Polycaprolactone - Vitamin E TPGS micelles for delivery of paclitaxel: In vitro and in vivo evaluation.

This study aimed to present findings on a paclitaxel (PTX)-loaded polymeric micellar formulation based on polycaprolactone-vitamin E TPGS (PCL-TPGS) and evaluate its in vitro anticancer activity as well as its in vivo pharmacokinetic profile in healthy mice in comparison to a marketed formulation. Micelles were prepared by a co-solvent evaporation method. The micelle's average diameter and polydispersity were determined using dynamic light scattering (DLS) technique. Drug encapsulation efficiency was assessed using an HPLC assay. The in vitro cytotoxicity was performed on human breast cancer cells (MCF-7 and MDA-MB-231) using MTT assay. The in vivo pharmacokinetic profile was characterized following a single intravenous dose of 4 mg/kg to healthy mice. The mean diameters of the prepared micelles were ≤ 100 nm. Moreover, these micelles increased the aqueous solubility of PTX from ∼0.3 µg/mL to reach nearly 1 mg/mL. While the PTX-loaded micelles showed an in vitro cytotoxicity comparable to the marketed formulation (Ebetaxel), drug-free PCL-TPGS micelles did not show any cytotoxic effects on both types of breast cancer cells (∼100% viability). Pharmacokinetics of PTX as part of PCL-TPGS showed a significant increase in its volume of distribution compared to PTX conventional formulation, Ebetaxel, which is in line with what was reported for clinical nano formulations of PTX, i.e., Abraxane, Genexol-PM, or Apealea. The findings of our studies indicate a significant potential for PCL-TPGS micelles to act as an effective system for solubilization and delivery of PTX.

RNA-Based Antipsoriatic Gene Therapy: An Updated Review Focusing on Evidence from Animal Models.

Psoriasis presents as a complex genetic skin disorder, characterized by the interaction between infiltrated immune cells and keratinocytes. Substantial progress has been made in understanding the molecular mechanisms of both coding and non-coding genes, which has positively impacted clinical treatment approaches. Despite extensive research into the genetic aspects of psoriasis pathogenesis, fully grasping its epigenetic component remains a challenging endeavor. In response to the pressing demand for innovative treatments to alleviate inflammatory skin disorders, various novel strategies are under consideration. These include gene therapy employing antisense nucleotides, silencing RNA complexes, stem cell therapy, and antibody-based therapy. There is a pressing requirement for a psoriasis-like animal model that replicates human psoriasis to facilitate early preclinical evaluations of these novel treatments. The authors conduct a comprehensive review of various gene therapy in different psoriasis-like animal models utilized in psoriasis research. The animals included in the list underwent skin treatments such as imiquimod application, as well as genetic and biologic injections, and the results of these interventions are detailed. Animal models play a crucial role in translating drug discoveries from the laboratory to clinical practice, and these models aid in improving the reproducibility and clinical applicability of preclinical data. Numerous animal models with characteristics similar to those of human psoriasis have proven to be useful in understanding the development of psoriasis. In this review, the article focuses on RNA-based gene therapy exploration in different types of psoriasis-like animal models to improve the treatment of psoriasis.

Skin delivery of synthetic benzoyl pterostilbenes suppresses atopic dermatitis-like inflammation through the inhibition of keratinocyte and macrophage activation.

