and encapsulation efficiency to those of LNPs. In comparison with LNPs, CLNPs (CHOL:CA ratio = 2:1) achieved increased cellular uptake and enhanced transfection efficacy while maintaining low cytotoxicity. In vivo results from chicken experiments demonstrated that CLNPs encapsulating DNA vaccines against avian influenza at a N/P ratio of 3 could elicit similar-level humoral and cellular immune responses compared with those of LNPs at a higher N/P ratio, thereby suggesting the induction of desirable immune effects using less ionizable lipids. Our study provides a reference for further research on the application of CA in LNPs for gene delivery, and the development of novel delivery systems for DNA vaccines against avian influenza., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Psoriasis is a consistently recurring, inflammatory skin disease, affecting about 2-5 % of the world population. Different types of psoriasis can be observed such as guttate psoriasis, pustular psoriasis, psoriatic arthritis, scalp psoriasis, flexural psoriasis etc. Several therapeutic approaches are available for the treatment of psoriasis. However, none of them are entirely safe and effective to treat the disease without compromising patient compliance. The traditional treatment plan is associated with harmful side effects such asimmune system suppression and damage of essential organs at high doses, which poses a challenge to treat psoriasis. Novel drug delivery systems are being developed to replace traditional therapy in order to address these shortcomings. Currently, nanoformulations have gained widespread application for treatment of psoriasis. Researchers have developed different types of lipid-based nanoparticles like liposomes, niosomes, ethosomes, transethosomes, nanostructured lipid carriers and solid lipid nanoparticles. These innovative formulations provide advantages in terms of reduction in dose, dosing frequency, dose-dependency with enhanced efficacy, improved encapsulation efficiency, controlled release, increased surface area, high bioavailability and greater stratum corneum permeability. This review highlights detailed and comparative discussion of lipid-based and polymer-based nanoparticles for psoriasis along with the pathophysiology and other treatments of psoriasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Understanding and controlling the drug solubilization in digestive environment is of great importance in the design of lipid based solid dispersion (LBSD) for oral delivery of poorly aqueous soluble drugs. In the current study we determined the extent of drug solubilization and supersaturation of supersaturating lipid based solid dispersion which is governed by formulation variables like drug payload, lipid composition, solid carrier properties and lipid to solid carrier ratio. Initially, the impact of lipid chain length and drug payload on drug solubilization in lipid preconcentrate and dispersibility were evaluated to design liquid LbF of the model antiretroviral drug, atazanavir. The temperature induced supersaturation method enhanced the drug payload in medium chain triglyceride formulation at 60 °C. Further, the selected liquid supersaturated LbF was transformed into solid state LbF by employing different solid carriers including silica (Neusilin® US2 and Aerosil® 200), clay (Montmorillonite and Bentonite) and polymer (HPMC-AS and Kollidon® CL-M). The fabricated LBSDs were evaluated for solid state characterization to identify the physical nature of drug. In vitro digestion studies were conducted using pH-stat lipolysis method to assess the supersaturation propensity in aqueous digestive phase. Results revealed that LBSDs with silica and polymer carriers showed maximum drug solubilization throughout experiment compared to liquid LbF. The ionic interaction between drug-clay particles significantly reduced the ATZ partitioning from clay based LBSDs. LBSDs with dual purpose solid carrier like HPMC-AS and Neusilin® US2 offers the potential to improve drug solubilization of ATZ for physiologically relevant time. Lastly, we conclude that evaluation of formulation variables is crucial to achieve optimal performance of supersaturating LBSD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Despite being potent, the marketed formulations of Docetaxel (DX) are associated with numerous side effects and are meant for intravenous administration. Advanced pharmaceutical nanotechnology has a significant potential to facilitate the 'intravenous (i.v) to oral switch'. The present research work deals with the development of an orally administrable, folate-receptor-targeted Nanostructured lipid carriers (NLCs) of