Immune cell-mediated drug delivery for the treatment of inflammatory diseases

Uncontrolled inflammation is a major pathological factor underlying a range of diseases including autoimmune conditions, cardiovascular disease and cancer. Improving localised delivery of immunosuppressive drugs to inflamed tissue in a non-invasive manner offers significant promise to reduce severe side effects caused by systemic administration. Employing immune cells for active transport of drugs and drug-loaded nanocarriers to a target site is a promising recent approach. Particularly, in the context of drug delivery for anti-inflammation therapy, immune cells have the intrinsic functions to migrate to and infiltrate the inflamed tissue. Here, a delivery strategy using neutrophils loaded with methotrexate (MTX)-liposomes ex vivo to deliver MTX to target sites was first investigated in vitro. This hybrid system efficiently migrated following an inflammatory chemokine gradient and triggered release of loaded liposomes via neutrophil extracellular traps (NETs) formation in an inflammatory environment was achieved. Subsequent re-uptake of the released liposomes by target macrophages provided detailed support for in vivo treatment studies. In parallel, macrophages were evaluated as alternative immune cells to carry nanoparticles. Given the advantage of a well-defined release mechanism (NETs formation), MTX-liposome loaded neutrophils were chosen over a macrophage-based system to be further validated in vivo using two mouse models of inflammation, a lipopolysaccharide (LPS)-injury skeletal muscle model and a myocardial ischemia reperfusion injury (IRI) model. The migratory behaviour of liposome-loaded neutrophils was confirmed by demonstrating the neutrophil-mediated delivery of liposomes to the inflamed muscle and the injured heart. A single low-dose injection of the hybrid system locally reduced inflammatory cytokine levels in the inflamed muscle and slightly improved the pumping efficiency of the IRI heart. These results highlight the advantages of immune cell-mediated drug delivery, which is a versatile strategy that allows combinations with different types of nanoparticles encapsulating various drugs to reduce tissue inflammation and actively promote repair in inflammatory diseases.Open Acces

Tuneable peptide cross-linked nanogels for enzyme-triggered protein delivery

Many diseases are associated with the dysregulated activity of enzymes, such as matrix metalloproteinases (MMPs). This dysregulation can be leveraged in drug delivery to achieve disease- or site-specific cargo release. Self-assembled polymeric nanoparticles are versatile drug carrier materials due to the accessible diversity of polymer chemistry. However, efficient loading of sensitive cargo, such as proteins, and introducing functional enzyme-responsive behaviour remain challenging. Herein, peptide-crosslinked, temperature-sensitive nanogels for protein delivery were designed to respond to MMP-7, which is overexpressed in many pathologies including cancer and inflammatory diseases. The incorporation of N-cyclopropylacrylamide (NCPAM) into N-isopropylacrylamide (NIPAM)-based copolymers enabled us to tune the polymer lower critical solution temperature from 33 to 44 °C, allowing the encapsulation of protein cargo and nanogel-crosslinking at slightly elevated temperatures. This approach resulted in nanogels that were held together by MMP-sensitive peptides for enzyme-specific protein delivery. We employed a combination of cryogenic transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS), small angle neutron scattering (SANS), and fluorescence correlation spectroscopy (FCS) to precisely decipher the morphology, self-assembly mechanism, enzyme-responsiveness, and model protein loading/release properties of our nanogel platform. Simple variation of the peptide linker sequence and combining multiple different crosslinkers will enable us to adjust our platform to target specific diseases in the future

Machine learning prediction of the electronic property of binary transition metal alloys

Machine learning methods have garnered much attention and use in computational catalysis. Previous studies have demonstrated rapid and accurate prediction of a variety of catalytic properties as well as the underlying potential energy landscapes. In particular, d-band center, defined as the first moment of the d-projected density of states, has been widely used as the key descriptor of activity trends for reactions catalyzed by metal surfaces. In this work, we construct a gradient boosting regression (GBR) model for prediction of the d-band center of bulk binary transition metal alloys. An accurate model is obtained using a dataset of over 1200 alloys from the Materials Project database spanning the entire d-block of the periodic table. The d-band centers, periodic groups, and relative compositions of the constituent metals are determined to have the highest feature importance scores, consistent with the underlying physics of the alloy. The regression model presented here offer a promising strategy of rapid property prediction with physical interpretability to aid the optimization and discovery of efficient heterogeneous catalysts

Ultrasound-responsive microparticles from droplet microfluidics

Ultrasound (US)-responsive microparticles show broad potential in controlled drug delivery systems. Compare with the traditional micron-scale material fabrication methods, capillary microfluidic technology features superior advantages in large-scale production, batch-to-batch similarity, high encapsulation efficiency, low cost, and so on. The excellent maneuverability and customizability of the capillary microfluidic devices allow the production of microparticles with various functionalities and fine-tuned chemical compartments. Moreover, the flexible regulation of the particle size and core-shell ratio can be easily realized by modulating the capillary orifices and flow rates of microfluidic channels. In this review, we introduce the fabrication of US-responsive microparticles with specific core-shell structures via capillary microfluidic methods, from single emulsion to triple emulsions. Then, we address some particular examples, where the drug delivery and US-triggered cargo release capacity of these microfluidic microparticles are demonstrated. Finally, we conclude the advanced achievements of the US-responsive microfluidic microparticles, summarize the obstacles to the development of this interdisciplinary field, and prospect their future applications

Castleman disease versus lymphoma in neck lymph nodes: a comparative study using contrast-enhanced CT