Atopic dermatitis (AD) is one of the most common skin autoimmune diseases needing continuous anti-inflammatory management. Pterostilbene is reported to exhibit anti-inflammatory activity with higher bioavailability and stability than its parent compound, resveratrol. In this study, a series of synthetic pterostilbene analogs were designed by the hybridization of pterostilbene with chalcones or benzoyl chloride. Seventeen analogs derived from pterostilbene were synthesized with differences in the positions of hydroxyl, methoxyl, or fluoro moieties. These compounds were screened by the inhibitory effect on the overexpressed Th2-associated cytokines/chemokines in the activated human keratinocytes (HaCaT). The anti-IL-5 and anti-CCL5 activity of these compounds led to the identification of three effective compounds: 3a ((E)- 4-(3,5-dimethoxystyryl)phenyl benzoate), 3d ((E)- 4-(3,5-dimethoxystyryl)phenyl 2-methoxybenzoate), and 3g ((E)- 4-(3,5-dimethoxystyryl)phenyl 2-fluorobenzoate). These benzoyl pterostilbenes also significantly decreased Th1/Th17-associated proinflammatory mediators in the activated macrophages (differentiated THP-1). The result showed that the conditioned medium of benzoyl pterostilbene-treated macrophages reduced the phosphorylated STAT3 in the keratinocytes, indicating the blockade of crosstalk between resident and immune cells. Compounds 3d and 3g generally showed greater skin absorption than 3a. The flux of 3g across barrier-defective skins mimicking the AD skin was 3-fold higher than that of across intact skin. The dinitrochlorobenzene (DNCB)-induced AD mouse model manifested that topical delivery with 3g improved the pathological signs through inhibiting cytokines/chemokines (IL-5, TNF-α, CCL17, and CCL22) and macrophage recruitment. The epidermal thickness was reduced from 76 to 55 µm after topical 3g delivery. The therapeutic activity of 3g was comparable to that of tacrolimus (TAC) used as a positive control. The benzoyl pterostilbenes attenuated the inflammation via the MAPK and c-Jun signaling. Furthermore, this study provided experimental evidence of benzoyl pterostilbene analogs for therapeutic potential on AD.

Development of Gefitinib-Loaded Solid Lipid Nanoparticles for the Treatment of Breast Cancer: Physicochemical Evaluation, Stability, and Anticancer Activity in Breast Cancer (MCF-7) Cells.

In the current study, the toxic effects of gefitinib-loaded solid lipid nanoparticles (GFT-loaded SLNs) upon human breast cancer cell lines (MCF-7) were investigated. GFT-loaded SLNs were prepared through a single emulsification-evaporation technique using glyceryl tristearate (Dynasan™ 114) along with lipoid® 90H (lipid surfactant) and Kolliphore® 188 (water-soluble surfactant). Four formulae were developed by varying the weight of the lipoid™ 90H (100-250 mg), and the GFT-loaded SLN (F4) formulation was optimized in terms of particle size (472 ± 7.5 nm), PDI (0.249), ZP (-15.2 ± 2.3), and EE (83.18 ± 4.7%). The optimized formulation was further subjected for in vitro release, stability studies, and MTT assay against MCF-7 cell lines. GFT from SLNs exhibited sustained release of the drug for 48 h, and release kinetics followed the Korsmeyer-Peppas model, which indicates the mechanism of drug release by swelling and/or erosion from a lipid matrix. When pure GFT and GFT-SLNs were exposed to MCF-7 cells, the activities of p53 (3.4 and 3.7 times), caspase-3 (5.61 and 7.7 times), and caspase-9 (1.48 and 1.69 times) were enhanced, respectively, over those in control cells. The results suggest that GFT-loaded SLNs (F4) may represent a promising therapeutic alternative for breast cancer.

Combining the dual antibacterial and regenerative activities of platelet-rich plasma with ß-lactams to mitigate MRSA-infected skin wounds.

The emergence of multidrug-resistant bacteria contributes to the necessity of developing novel infection treatment approaches. This study was designed to evaluate the antimicrobial and wound healing activities of platelet-rich plasma (PRP) in combination with ß-lactams (ampicillin and/or oxacillin) for the application on methicillin-resistant Staphylococcus aureus (MRSA)-infected skin. PRP was collected from the peripheral blood of healthy donors. The anti-MRSA activity was tested through a growth inhibition curve, colony-forming unit (CFU), and SYTO 9 assay. The PRP incorporation lowered the minimum inhibitory concentration (MIC) of ampicillin and oxacillin against MRSA. The combination of ß-lactams together with PRP showed a three-log CFU reduction of MRSA. The major components of PRP for eliminating MRSA were found to be the complement system and iron sequestration proteins, according to the proteomic analysis. The adhesive bacterial colony in the microplate was decreased from 2.9 × 107 to 7.3 × 105 CFU after the treatment of cocktails containing ß-lactams and PRP. The cell-based study indicated that keratinocyte proliferation was stimulated by PRP. The in vitro scratch and transwell experiments revealed that PRP improved keratinocyte migration. In the MRSA-infected mouse skin model, PRP appeared to show a synergistic effect for wound area reduction by 39% when combined with ß-lactams. The MRSA burden in the infected area was lessened two-fold after topical administration of the combined ß-lactams and PRP. PRP inhibited macrophage infiltration in the wound site to shorten the inflammatory phase and accelerate the initiation of the proliferative phase. No skin irritation was detected with the topical delivery of this combination. Our findings suggested that ß-lactams plus PRP was applicable to alleviate the problems associated with MRSA via dual antibacterial and regenerative activities.