DX (FA-DX-NLCs) for facilitating oral chemotherapy of lung cancer while overcoming the bioavailability and toxicity issues. The nanoformulation prepared to employ high-pressure homogenization and lyophilization, was evaluated and statistically analyzed for various in-vitro and in-vivo formulation characteristics. The lyophilized nanoparticles were observed to be spherical with a particle size of 183.4 ± 2.13 (D90), Pdi of 0.358 ± 0.03, % EE of 82.41 ± 2.44, % DL of 4.41 ± 0.54 and a zeta potential of -3.3 ± 0.7 mv. The increased oral in-vivo bioavailability of DX was evident from the plasma-concentration area under the time curve (AUC 0-t ), which was ∼ 27-fold greater for FA-DX-NLCs as compared to DX suspension. The orally administered FA-DX-NLCs exhibited excellent antitumor efficacy in a pre-clinical model of lung carcinoma. Tumor staging, histopathology, and immunostaining of the tumors suggested greater anti-proliferative, apoptotic, anti-metastatic, and anti-angiogenic potential as compared to DX-suspension. The pre-clinical toxicity studies affirmed the excellent safety and bio-compatibility of FA-DX-NLCs. The research work presents immense translational potential for switching the DX-based chemotherapy for lung cancer from 'hospital to home.', Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Nanotechnology has been widely used to improve stability, efficacy, release control and biopharmaceutical aspects of natural and synthetic cannabinoids. In this review, the main types of cannabinoid-based nanoparticles (NPs) reported so far are addressed, taking into account the advantages and disadvantages of each system. Formulation, preclinical and clinical studies performed with colloidal carriers were individually analyzed. Lipid-based nanocarriers have been recognized for their high biocompatibility and ability to improve both solubility and bioavailability. Δ 9 -tetrahydrocannabinol-loaded lipid systems designed to treat glaucoma, for example, showed superior in vivo efficacy in comparison to market formulations. The analyzed studies have shown that product performance can be modulated by varying particle size and composition. In the case of self-nano-emulsifying drug delivery systems, the reduced particle size shortens the time to reach high plasma concentrations while the incorporation of metabolism inhibitors extends the plasma circulation time. The use of long alkyl chain lipids in NP formulations, in turn, is strategized to achieve intestinal lymphatic absorption. Polymer NPs have been prioritized when a sustained or site-specific cannabinoid release is desirable (e.g., CNS-affecting diseases/cancer). The functionalization of the surface of polymer NPs makes their action even more selective whereas surface charge modulation is highlighted to provide mucoadhesion. The present study identified promising systems for targeted applications, making the process of optimizing new formulations more effective and faster. Although NPs have shown a promising role in the treatment of several difficult-to-treat diseases, more translational studies should be performed to confirm the benefits reported here., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Archaea are microorganisms more closely related to eukaryotes than bacteria. Almost 50 years after being defined as a new domain of life on earth, new species continue to be discovered and their phylogeny organized. The study of the relationship between their genetics and metabolism and some of their extreme habitats has even positioned them as a model of extraterrestrial life forms. Archaea, however, are deeply connected to the life of our planet: they can be found in arid, acidic, warm areas; on most of the earth's surface, which is cold (below 5 °C), playing a prominent role in the cycles of organic materials on a global scale and they are even part of our microbiota. The constituent materials of these microorganisms differ radically from those produced by eukaryotes and bacteria, and the nanoparticles that can be manufactured using their ether lipids as building blocks exhibit unique properties that are of interest in nanomedicine. Here, we present for the first time a complete overview of the pre-clinical applications of nanomedicines based on ether archaea lipids, focused on drug delivery and adjuvancy over the last 25 years, along with a discussion on their pros, cons and their future industrial implementation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Triple-negative breast cancer (TNBC) represents 15-25 % of the new breast cancer cases diagnosed worldwide every year. TNBC is among the most aggressive and worst prognosis breast cancer, mainly