Antiproliferative and Anti-Inflammatory Effects of the Polyphenols Phloretin and Balsacone C in a Coculture of T Cells and Psoriatic Keratinocytes.

Plaque psoriasis is a chronic inflammatory skin disease causing red inflamed lesions covered by scales. Leukocytes, including dendritic cells and T cells, participate in the inflammation of the skin by producing multiple cytokines, thus contributing to the hyperproliferation of keratinocytes. Lack of effectiveness and toxic side effects are the main concerns with conventional treatments, and research involving new antipsoriatic molecules is essential. In this study, the anti-inflammatory and antiproliferative effects of two natural polyphenols, phloretin and balsacone C, were investigated using the coculture of T cells and psoriatic keratinocytes. Phloretin exerted antiproliferative activity by regulating the expression of antigen Ki67 and proliferating cell nuclear antigen (PCNA). These effects were comparable to those of methotrexate, a reference treatment for moderate to severe psoriasis. With balsacone C, the expression of Ki67 was also reduced. Additionally, phloretin decreased the levels of multiple pro-inflammatory cytokines: monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1α (MIP-1α), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interleukin-17A (IL-17A), and tumor necrosis factor alpha (TNF-α). The increased interleukin-2 (IL-2) levels with phloretin and methotrexate also represented anti-inflammatory activity. Balsacone C and methotrexate decreased the levels of IL-1α and IL-1ß, but methotrexate exerted a higher reduction. In summary, the anti-inflammatory effects of phloretin were more pronounced than those of methotrexate and balsacone C. In addition, the expression of lymphocyte common antigen (CD45) was more similar to that of the healthy condition after using phloretin or methotrexate. Finally, phloretin stood out from the other compounds and appears promising for psoriasis treatment.

Parastomal hernia: an overview.

Parastomal hernia (PH) is one of the most frequent ostomy complications, and the reported incidence in the literature is highly variable. As highlighted by the Association of Stoma Care Nurses UK, this complication develops mainly in children and older men over 70, but many predisposing factors are related to the individual patient and surgery. There is no standardised system for assessing PH. The main assessment techniques include objective examination, ultrasound scan and computed tomography. Prevention is based on various interventions by surgeons and stoma care nurses (SCNs). The SCN's primary interventions include accurate patient evaluation, pre-operative ostomy siting, education about body weight management and advice on appropriate exercises. The treatment of PH can be conservative or surgical, and the choice is based on the patient's clinical condition. Ostomy can significantly impact on a patient's quality of life (QoL), and the presence of PH can further aggravate the situation. This overview of PH considers the incidence, aetiology, prevention, treatment and impact on QoL.

Optimization of a Liposomal DNase I Formulation with an Extended Circulating Half-Life.

Drug delivery systems such as liposomes are widely used to stabilize and increase the plasma half-life of therapeutics. In this article, we have investigated two strategies to increase the half-life of deoxyribonuclease I, an FDA-approved enzyme used for the treatment of cystic fibrosis, and a potential candidate for the reduction of uncontrolled inflammation induced by neutrophil extracellular traps. We demonstrate that our optimized preparation procedure resulted in nanoparticles with improved plasma half-life and total exposure relative to native protein, while maintaining enzymatic activity.

The frequency of early stomal, peristomal and skin complications.

BACKGROUND: The incidence of early complications after stoma formation (within 30 days of surgery) is difficult to determine and has been reported to be in a range of 3%-82%. AIM: The aim of this study was to analyse the onset of stomal, peristomal and skin complications one month (30 days) after ostomy creation. METHOD: This review analysed enteral stoma therapy nurse reports on patients who had an ostomy created between January 2016 and December 2020. FINDINGS: Complications were analysed according to ostomy type: colostomy, ileostomy and urostomy. There were 1292 incidences of complications: skin complications were the most common (26%), and abscess the least common (0%). CONCLUSION: A majority (63%) of patients experienced at least one or more complications within 30 days of surgery. Haemorrhage was reported as a complication (2%) but the authors found no data on its incidence in the literature. In addition to early complications, late complications were detected.

Advances in the Design of Transdermal Microneedles for Diagnostic and Monitoring Applications.