Eluxadoline-Loaded Eudragit Nanoparticles for Irritable Bowel Syndrome with Diarrhea: Formulation, Optimization Using Box-Behnken Design, and Anti-Diarrheal Activity.

Eluxadoline (ELD), a recently approved drug, exhibits potential therapeutic effects in the management and treatment of IBS-D. However, its applications have been limited due to poor aqueous solubility, leading to a low dissolution rate and oral bioavailability. The current study's goals are to prepare ELD-loaded eudragit (EG) nanoparticles (ENPs) and to investigate the anti-diarrheal activity on rats. The prepared ELD-loaded EG-NPs (ENP1-ENP14) were optimized with the help of Box-Behnken Design Expert software. The developed formulation (ENP2) was optimized based on the particle size (286 ± 3.67 nm), PDI (0.263 ± 0.01), and zeta potential (31.8 ± 3.18 mV). The optimized formulation (ENP2) exhibited a sustained release behavior with maximum drug release and followed the Higuchi model. The chronic restraint stress (CRS) was successfully used to develop the IBS-D rat model, which led to increased defecation frequency. The in vivo studies revealed a significant reduction in defecation frequency and disease activity index by ENP2 compared with pure ELD. Thus, the results demonstrated that the developed eudragit-based polymeric nanoparticles can act as a potential approach for the effective delivery of eluxadoline through oral administration for irritable bowel syndrome diarrhea treatment.

Lipid-based nanoformulation optimization for achieving cutaneous targeting: Niosomes as the potential candidates to fulfill this aim.

The present study screened the utility of topically-applied nanoformulations to target the drugs/actives into the skin reservoir with the reduction of possible systemic absorption. The lipid-based nanoformulations selected in this study included solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), nanoemulsions (NEs), liposomes, and niosomes. We loaded flavanone and retinoic acid (RA) as the penetrants. The prepared nanoformulations were assessed for their average diameter, polydispersity index (PDI), and zeta potential. An in vitro permeation test (IVPT) was utilized to determine the skin delivery into/across pig skin, atopic dermatitis (AD)-like mouse skin, and photoaged mouse skin. We found an increased skin absorption of lipid nanoparticles following the increase of solid lipid percentage in the formulations (SLNs > NLCs > NEs). The use of liposomes even reduced the dermal/transdermal selectivity (S value) to lessen the cutaneous targeting. The niosomes resulted in significantly greater RA deposition and reduced permeation in the Franz cell receptor compared to the other nanoformulations. The S value of the RA delivery via stripped skin was increased by 26-fold in the niosomes compared to the free RA. The dye-labeled niosomes displayed a strong fluorescence in the epidermis and upper dermis through the visualization of fluorescence and confocal microscopies. The cyanoacrylate skin biopsy manifested greater hair follicle uptake of the niosomes compared to the free penetrants by 1.5 to three-fold. The 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay indicated an increase in antioxidant ability from 55% to 75% after flavanone entrapment in the niosomes. In the activated keratinocytes, the niosomal flavanone could suppress the overexpressed CCL5 to the baseline control because of the facile cell internalization. After the formulation optimization, the niosomes with higher phospholipid amount had a superior effect in delivering penetrants into the skin reservoir, with limited permeation to the receptors.

Anti-Inflammatory microRNAs for Treating Inflammatory Skin Diseases.