because targeted therapies are not available. Herein, we developed a magnetic theranostic hybrid nanovehicle for targeted treatment of TNBC through pH-triggered tumour associated macrophages (TAMs) targeting. The lipid core of the nanovehicle was composed of a Carnaúba wax matrix that simultaneously incorporated iron oxide nanoparticles and doxorubicin (DOX) - a chemotherapeutic drug. These drug-loaded wax nanovehicles were modified with a combination of two functional and complementary molecules: (i) a mannose ligand (macrophage targeting) and (ii) an acid-sensitive sheddable polyethylene glycol (PEG) moiety (specificity). The TAMs targeting strategy relied on the mannose - mannose receptor recognition exclusively after acid-sensitive "shedding" of the PEG in the relatively low tumour microenvironment pH. The pH-induced targeting capability towards TAMs was confirmed in vitro in a J774A.1 macrophage cell line at different pH (7.4 and 6.5). Biocompatibility and efficacy of the final targeted formulations were demonstrated in vitro in the TNBC MDA-MB-231 cell line and in vivo in an M-Wnt tumour-bearing (TNBC) mouse model. A preferential accumulation of the DOX-loaded lipid nanovehicles in the tumours of M-Wnt-tumour bearing mice was observed, which resulted both on an efficient tumour growth inhibition and a significantly reduced off-target toxicity compared to free DOX. Additionally, the developed magnetic hybrid nanovehicles showed outstanding performances as T 2 -contrast agents in magnetic resonance imaging (r 2 ≈ 400-600 mM -1 ·s -1 ) and as heat generating sources in magnetic hyperthermia (specific absorption rate, SAR ≈ 178 W·g -1 Fe ). These targeted magnetic hybrid nanovehicles emerge as a suitable theranostic option that responds to the urgent demand for more precise and personalized treatments, not only because they are able to offer localized imaging and therapeutic potential, but also because they allow to efficiently control the balance between safety and efficacy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Warming the skin is a key means of promoting solute permeation through the skin. Changes in solute permeation associated with variations in skin temperature also assist in understanding the mechanism by which solutes permeate the skin. However, few studies have considered the relative impact of temperature on the main determinants of the maximum flux for a solute across the skin, the solubility of a solute and its diffusivity in the stratum corneum. In this study, we quantified for the first time the thermodynamics associated with the maximum skin fluxes for a series of phenolic compounds of similar size but with varying lipophilicity (defined by the logarithms of their octanol/water partition coefficient, logP). These studies were undertaken using aqueous donor solutions (along with testosterone as a reference solute) across human epidermal membranes in vertical Franz diffusion cells at 4 °C, 24 °C and 37 °C with intermittent receptor sampling and volume replacement over 24 h. Kinetic and thermodynamic analyses included the estimation of the stratum corneum (SC) apparent SC diffusivity from the SC maximum fluxes and SC solubilities and the associated activation energies, enthalpies and entropies for diffusion. The key findings were that the differences in the maximum flux of phenolic compounds varying in lipophilicity mainly arose from differences in SC solubility at the various temperatures and that, at the highest temperature, SC permeability and SC diffusion were affected by SC lipid fluidisation and that variations in SC - water partitioning enthalpies explain some of the previously low activation energies for permeation of the more lipophilic phenols. Higher enthalpies for diffusion were seen for solutes with addition hydrogen bonding capacity and the highest negative entropy was observed with the more compact solutes. Various relationships between the derived thermodynamic parameters were explored and interpreted in a proposed model for solute partitioning into and permeation through the SC intercellular lipid lamellae., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Warming of the skin is now an accepted means of promoting skin permeation. Accordingly, the usually quite onerous thermodynamic studies on solute transport through the skin have practical applications. Phenolic compounds permeate through the skin by partitioning into and diffusing through the stratum corneum (SC) intercellular lipids, with their size being the main determinant of their maximal solute flux through skin. This paper sought to characterise the enthalpic and entropic changes associated with the