Due to their intrinsic advantages over classical hypodermic needles, microneedles have received much attention over the last two decades and will likely soon appear in clinics. Although the vast majority of research is focused on designing microneedles for the painless delivery of drugs, their applications for diagnostic purposes have also provided promising results. In this paper, the main advances in the field of microneedles for diagnostic and patient monitoring purposes are introduced and critically discussed.

Poly(2-oxazoline)-Pterostilbene Block Copolymer Nanoparticles for Dual-Anticancer Drug Delivery.

Functional block copolymers based on poly(2-oxazoline)s are versatile building blocks for the fabrication of dual-drug delivery nanoparticles (NPs) for anticancer chemotherapy. Core-shell NPs are fabricated from diblock copolymers featuring a long and hydrophilic poly(2-methyl-2-oxazoline) (PMOXA) block coupled to a relatively short and functionalizable poly(2-methylsuccinate-2-oxazoline) (PMestOXA) segment. The PMOXA block stabilizes the NP dispersions, whereas the PMestOXA segment is used to conjugate pterostilbene, a natural bioactive phenolic compound that is used as lipophilic model-drug and constitutes the hydrophobic core of the designed NPs. Subsequent loading of the NPs with clofazimine (CFZ), an inhibitor of the multidrug resistance pumps typically expressed in a large variety of cancer cells, provides an additional function to their formulation. Optimization of the copolymer composition allows the design of polymer scaffolds showing low toxicity and capable of assembling into highly stable NPs dispersions at physiologically relevant pH. In addition, the incorporation of CFZ increases the stability of the NPs and stimulates their internalization by RAW 264.7 cells.

Antibody-functionalized polymer nanoparticle leading to memory recovery in Alzheimer's disease-like transgenic mouse model.

Alzheimer's disease (AD) is a neurodegenerative disorder related, in part, to the accumulation of amyloid-ß peptide (Aß) and especially the Aß peptide 1-42 (Aß1-42). The aim of this study was to design nanocarriers able to: (i) interact with the Aß1-42 in the blood and promote its elimination through the "sink effect" and (ii) correct the memory defect observed in AD-like transgenic mice. To do so, biodegradable, PEGylated nanoparticles were surface-functionalized with an antibody directed against Aß1-42. Treatment of AD-like transgenic mice with anti-Aß1-42-functionalized nanoparticles led to: (i) complete correction of the memory defect; (ii) significant reduction of the Aß soluble peptide and its oligomer level in the brain and (iii) significant increase of the Aß levels in plasma. This study represents the first example of Aß1-42 monoclonal antibody-decorated nanoparticle-based therapy against AD leading to complete correction of the memory defect in an experimental model of AD.

Development of a Modular Ratiometric Fluorescent Probe for the Detection of Extracellular Superoxide.

Extracellular detection of endogeneous analytes (e.g., superoxide) can provide important insights into mechanisms of homeostasis and diseases, such as tumorigenesis. A ratiometric probe with a fluorescent reference and an analyte-specific switch-on dye was developed. Detection of ROS in the extracellular milieu was ensured by connecting the two fluorophores with a modular peptide-nucleic-acid-based linker. The ROS-sensing ability was assessed and validated in cell-free assays and in cell culture.

Accumulation of HIV-1 drug resistance in patients on a standard thymidine analogue-based first line antiretroviral therapy after virological failure: implications for the activity of next-line regimens from a longitudinal study in Mozambique.