Skin inflammation occurs due to immune dysregulation because of internal disorders, infections, and allergic reactions. The inflammation of the skin is a major sign of chronic autoimmune inflammatory diseases, such as psoriasis, atopic dermatitis (AD), and lupus erythematosus. Although there are many therapies for treating these cutaneous inflammation diseases, their recurrence rates are high due to incomplete resolution. MicroRNA (miRNA) plays a critical role in skin inflammation by regulating the expression of protein-coding genes at the posttranscriptional level during pathogenesis and homeostasis maintenance. Some miRNAs possess anti-inflammatory features, which are beneficial for mitigating the inflammatory response. miRNAs that are reduced in inflammatory skin diseases can be supplied transiently using miRNA mimics and agomir. miRNA-based therapies that can target multiple genes in a given pathway are potential candidates for the treatment of skin inflammation. This review article offers an overview of the function of miRNA in skin inflammation regulation, with a focus on psoriasis, AD, and cutaneous wounds. Some bioactive molecules can target and modulate miRNAs to achieve the objective of inflammation suppression. This review also reports the anti-inflammatory efficacy of these molecules through modulating miRNA expression. The main limitations of miRNA-based therapies are rapid biodegradation and poor skin and cell penetration. Consideration was given to improving these drawbacks using the approaches of cell-penetrating peptides (CPPs), nanocarriers, exosomes, and low-frequency ultrasound. A formulation design for successful miRNA delivery into skin and target cells is also described in this review. The possible use of miRNAs as biomarkers and therapeutic modalities could open a novel opportunity for the diagnosis and treatment of inflammation-associated skin diseases.

Nanoencapsulation of Tea Catechins for Enhancing Skin Absorption and Therapeutic Efficacy.

Tea catechins are a group of flavonoids that show many bioactivities. Catechins have been extensively reported as a potential treatment for skin disorders, including skin cancers, acne, photoaging, cutaneous wounds, scars, alopecia, psoriasis, atopic dermatitis, and microbial infection. In particular, there has been an increasing interest in the discovery of cosmetic applications using catechins as the active ingredient because of their antioxidant and anti-aging activities. However, active molecules with limited lipophilicity have difficulty penetrating the skin barrier, resulting in low bioavailability. Nevertheless, topical application is a convenient method for delivering catechins into the skin. Nanomedicine offers an opportunity to improve the delivery efficiency of tea catechins and related compounds. The advantages of catechin-loaded nanocarriers for topical application include high catechin loading efficiency, sustained or prolonged release, increased catechin stability, improved bioavailability, and enhanced accumulation or targeting to the nidus. Further, various types of nanoparticles, including liposomes, niosomes, micelles, lipid-based nanoparticles, polymeric nanoparticles, liquid crystalline nanoparticles, and nanocrystals, have been employed for topical catechin delivery. These nanoparticles can improve catechin permeation via close skin contact, increased skin hydration, skin structure disorganization, and follicular uptake. In this review, we describe the catechin skin delivery approaches based on nanomedicine for treating skin disorders. We also provide an in-depth description of how nanoparticles effectively improve the skin absorption of tea catechins and related compounds, such as caffeine. Furthermore, we summarize the possible future applications and the limitations of nanocarriers for topical delivery at the end of this review article.

The effectiveness of synthetic methoxylated isoflavones in delivering to the skin and alleviating psoriasiform lesions via topical absorption.