solubility and equilibrium partitioning into the human SC of a series of phenols similar in size but with differing log P from aqueous vehicles. The solubilities of 9 phenolic compounds, covering a range of polarities, were determined in water and SC following 72 h at 4, 24, 32 and 37 °C which allowed the estimation of the SC-water partition coefficients. Van't Hoff plots were then used to estimate the enthalpies and entropies for the SC solubility, water solubility and SC partitioning of phenols. In addition, partition coefficients of 3 of the 9 phenols from mineral oil into hydrated and dehydrated SC were measured at the same temperatures. Van't Hoff plots were then used to estimate the enthalpies and entropies for the SC solubility, water solubility and SC partitioning of phenols from the oil. The SC solubility for the polar phenols increased more with temperature than the non-polar phenols, with the SC-water partition coefficients increasing with temperature for the polar phenols but decreasing with temperature for the non-polar phenols. Thermodynamic analyses suggest that, while enthalpy and entropy effects are involved in the SC partitioning of the non-polar solutes, the SC partitioning of the polar phenols were almost entirely entropy driven. The resultant thermodynamic parameters are consistent with the polar phenols being mainly associated with the SC polar head groups whereas the nonpolar phenols were more likely to be located in the interior interface SC lipid region adjacent to the polar head groups. Further, hydrating the SC led to an increase in the enthalpy of partitioning for both the polar and non-polar phenols studied. The estimated entropy of the partitioning for solutes from dehydrated SC suggests this is not only a hydrophobic effect in water but that the partitioning arises from the nature of phenolic compound - SC intercellular lipid interactions and SC intercellular lipid entropy. This partitioning process is dominated more by the extent of interaction between the SC and solute than the hydrophobic effect in water and is likely to be even greater above the SC lipid phase transition at around 36 °C for hydrated epidermal membranes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

[Display omitted] Vitiligo is an autoimmune disease where its current treatment strategies are lengthy in course and do not guarantee complete cure. Tofacitinib citrate (JAK inhibitor) is a potential cure of vitiligo through halting JAK-STAT pathway preventing the destruction of melanocytes. The dermato-pharmacokinetics of the prepared transethosomes (Et) and the hybridized ethosomes/nanostructured lipid carriers (Eth/NLC), namely formulations; M.E-Cr and M.E-S.M, were evaluated. In addition, in vivo studies on C57/BL6 vitiligo mouse model were conducted to confirm effectiveness of Tofacitinib citrate delivery. The results unveiled that the transethosomes (359.46 ± 11.82 nm) were suitable for dermal delivery while M.E-Cr (179.64 ± 11.16 nm), a hybrid Eth/NLC formulation, was mostly suitable for transdermal delivery. Nevertheless, another hybrid formulation, M.E-S.M (253.60 ± 14.64 nm), was apt for both dermal and transdermal delivery. The histopathology confirmed re-pigmentation of mice skin where formulations Et and M.E-S.M showed severe pigmentation compared to the control healthy and induced mice. On the other hand, M.E-Cr showed mild pigmentation. Immunohistochemical assay was performed to evaluate infiltration of CD 8+ T -lymphocytes where mild infiltration was observed. However, the systemic IFN-γ was significantly reduced in case of M.E-Cr and M.E-S.M. The present work proposed potential effective formulations to improve the treatment of vitiligo with potential reduction in the total therapeutic dose, drug's side effects, and treatment costs. [ABSTRACT FROM AUTHOR]

[Display omitted] Nanoparticle technology has promising effects on multiple therapeutic purposes, particularly in controlling drug delivery as Drug Delivery System. The unique properties of nanoparticles significantly enhance drug delivery, efficiency, and toxicity. For cancer therapy, controlling chemotherapy delivery can increase the drug concentration in the desired locations, improve drug efficacy, and limit drug toxicity. Liposomes are used in this project to encapsulate paclitaxel due to their ability to carry hydrophobic molecules, low toxicity, and prolonged half-life. Among the multiple liposome preparation methods, microfluidic technology was used to produce liposomes. Microfluidics excels in other conventional methods by offering a high-level control of the process's parameters, which help control particle size, size distribution, and