Abstract Background The purpose of this study was to determine the contrast-enhanced CT characteristics for differentiating between Castleman disease (CD) and lymphoma in neck lymph nodes. Methods This retrospective study evaluated the number (solitary or multiple), strength of contrast-enhancement, type of contrast-enhancement, surrounding vessels, contrast-enhanced Hounsfield unit (HU) values, and anatomical distributions of lymph nodes in 34 patients with confirmed CD and 55 patients with newly diagnosed untreated lymphoma. Independent t-tests, receiver operating characteristic (ROC) curve analysis, and chi-square tests were used to evaluate the variables and CT features. Results Several significant differences were found between CD and lymphoma. The interval between first contrast-enhanced CT and biopsy/surgery was significantly longer in the CD group (mean 72 ± 105 days, median 60 days) than in the lymphoma patients (mean 30 ± 2 days, median 12 days; p = 0.015). The lymphoma patients presented significantly more often with fatigue and fever (p = 0.023 and p = 0.016 respectively) than did the CD subjects. HU values of nodules after enhancement were significantly higher in the CD patients than in the lymphoma patients. In cases involving multiple lymph nodes, in all the CD cases, all affected nodes were located in only the left or right side of the neck, not bilaterally. ROC analysis showed a significant difference in contrast-enhanced CT attenuation values between lymphoma and CD (p < 0.001, area under the curve = 0.954), with a cut-off value of 92.5 HU. We constructed a decision tree according to these imaging characteristics. Conclusions Contrast-enhanced CT can be useful for differentiating between CD and lymphoma

Treatment of Alzheimer's disease by microcapsule regulates neurotransmitter release via microfluidic technology

Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complex etiology. The main neuropathological feature is the accumulation of amyloid-beta (Aβ), and the dysregulation of the cholinergic system is well associated with its mechanism of occurrence, for which no effective treatment is yet available. Daily oral administration remains the mainstay of treatment with AD, and how to improve the efficacy, prolong adsorption and medication compliance is still the focus of the current solution. We proposed a microcapsule based on microfluidic electrospray to form an intestinal epithelial lining for AD treatment, reducing the frequency of administration. Microfluidic electrospray technology was recruited to overcome the limitations associated with the variability in the microencapsulation production process and to produce functional microcapsules with finely adapted chemical composition, capsule thickness and encapsulant volume ratio. These microcapsules could slowly release drugs after adhering to the intestine, and their effectiveness and safety were further evaluated using cell culture studies and animal model studies. The results from the in vivo and in vitro experiments showed a significant reduction in administration frequency (i.e., from daily medication to once every five days), superior therapeutic efficacy and sufficient safety of these microcapsules in cell culture and APP/PS1 mice. These features make the microcapsules an excellent drug delivery system and represent great potential for clinical applications in AD

Enhanced Antimalarial and Antisequestration Activity of Methoxybenzenesulfonate-Modified Biopolymers and Nanoparticles for Tackling Severe Malaria

Severe malaria is a life-threatening condition that is associated with a high mortality. Severe Plasmodium falciparum infections are mediated primarily by high parasitemia and binding of infected red blood cells (iRBCs) to the blood vessel endothelial layer, a process known as sequestration. Here, we show that including the 5-amino-2-methoxybenzenesulfonate (AMBS) chemical modification in soluble biopolymers (polyglutamic acid and heparin) and poly(acrylic acid)-exposing nanoparticles serves as a universal tool to introduce a potent parasite invasion inhibitory function in these materials. Importantly, the modification did not add or eliminated (for heparin) undesired anticoagulation activity. The materials protected RBCs from invasion by various parasite strains, employing both major entry pathways. Two further P. falciparum strains, which either expose ligands for chondroitin sulfate A (CSA) or intercellular adhesion molecule 1 (ICAM-1) on iRBCs, were tested in antisequestration assays due to their relevance in placental and cerebral malaria, respectively. Antisequestration activity was found to be more efficacious with nanoparticles vs gold-standard soluble biopolymers (CSA and heparin) against both strains, when tested on receptor-coated dishes. The nanoparticles also efficiently inhibited and reversed the sequestration of iRBCs on endothelial cells. First, the materials described herein have the potential to reduce the parasite burden by acting at the key multiplication stage of reinvasion. Second, the antisequestration ability could help remove iRBCs from the blood vessel endothelium, which could otherwise cause vessel obstruction, which in turn can lead to multiple organ failure in severe malaria infections. This approach represents a further step toward creation of adjunctive therapies for this devastating condition to reduce morbidity and mortality

Biomimetic platelet nanoparticles encapsulated with proteasome inhibitor bortezomib for multiple myeloma treatment

The discovery of bortezomib (BTZ) has been a major clinical breakthrough for multiple myeloma (MM) treatment. However, its clinical application is restricted to a low tumor-targeting ability, fast clearance, and treatment-related toxicity. Here, we report a targeting strategy of MM by poly(lactic-co-glycolic acid)(PLGA) nanoparticles cloaking with platelet membranes (PMs) encapsulating BTZ (PM/BTZNPs). The drug delivery system could encapsulate sufficient BTZ with suitable nanoparticle characteristics for cellular uptake via an easy fabrication process. Of note, PM coating markedly enhances the selectivity, cellular uptake, and anticancer effects of BTZ in LP-1 cells. PM/BTZNPs further display a targeted drug delivery system to MM, causing a low toxicity effect and exhibiting an obvious survival advantage compared to nontargeted BTZ. Therefore, PM/BTZNPs, as a biomimetic nanotherapeutic formulation, demonstrate a high potential for MM patients