This study was conducted to appraise the possible potential of synthetic isoflavones (SIFs) on psoriasis treatment. A practical and easy-to-operate approach was employed in synthesizing a series of SIFs, considering that acquiring flavonoids from natural resources is usually expensive, time-consuming, and non-eco-friendly. Seven SIFs derived from daidzein were produced with differences in the location of the hydroxyl groups and degree of methoxylation. The in vitro and in vivo skin absorption of topically applied SIFs was estimated. Further, keratinocytes (HaCaT) were employed as the model to investigate the anti-inflammatory activity of the isoflavones. The lipophilicity was increased from SIF-1 to -7. Noteworthily, there was a parabolic relationship between lipophilicity and skin absorption, with SIF-5 (4',7-dihydroxyisoflavone, daidzein) and SIF-6 (7-hydroxy-3',4'-dimethoxyisoflavone, cladrin) demonstrating the highest retention in pig skin. The methoxylated isoflavone SIF-5 showed the greatest permeation into barrier-deficient skin among the compounds tested, with a 6- and 8-fold increase after lipid and protein removal. The cell-based study exhibited the capability of SIFs to restrain the overexpressed IL-6, IL-8, and CXCL1 in stimulated HaCaT. The therapeutic index (TI) predicted the potential candidates of SIF-5 and SIF-6 for topical application to treat psoriatic inflammation. The imiquimod (IMQ)-driven psoriasiform murine model manifested the inhibition of hyperplasia and immune cell infiltration by topically administered SIF-5 and SIF-6. The epidermal thickness of IMQ-treated skin was decreased from 172 to 40 µm by both isoflavones. This effect was comparable with that of betamethasone, the positive control. The topical treatment of SIF-6 significantly reduced cytokine/chemokine upregulation by IMQ. The methoxylated isoflavone with dramatic anti-inflammatory activity is promising for the development of an antipsoriatic agent.

Cutaneous Delivery of Cosmeceutical Peptides Enhanced by Picosecond- and Nanosecond-Domain Nd:YAG Lasers with Quick Recovery of the Skin Barrier Function: Comparison with Microsecond-Domain Ablative Lasers.

Picosecond or nanosecond-domain non-ablative lasers generate faster photothermal effects and cause less injury than microsecond lasers. In this study, we investigated the enhancing effect of 1064 nm picosecond- and nanosecond-domain neodymium (Nd):yttrium-aluminum-garnet (YAG) lasers on the cutaneous delivery of cosmeceutical peptides. Microsecond-domain fractional ablative CO2 and fully ablative erbium (Er):YAG lasers were also used for comparison. In the Franz diffusion cell study, pig or mouse skin was treated with a laser before exposure to palmitoyl tripeptide (PT)-1, PT-38, and copper tripeptide (CT)-1 at a concentration of 150 µM. Psoriasiform, atopic dermatitis (AD)-like, and photoaged skins were also developed as permeation barriers. The non-ablative laser elicited the ultrastructural disruption of the stratum corneum and epidermal vacuolation. All laser modalities significantly increased the skin permeation of peptides in vitro. The non-ablative laser chiefly enhanced peptide delivery to the receptor compartment, whereas the ablative laser mainly increased the intracutaneous peptide deposition. The picosecond- and nanosecond-domain Nd:YAG lasers elevated the amount of PT-1 in the receptor up to 40- and 22-fold compared with untreated skin, respectively. Laser treatment promoted peptide delivery in barrier-deficient and inflamed skins, although this enhancement effect was less than that observed in healthy skin. Fluorescence microscopy indicated the capability of the non-ablative laser to deliver peptides to deeper skin strata. The ablative laser confined the peptide distribution in the epidermis. Confocal microscopy showed that peptides penetrated the skin along the microdots created by the fractional Nd:YAG and CO2 lasers. The skin barrier function determined by transepidermal water loss suggested quick recovery when using a nanosecond-domain laser (within 4 h). A longer period was needed for the skin treated with the fully ablative Er:YAG laser (76-84 h). Nanosecond non-ablative laser-facilitated peptide delivery may become an efficient and safe approach for cosmeceutical applications.

Rhubarb hydroxyanthraquinones act as antiobesity agents to inhibit adipogenesis and enhance lipolysis.