BACKGROUND: We describe the accumulation of HIV-1 drug resistance and its effect on the activity of next-line components in patients with virological failure (HIV-1 RNA >1000 copies/mL) after 1 year (t1) of first-line antiretroviral therapy (ART) not switching to second-line drugs for one additional year (t2) in low-middle income countries (LMIC). METHODS AND RESULTS: We selected 48 patients from the DREAM cohort (Maputo, Mozambique); their median pre-ART CD4+ cell count was 165 cells/µl. At t1 patients were receiving ART since a median of 12.2 months (mainly zidovudine/lamivudine/nevirapine), their median HIV RNA was 3.8 log10 copies/mL, 43 (89.6%) presented at least one resistance-associated mutation (RAM), most frequently for lamivudine/emtricitabine, nevirapine and efavirenz. Resistance to tenofovir, was 10% at 1 year and higher than 20% at 2 years, while projection at 3 years was >30%. At t2, 42 (89.4%) had a predicted low-level or higher resistance to at least 1 s-line drug. At t1, the frequency of RAM in patients with a lower adherence to pharmacy appointments (<95%) was significantly lower (12/20, 60% for NRTI and 14/20, 70% for NNRTI) than in those with a better adherence (26/28, 92.8% for NRTI and 25/28, 89.3% for NNRTI) (OR 0.12, 95% CI 0.02-0.63, p = 0.012 and OR 0.28, 95% CI 0.06-1.29, p = 0.103, respectively). Overall thymidine analogue mutations (TAMs) accumulation rate was 0.32/year, 0.50/year in the subgroup with HIV RNA >10,000 copies/mL; NNRTI RAM accumulation rate was 0.15/year, 0.40/year in the subgroup with HIV RNA >10,000 copies/mL. CONCLUSIONS: While the activity of NNRTIs is compromised early during failure, tenofovir and zidovudine activity are reduced more frequently after 1 year of documented virological failure of thymidine analogue-based first-line ART, with RAMs accumulating faster in patients with higher viral loads. The present observation may help informing decisions on when to switch to a second line ART in patients on virological failure in LMIC.

Microneedles for the Noninvasive Structural and Functional Assessment of Dermal Lymphatic Vessels.

The medical and scientific communities' interest in the lymphatic system has been growing rapidly in recent years. It has become evident that the lymphatic system is much more than simply a homeostasis controller and that it plays key roles in several pathological conditions. This work describes the identification of the optimal combination of poly(N-vinylpyrrolidone) and a near-infrared dye (indocyanine green) for the manufacturing of soluble microneedles and their application to the imaging of the lymphatic system. Upon application to the skin, the microneedle-bearing indocyanine green is delivered in the dermal layer, where the lymphatic vessels are abundant. The draining lymphatics can then be visualized and the clearance kinetics from the administration site simply determined using a near-infrared camera. This painless functional "tattooing" procedure can be used for quantitative assessment of the dermal lymphatic function in several dermal conditions and treatment-response evaluations. The two components of these microneedles are extensively used in routine medical care, potentially leading to rapid clinical translation. Moreover, this procedure may have a significant impact on preclinical lymphatic studies.

Design, functionalization strategies and biomedical applications of targeted biodegradable/biocompatible polymer-based nanocarriers for drug delivery.

Design and functionalization strategies for multifunctional nanocarriers (e.g., nanoparticles, micelles, polymersomes) based on biodegradable/biocompatible polymers intended to be employed for active targeting and drug delivery are reviewed. This review will focus on the nature of the polymers involved in the preparation of targeted nanocarriers, the synthesis methods to achieve the desired macromolecular architecture, the selected coupling strategy, the choice of the homing molecules (vitamins, hormones, peptides, proteins, etc.), as well as the various strategies to display them at the surface of nanocarriers. The resulting morphologies and the main colloidal features will be given as well as an overview of the biological activities, with a special focus on the main in vivo achievements.

Integrating microneedles and sensing strategies for diagnostic and monitoring applications: The state of the art.

Microneedles (MNs) offer minimally-invasive access to interstitial fluid (ISF) - a potent alternative to blood in terms of monitoring physiological analytes. This property is particularly advantageous for the painless detection and monitoring of drugs and biomolecules. However, the complexity of the skin environment, coupled with the inherent nature of the analytes being detected and the inherent physical properties of MNs, pose challenges when conducting physiological monitoring using this fluid. In this review, we discuss different sensing mechanisms and highlight advancements in monitoring different targets, with a particular focus on drug monitoring. We further list the current challenges facing the field and conclude by discussing aspects of MN design which serve to enhance their performance when monitoring different classes of analytes.

Impact of the crystal size of crystalline active pharmaceutical compounds on loading into microneedles.