physiochemical properties. This project aims to produce paclitaxel-loaded liposomes with a diameter below 200 nm with low polydispersity index, high homogeneity, and good stability. Different lipid types (DMPC, DPPC, DSPC, and DOPC) were used with different ratios to investigate their impact on empty liposome formulation. Alongside changing the different microfluidic parameters including the total flow ratio and flow rate ratio to study their effects on liposomes' physiochemical properties. The obtained formulations were tested to analyse different physiochemical properties (DLS, FTIR) and stability studies. DMPC and DPPC are determined to study their encapsulation efficiency and in vitro drug release of paclitaxel at total flow rate 1 ml min−1 and 1:4 flow rate ratio. The paclitaxel-loaded liposomes are subjected to the same physiochemical characteristics and stability study. Promising encapsulation efficiency was reported from both DPPC and DMPC, and sustained drug release was observed. [ABSTRACT FROM AUTHOR]

[Display omitted] • Lipid nanocapsules (LNCs) were tailored for indomethacin, diclofenac or caffeine dermal and/or transdermal delivery. • LNCs are able to encapsulate indomethacin and diclofenac with greater than 98 % efficiency. Caffeine is not encapsulated inside the lipid core. • FTIR confirmed the incorporation (or lack thereof) of the respective drug in lipid nanoparticles. • Ex vivo topical application of all studied drugs in LNCs is more effective than application of other conventional formulations. The transdermal application of actives offers numerous advantages over other conventional routes. Namely, a stable level of drugs in the bloodstream and reduced side effects are the argument for topical administration. Unfortunately, the exceptional skin barrier and unsuitable physico-chemical properties of drugs are the limiting factors for the transdermal passage. It is possible to overcome this by incorporating the drug into nano-carriers to enhance its permeation through the skin barrier. For this purpose, we prepared lipid nanocapsules (LNCs) to modulate skin passage of three pharmaceutically important drugs – indomethacin (IND), diclofenac sodium (DF) and caffeine (CF). We present a stable system prepared by the phase inversion temperature method with particle size under 100 nm and PDI < 0.1 with great encapsulation efficiency for indomethacin and diclofenac. By FTIR it was possible to confirm (for IND and DF) or disprove (in case of CF) the incorporation of a drug into the LNCs. By ex vivo permeation experiments on porcine skin, we confirmed the superior effect of the LNCs on the APIs skin passage. The drug permeated through the skin with higher intensity when delivered from LNCs compared to other standard formulations. We show that lipid nanocapsules play an important role in enhanced topical application of actives. [ABSTRACT FROM AUTHOR]

[Display omitted] Lipid/polymer hybrid nanoparticles loaded with red fluorescent protein (RFP) encoded plasmid DNA (pDNA) was formulated using poly-lactic-co-glycolic acid (PLGA), cationic lipid DC-cholesterol and surfactant mPEG 2000 - DSPE. A lipid/ polymer ratio of 1: 10 at 1 mg/mL surfactant concentration was found to be optimal for producing nanoparticles with diameters of 100–120 nm that remained stable upon ultracentrifugation. The production of lipid/ polymer hybrid nanoparticles was investigated using microfluidics with a toroidal mixer design. Our results showed that the flow parameters significantly influenced the physicochemical characteristics of nanoparticles and loading of pDNA was only achieved at flow rate ratio (FRR) of 3: 1. The pDNA associated with nanoparticles was demonstrated to be structurally intact using gel electrophoresis, and the encapsulation efficiency (EE) was measured to be ∼65%. The prepared hybrid nanoparticles resulted in 20% of transfection efficacy in human embryonic kidney cells (HEK293T). This study demonstrated the potential of microfluidics in the development of hybrid nanoparticles for pDNA delivery, thus facilitating the clinical translation of DNA therapeutics. [ABSTRACT FROM AUTHOR]