Rhubarb as an herbal medicine has been shown to exhibit antiadipogenic activity. This study evaluated and compared the lipid-lowering activity of five rhubarb hydroxyanthraquinones (HAQs), including chrysophanol, aloe emodin, emodin, physcion, and rhein, aiming to identify candidate compounds for obesity treatment. Examination of the antiobesity effects of HAQs in 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese rats showed that these anthraquinone compounds inhibited lipid accumulation in 3T3-L1 cells before and after differentiation. Emodin and rhein showed greater inhibition than the other compounds; dosage at 50 µM reduced intracellular triglyceride (TG) by about 30% in the differentiated adipocytes. Both compounds also revealed lipolytic effects to increase glycerol release from adipocytes. Adipokine overexpression induced by differentiation was downregulated by emodin and rhein through mitogen-activated protein kinase (MAPK) signaling. Despite their structural similarity, emodin and rhein exhibited different mechanisms on adipogenesis and lipid metabolism. Rhein restrained lipid deposition by controlling adipogenic transcriptional factors and lipolytic lipases during differentiation. The lipid-lowering effects of emodin did not use these pathways but reduced levels of lipogenic enzymes. HFD consumption in rats significantly increased body weight, visceral fat mass and adipocyte size, which were attenuated by intraperitoneal delivery of emodin or rhein. Rhein showed greater amelioration of obesity than emodin, decreasing plasma cholesterol by 29% and 14%, respectively. HAQs also suppressed cytokine upregulation in the liver and adipose tissues of obese rats. Rhein is a potential antiobesity agent through its ability to regulate obesity-associated adipogenesis, lipolysis and inflammation.

Value drivers for pharmaceutical products in health technology assessment (HTA) in Saudi Arabia: Results from a capacity Building, Multi-Stakeholder workshop.

OBJECTIVES: Capacity building exercises are important to increase understanding of healthcare processes by key stakeholders, and to facilitate open discussions to build consensus. This study explored the views of a multi-stakeholder group of local Saudi experts on possible value elements that could be important for health technology assessment (HTA) processes and methods regarding pharmaceutical products in Saudi Arabia ('value drivers'). METHODS: A diversified group of local experts were invited to a two-day capacity building workshop from 18 to 19 December 2019 in Riyadh, Saudi Arabia. Information regarding the participants' demographic and educational/professional background, along with their self-assessed knowledge and experience of HTAs and the concept of value in the pharmaceutical market was collected. For each of 22 value drivers identified during a targeted literature search, participants were asked either to 'opt out' of its consideration for future HTA assessments, or rate it from 1 to 10 (low-high) on feasibility and acceptability. RESULTS: Efficacy and safety were the highest rated value drivers for acceptability and feasibility. Explicit cost-effectiveness thresholds had the lowest ratings for acceptability and feasibility. Participants highlighted data availability and accuracy as a potential challenge to HTA implementation in Saudi Arabia. CONCLUSIONS: Participants valued a pharmaceutical product's efficacy and safety alongside the consideration of disease characteristics for HTA processes. Participants also valued a binding HTA recommendation and the use of local real-world evidence, where available, to support HTA submissions.

Empirical Monetary Valuation of a Quality-Adjusted Life-Year in the Kingdom of Saudi Arabia: A Willingness-to-Pay Analysis.

BACKGROUND: No willingness-to-pay (WTP) per quality-adjusted life-year (QALY) value exists for the Kingdom of Saudi Arabia (KSA). OBJECTIVE: The primary objective of this study was to determine the WTP for a QALY in the KSA. METHODS: Adult citizens of the KSA, patients with cancer, or members of the general public (MGP) were recruited to participate in a time trade-off survey to elicit health utilities. Cancer was chosen as the disease of interest for patients and the MGP, with a scenario describing stage 3 colorectal cancer, because it is a disease condition that impacts on both quality of life and survival time. In a second step, respondents were asked about their WTP to move from the estimated health state to a state of perfect health for 1 year (QALY). Finally, that amount was processed to generate the WTP for a full QALY. The second step was repeated with a 5-year horizon. Sensitivity analyses were performed without outliers. RESULTS: From 400 participants, data from 378 subjects were obtained and usable: 177 patients, 201 MGP; 278 male, 100 female subjects; 231 aged 26-65 years. Demographic distribution varied widely between the two subgroups for age, education level, and employment status, but with less variation in sex and income. Elicited health utilities were 0.413 (0.472 after adjustment) for the overall group, 0.316 (0.416) for patients, and 0.499 (0.508) for MGP. Overall WTP for a QALY was $US25,600 (adjusted $US32,000) for the 1-year horizon and $US19,200 (adjusted $US22,720) for the 5-year horizon. CONCLUSION: This was the first empirical attempt to estimate the WTP per QALY for the KSA. Results are comparable to those in some other countries and to gross domestic product figures for the KSA. Further research in a country-wide sample is warranted.