Microneedle (MN) technology offers a promising platform for the delivery of a wide variety of active pharmaceutical compounds into and/or through the skin. Yet, the low loading capacity of MNs limits their clinical translation. The solid state of loaded compounds, crystallinity versus amorphousness and crystal size of the former, could greatly affect their loading. Here, we investigated the effect of the crystal size of crystalline compounds on their loading into dissolving MNs, prepared using the solvent-casting technique. A model crystalline compound was subjected to crystal size reduction via wet bead milling and loaded into dissolving MNs. A range of crystal sizes, from micro to nano, was obtained via different milling periods. The obtained crystals were characterized for their size, morphology, and sedimentation behavior. Besides, their content, solid state inside the MNs, and impact on the MN mechanical strength were assessed. The crystals exhibited size-dependent sedimentation, which dramatically affected their loading inside the MNs. However, crystal size and sedimentation demonstrated a negligible effect on the mechanical strength and sharpness of the needles, hence no anticipated impact on the MNs' drug delivery efficiency. The elucidation of the correlation between the crystal size and MN loading opens new potentials to address a major drawback in MN technology.

Current Advances and Material Innovations in the Search for Novel Treatments of Phenylketonuria.

Phenylketonuria (PKU) is a genetically inherited disease caused by a mutation of the gene encoding phenylalanine hydroxylase (PAH) and is the most common inborn error of amino acid metabolism. A deficiency of PAH leads to increased blood and brain levels of phenylalanine (Phe), which may cause permanent neurocognitive symptoms and developmental delays if untreated. Current management strategies for PKU consist of early detection through neonatal screening and implementation of a restrictive diet with minimal amounts of natural protein in combination with Phe-free supplements and low-protein foods to meet nutritional requirements. For milder forms of PKU, oral treatment with synthetic sapropterin (BH4), the cofactor of PAH, may improve metabolic control of Phe and allow for more natural protein to be included in the patient's diet. For more severe forms, daily injections of pegvaliase, a PEGylated variant of phenylalanine ammonia-lyase (PAL), may allow for normalization of blood Phe levels. However, the latter treatment has considerable drawbacks, notably a strong immunogenicity of the exogenous enzyme and the attached polymeric chains. Research for novel therapies of PKU makes use of innovative materials for drug delivery and state-of-the-art protein engineering techniques to develop treatments which are safer, more effective, and potentially permanent.

Recent advances in biomimetic strategies for the immunotherapy of glioblastoma.

Immunotherapy is regarded as one of the most promising approaches for treating tumors, with a multitude of immunotherapeutic thoughts currently under consideration for the lethal glioblastoma (GBM). However, issues with immunotherapeutic agents, such as limited in vivo stability, poor blood-brain barrier (BBB) penetration, insufficient GBM targeting, and represented monotherapy, have hindered the success of immunotherapeutic interventions. Moreover, even with the aid of conventional drug delivery systems, outcomes remain suboptimal. Biomimetic strategies seek to overcome these formidable drug delivery challenges by emulating nature's intelligent structures and functions. Leveraging the variety of biological structures and functions, biomimetic drug delivery systems afford a versatile platform with enhanced biocompatibility for the co-delivery of diverse immunotherapeutic agents. Moreover, their inherent capacity to traverse the BBB and home in on GBM holds promise for augmenting the efficacy of GBM immunotherapy. Thus, this review begins by revisiting the various thoughts and agents on immunotherapy for GBM. Then, the barriers to successful GBM immunotherapy are analyzed, and the corresponding biomimetic strategies are explored from the perspective of function and structure. Finally, the clinical translation's current state and prospects of biomimetic strategy are addressed. This review aspires to provide fresh perspectives on the advancement of immunotherapy for GBM.

Novel isoprenoyl nanoassembled prodrug for paclitaxel delivery.