[Display omitted] • Vitamin A-Myrj52 easter conjugate could be used as a liver targeting ligand. • Vitamin A coupled SLNs were prepared to target liver fibrosis in rats. • Vitamin A coupled butein loaded SLNs normalize liver function markers and oxidative stress markers after 4 weeks of treatment. • Butein decreases kidney injury and reduces serum urea and creatinine levels. The development of a therapeutic system for hepatic fibrosis has become a research hotspot to date. Butein, a simple chalcone derivative, displays anti-fibrotic effects through different pathways. However, impurities, low solubility, and low concentration in the target tissue hinder therapy with herbal ingredients. Hepatic stellate cells (HSCs), the vitamin A (VA) storage cells, as the main contributors to liver fibrogenesis, are not readily accessible to drugs owing to their anatomical location. Targeted delivery of therapeutics to the activated HSCs is therefore critical for successful treatment. For these reasons, the current study aimed at increasing butein delivery to the liver. Hence, high purity butein was synthesized in three steps. A novel VA-Myrj52 ester conjugate was also synthesized using all-trans retinoic acid and a hydrophilic emulsifier (Myrj52) as a targeting agent. Next, butein was encapsulated inside the novel VA-modified solid lipid nanoparticles (VA-SLNs) and studied in vitro and in vivo. According to our evaluations, negatively charged SLNs with a mean diameter of 150 nm and entrapment efficacy of 75 % were successful in liver fibrosis amelioration. Intraperitoneal (i.p.) injection of VA-SLNs in fibrotic rats, for four weeks long, reduced serum AST and ALT by 58% (P, 0.001) and 72% (P, 0.05), respectively, concerning the CCl 4 group. Additionally, histologic damage score decline and normalization of tissue oxidative stress markers collectively confirmed the efficacy of formulations in hepatic fibrosis and kidney damage amelioration. [ABSTRACT FROM AUTHOR]

[Display omitted] Programmed cell death 1 (PD-1) blockade combination to other drugs have attracted the interest of scientists for treating tumors resistant to PD-1 blockade. In this study, the impact of the interval, order of administration, and number of cycles of immunotherapeutic combination of stimulator of interferon genes (STING) pathway agonist loaded lipid nanoparticle (STING-LNP) and PD-1 antibody for inducing the optimal combined antitumor activity against a melanoma lung metastasis is reported. One cycle had no effect, but two and three cycles resulted in a combined antitumor effect. The interval between the administration was found to influence the induction of the combined effect. The second and third doses increased the gene expression of the NK cell activation marker, interferon γ (IFN-γ), PD-1 and a ligand of PD-1 (PD-L1), whereas the first dose failed. NK cells in the lung showed an increase in the expression of the activation markers and PD-1 after the second dose. The combined antitumor effect of this combination therapy against melanoma lung metastasis model could be dependent on the interval as well as the number of doses of STING-LNP. These findings suggest the importance of the protocol setting when combining a nano system loaded with an immune adjuvant and PD-1 antibody. [ABSTRACT FROM AUTHOR]

[Display omitted] Cancer treatments are always associated with various challenges, and scientists are constantly trying to find new therapies and methods. Erlotinib (ELT) is a well-known medicine against non-small cell lung cancer (NSCLC). However, treatments by ELT disrupt therapy due to drug resistance and pose severe challenges to patients. To achieve high-performance treatment, we gained nanostructured lipid carriers (NLCs) to evaluate synergistic anticancer effects of co-delivery of ELT and resveratrol (RES), a natural herbal derived phenol against NSCLC. NLCs are prepared via the hot homogenization method and characterized. In vitro cytotoxicity of formulations were evaluated on adenocarcinoma human alveolar basal epithelial (A549) cells. Prepared NLCs showed a narrow particle size (97.52 ± 17.14 nm), negative zeta potential (-7.67 ± 4.55 mV), and high encapsulation efficiency (EE%) was measured for the prepared co-delivery system (EE% 89.5 ± 5.16 % for ELT and 90.1 ± 6.61 % for RES). In vitro outcomes from cell viability study (12.63 % after 48 h of treatment), apoptosis assay (85.50%.), cell cycle (40.00% arrest in G2-M), and western blotting investigations (decreasing of protein expression levels of survivin, Bcl-2, P-Caspase 3P-caspase 9, and P-ERK 1/2, and additionally, increasing protein levels of BAX, P53, C-Caspase 3 and 9), DAPI staining, and colony formation assays showed the augment cytotoxic performances for co-delivery of ELT and RES loaded NLCs. Our study introduced the co-delivery of ELT and RES by NLCs as a novel strategy to elevate the efficacy of chemotherapeutics for NSCLC. [ABSTRACT FROM AUTHOR]