Intravenous anti-MRSA phosphatiosomes mediate enhanced affinity to pulmonary surfactants for effective treatment of infectious pneumonia.

The aim of this study was to develop PEGylated phosphatidylcholine (PC)-rich nanovesicles (phosphatiosomes) carrying ciprofloxacin (CIPX) for lung targeting to eradicate extracellular and intracellular methicillin-resistant Staphylococcus aureus (MRSA). Soyaethyl morphonium ethosulfate (SME) was intercalated in the nanovesicle surface with the dual goals of achieving strengthened bactericidal activity of CIPX-loaded phosphatiosomes and delivery to the lungs. The isothermal titration calorimetry (ITC) results proved the strong association of SME phosphatiosomes with pulmonary surfactant. We demonstrated a superior anti-MRSA activity of SME phosphatiosomes compared to plain phosphatiosomes and to free CIPX. A synergistic effect of CIPX and SME nanocarriers was found in the biofilm eradication. SME phosphatiosomes were readily engulfed by the macrophages, restricting the intracellular MRSA count by 1-2 log units. SME phosphatiosomes efficiently accumulated in the lungs after intravenous injection. In a rat model of lung infection, the MRSA burden in the lungs could be decreased by 8-fold after SME nanosystem application.

Derivatization of honokiol by integrated acetylation and methylation for improved cutaneous delivery and anti-inflammatory potency.

A set of honokiol derivatives was synthesized to evaluate skin permeation and bioactivity. The reaction for derivatization included acetylation and methylation. The anti-inflammatory activity against neutrophils and macrophages was examined. The experimental setup for the assessment of cutaneous absorption was the in vitro Franz diffusion assembly. Honokiol and its derivatives significantly downregulated superoxide anion and elastase production in neutrophils, with honokiol showing the greatest inhibition. All derivatives could be completely hydrolyzed to the parent compounds after passing into the skin. The skin deposition of honokiol at an infinite dose (3mM) was 0.33nmol/mg 4'-O-acetylhonokiol (AH), and 2,4'-diacetylhonokiol (DAH) exhibited comparable or less absorption than honokiol. The integrated acetylation and methylation (2-O-acetyl-4'-O-methylhonokiol, AMH) led to a 10.5-fold improvement of absorption compared to honokiol. AMH was advantageous for the targeted cutaneous treatment due to the high skin deposition and minimal penetration across the skin (8.40nmol/cm2 compared to 93.49nmol/cm2 for honokiol). The predicted therapeutic index for superoxide and interleukin (IL)-6 inhibition was much higher for topically applied AMH than for the other penetrants tested. The total polarity surface and hydrogen bond acceptor number calculated by molecular modeling were the parameters used to anticipate the cutaneous absorption. Our data suggest that AMH is a potent and safe candidate for cutaneous inflammation therapy.

Naphtho[1,2-b]furan-4,5-dione is a potent anti-MRSA agent against planktonic, biofilm and intracellular bacteria.

AIM: Naphtho[1,2-b]furan-4,5-dione (N12D) and naphtho[2,3-b]furan-4,9-dione (N23D) are furanonaphthoquinone derivatives from natural resources. We examined the antimicrobial activity of N12D and N23D against drug-resistant Staphylococcus aureus. MATERIALS & METHODS: Minimum inhibitory concentration, minimum bactericidal concentration, bacterial viability and agar diffusion assay were conducted against methicillin-resistant S. aureus (MRSA) and clinical isolates of vancomycin-resistant S. aureus. RESULTS & CONCLUSION: The minimum inhibitory concentration of N12D and N23D against MRSA was 4.9-9.8 and 39 µM, respectively. With regard to the agar diffusion test, the inhibition zone of the quinone compounds was threefold larger than that of oxacillin. N12D was found to inhibit MRSA biofilm thickness from 24 to 16 µm as observed by confocal microscopy. N12D showed a significant reduction of the intracellular MRSA burden without decreasing the macrophage viability. The antibacterial mechanisms of N12D may be bacterial wall/membrane damage and disturbance of gluconeogenesis and the tricarboxylic acid cycle.