A new paclitaxel (Ptx) prodrug was designed by coupling a single terpene unit (MIP) to the hydroxyl group in position 2' of the drug molecule. Using a squalene derivative of polyethylene glycol (SQ-PEG) as surface active agent, the resulting bioconjugate (PtxMIP) self-assembled in water leading to the formation of stable nanoparticles (PtxMIP_SQ-PEG NPs) with an impressively high drug loading (82%). In vivo, the anticancer activity of this novel Ptx nanoassembled prodrug was compared to the conventional Cremophor-containing formulation (Taxol) on a murine model of breast cancer lung metastasis induced by intravenous injection of 4T1 tumor cells, genetically modified to stably express firefly luciferase. Cell growth was assessed noninvasively by bioluminescence imaging (BLI) which enabled monitoring tumor metastatic burden in the same animals. PtxMIP_SQ-PEG nanoparticles slowed metastatic spread and were better tolerated than the Cremophor-containing formulation (i.e., free drug), thus demonstrating the potential of terpene-based nanoassembled prodrugs in the improvement of the therapeutic index of Ptx in balb/c mice.

Template-Based Porous Hydrogel Microparticles as Carriers for Therapeutic Proteins.

Hydrogels have been extensively researched for over 60 years for their limitless applications in biomedical research. In this study, porous hydrogel microparticles (PHMPs) made of poly(ethylene glycol) diacrylamide were investigated for their potential as a delivery platform for therapeutic proteins. These particles are made using hard calcium carbonate (CaCO3) templates, which can easily be dissolved under acidic conditions. After optimization of the synthesis processes, both CaCO3 templates and PHMPs were characterized using a wide range of techniques. Then, using an array of proteins with different physicochemical properties, the encapsulation efficiency of proteins in PHMPs was evaluated under different conditions. Strategies to enhance protein encapsulation via modulation of particle surface charge to increase electrostatic interactions and conjugation using EDC/NHS chemistry were also investigated. Conjugation of bovine serum albumin to PHMPs showed increased encapsulation and diminished release over time, highlighting the potential of PHMPs as a versatile delivery platform for therapeutic proteins such as enzymes or antibodies.

Therapeutic applications of nanoparticles targeting neutrophil and extracellular traps.

Neutrophils, the most abundant leukocytes in human circulation, are key effectors and regulators of both innate and adaptive immunity which migrate from the bloodstream to sites of inflammation or infection in response to different stimuli. A growing body of evidence has revealed that dysregulated neutrophil activity contributes to the development of several diseases. Targeting their function has been proposed as a potential strategy to treat or mitigate the progression of these disorders. Additionally, neutrophil tropism has been proposed as a strategy to drive therapeutic agents towards targeted disease sites. In this article, we review the proposed nanomedicine approaches to target neutrophils and their components, the regulation of their function and the use of their tropism in drug delivery for therapeutic purposes.

Lipid Nanoparticle-Mediated Hit-and-Run Approaches Yield Efficient and Safe In Situ Gene Editing in Human Skin.

Despite exciting advances in gene editing, the efficient delivery of genetic tools to extrahepatic tissues remains challenging. This holds particularly true for the skin, which poses a highly restrictive delivery barrier. In this study, we ran a head-to-head comparison between Cas9 mRNA or ribonucleoprotein (RNP)-loaded lipid nanoparticles (LNPs) to deliver gene editing tools into epidermal layers of human skin, aiming for in situ gene editing. We observed distinct LNP composition and cell-specific effects such as an extended presence of RNP in slow-cycling epithelial cells for up to 72 h. While obtaining similar gene editing rates using Cas9 RNP and mRNA with MC3-based LNPs (10-16%), mRNA-loaded LNPs proved to be more cytotoxic. Interestingly, ionizable lipids with a pKa ∼ 7.1 yielded superior gene editing rates (55%-72%) in two-dimensional (2D) epithelial cells while no single guide RNA-dependent off-target effects were detectable. Unexpectedly, these high 2D editing efficacies did not translate to actual skin tissue where overall gene editing rates between 5%-12% were achieved after a single application and irrespective of the LNP composition. Finally, we successfully base-corrected a disease-causing mutation with an efficacy of ∼5% in autosomal recessive congenital ichthyosis patient cells, showcasing the potential of this strategy for the treatment of monogenic skin diseases. Taken together, this study demonstrates the feasibility of an in situ correction of disease-causing mutations in the skin that could provide effective treatment and potentially even a cure for rare, monogenic, and common skin diseases.