[Display omitted] In this study PEG-free and zeta potential changing lipid-based nanocarriers providing enhanced cellular uptake were developed. Nanostructured lipid carriers (NLC), consisting of paraffin wax, caprylic/ capric triglyceride, cetyltrimethylammoniumchloride and either soy lecithin or polyglycerol-4 laurate and solid lipid nanoparticles (SLN) with the same composition but without the liquid lipid content were developed. All formulations exposed a positive surface charge and were then coated with the polyphosphate Graham's salt. Phosphate release from these formulations was evaluated by incubation with intestinal alkaline phosphatase as well as on a Caco-2 monolayer and zeta potentials were measured. Additionally, cellular uptake studies were performed. Within 5 h, a remarkable amount of phosphate was released from all formulations incubated with intestinal alkaline phosphatase. Enzymatically induced phosphate release with intestinal alkaline phosphatase led to a zeta potential shift up to Δ 26 mV. Results of phosphate release and zeta potential change were confirmed on Caco-2 cells. Cellular uptake studies on Caco-2 cells showed an up to 5.6-times higher uptake compared to cells with inhibited phosphatase. According to these results, polyphosphate coating is a powerful tool to obtain lipid-based nanocarriers for enhanced cellular uptake. [ABSTRACT FROM AUTHOR]

[Display omitted] Lornoxicam (LRX) is a potent nonsteroidal anti-inflammatory drug (NSAID) used extensively to manage pain and inflammatory conditions. However, the drug possesses poor aqueous solubility (i.e., BCS class II) and a short half-life (3–4 h). Mucoadhesive buccal tablets containing LRX -loaded solid lipid nanoparticles (SLNs) were developed to enhance the drug solubility and bioavailability and achieve a controlled release pattern for a better anti-inflammatory effect. Different LRX-loaded SLNs were prepared using the hot homogenization /ultra-sonication technique and evaluated using size analysis and entrapment efficiency (EE%). Optimized LRX -loaded SLNs formulation showed particle size of 216 ± 7.4 nm, zeta potential of −27.3 ± 4.6 mV, and entrapment efficiency of 92.56 ± 2.3 %. Dried LRX-loaded SLNs alongside mucoadhesive polymers blend (PVP K30 /HPMC K15) were compressed to prepare the mucoadhesive buccal tablets. The tablets showed proper physicochemical properties, good mucoadhesive strength, long mucoadhesive time, suitable pH surface, good swelling capacity, and controlled drug release profile. Furthermore, Fourier transform-infrared (FTIR) spectroscopy, Powder X-Ray diffraction (PXRD), and Scanning electron microscopy (SEM) studies were carried out. The in vivo anti-inflammatory effect of pure LRX, market LRX and optimized mucoadhesive buccal tablet of LRX -loaded SLNs (T3) against carrageenan-induced models were evaluated. T3 showed a significant and early anti-inflammatory response after 1 and 2 h (63.62–77.84 % inhibition) as well as an extended effect after 4 h as compared to pure and market LRX. In parallel, T3 showed the best amelioration of PGE2, COX2, and TNF-α serum levels after 4 h of carrageenan injection. [ABSTRACT FROM AUTHOR]

[Display omitted] Phosphatidylcholine (PC) vesicles loaded with Triiodothyronine (T3) were fabricated using different manufacturing methods: thin layer hydration plus sonication (TF-UF), supercritical liposome formation (SC), and microfluidic technology (MF). Vesicles obtained by MF had the lowest mean diameter (88.61 ± 44.48 nm) with a Zeta Potential of −20.1 ± 5.90 mV and loading of 10 mg/g (encapsulation efficiency: 57%). In contrast, SC vesicles showed extremely low encapsulation efficiency (<10%) probably due to T3 solubility in ethanol/carbon dioxide mixture; despite TF-UF vesicles exhibiting good size (167.7 ± 90 nm; Zp −8.50 ± 0.60 mV) and loading (10 mg/g), poor mass recovery was obtained (50% loss). MF vesicles had low cytotoxicity, and they were well enough internalized by both HeLa and human tendon stem/progenitor cells (hTSPCs). Their biological activity was also monitored in both 2D and 3D cultures of hTSPCs supplemented with therapeutical concentrations of PC/T3 nano-liposomes. 2D culture showed almost similar constitutive gene expression compared to control culture supplemented with free-T3. On the contrary, when hTPSCs 3D culture was assembled, it showed a more evident homogeneous distribution of FITC labeled vesicles within the high-density structure and a significant upregulation of cell constitutive genes, such as type I Collagen (4.8-fold; p < 0.0001) at day 7, compared to the control, suggesting that T3/PC formulation has increased T3 cytosolic concentration, thus improving cells metabolic activity. The study supported MF technology for nano-carriers fabrication and opens perspectives on the activity of PC/T3 nano-vesicles as innovative formulations for TPSCs stimulation in ECM secretion. [ABSTRACT FROM AUTHOR]