Current pathogenic Escherichia coli foodborne outbreak cases and therapy development.

Food contamination by pathogenic microorganisms has been a serious public health problem and a cause of huge economic losses worldwide. Foodborne pathogenic Escherichia coli (E. coli) contamination, such as that with E. coli O157 and O104, is very common, even in developed countries. Bacterial contamination may occur during any of the steps in the farm-to-table continuum from environmental, animal, or human sources and cause foodborne illness. To understand the causes of the foodborne outbreaks by E. coli and food-contamination prevention measures, we collected and investigated the past 10 years' worldwide reports of foodborne E. coli contamination cases. In the first half of this review article, we introduce the infection and symptoms of five major foodborne diarrheagenic E. coli pathotypes: enteropathogenic E. coli (EPEC), Shiga toxin-producing E. coli/enterohemorrhagic E. coli (STEC/EHEC), Shigella/enteroinvasive E. coli (EIEC), enteroaggregative E. coli (EAEC), and enterotoxigenic E. coli (ETEC). In the second half of this review article, we introduce the foodborne outbreak cases caused by E. coli in natural foods and food products. Finally, we discuss current developments that can be applied to control and prevent bacterial food contamination.

Exploring the structure-permeation relationship of topical tricyclic antidepressants used for skin analgesia.

The purpose of this study was to evaluate the skin permeation of tricyclic antidepressants (TCAs) with propamine moiety to select candidates for the development of topical analgesics to treat cutaneous pain. We sought to establish the structure-permeation relationship (SPR) of topical TCAs. The lipophilicity, melting point, and aqueous solubility were determined to develop the physicochemical characterization. The TCA permeation into pig and nude mouse skins was estimated using Franz diffusion cell. TCAs and lidocaine were comparatively examined for cutaneous analgesia by pinprick assay. Cutaneous tolerance to TCAs was assessed using nude mouse skin. The skin deposition increased following the increase of lipophilicity after excluding the effect of solubility, with clomipramine exhibiting the highest skin retention. A contrary result was observed for TCA penetration into the receptor. Of the permeants tested, clomipramine demonstrated the best skin-targeting ability. Nortriptyline and clomipramine demonstrated selective uptake into the hair follicles, exhibiting a 2.5-fold higher follicular accumulation than desipramine. Replacement of nitrogen with carbon in the seven-member ring increased skin absorption. The tertiary amine TCAs demonstrated higher absorption than the secondary amine TCAs. The position of the double bond also affected skin transport. Topical clomipramine had a longer duration of analgesic action than lidocaine (240min versus 60min). Exploring the SPR revealed that clomipramine could be an analgesic candidate drug for future development.

Injectable Drug-Loaded Nanocarriers for Lung Cancer Treatments.

Different types of injectable nanoparticles, including metallic nanoparticles, polymeric nanocarriers, dendrimers, liposomes, niosomes, and lipid nanoparticles, have been employed to load drugs for lung delivery. Nanoparticles used for lung delivery offer some benefits over conventional formulations, including increased solubility, enhanced stability, improved epithelium permeability and bioavailability, prolonged half-life, tumor targeting, and minimal side effects. In recent years, the concept of using injectable nanocarriers as vehicles for drug delivery has attracted increasing attention. This review highlights recent developments using nanomedical approaches for drug targeting to the lungs. We systematically introduce the concepts and amelioration mechanisms of the nanomedical techniques for lung cancer therapy. Passive targeting by modulating the nanoparticulate structure and the physicochemical properties is an option for efficient drug delivery to the lungs. In addition, active targeting such as antibody or peptide conjugation to nanoparticles is another efficient way to deliver the drugs to the targeted site. This review describes various nanocarriers loaded with anticancer drugs for passive or active targeting of lung malignancy. In this review, we principally focus on the nanomedical application in animal studies. The article excludes investigations limited to cell-based experiments. The review ends by anticipating future developments and trends.