Bone Regeneration in Small and Large Segmental Bone Defect Models after Radiotherapy Using Injectable Polymer-Based Biodegradable Materials Containing Strontium-Doped Hydroxyapatite Particles.

The reconstruction of bones following tumor excision and radiotherapy remains a challenge. Our previous study, performed using polysaccharide-based microbeads that contain hydroxyapatite, found that these have osteoconductivity and osteoinductive properties. New formulations of composite microbeads containing HA particles doped with strontium (Sr) at 8 or 50% were developed to improve their biological performance and were evaluated in ectopic sites. In the current research, we characterized the materials by phase-contrast microscopy, laser dynamic scattering particle size-measurements and phosphorus content, before their implantation into two different preclinical bone defect models in rats: the femoral condyle and the segmental bone. Eight weeks after the implantation in the femoral condyle, the histology and immunohistochemistry analyses showed that Sr-doped matrices at both 8% and 50% stimulate bone formation and vascularization. A more complex preclinical model of the irradiation procedure was then developed in rats within a critical-size bone segmental defect. In the non-irradiated sites, no significant differences between the non-doped and Sr-doped microbeads were observed in the bone regeneration. Interestingly, the Sr-doped microbeads at the 8% level of substitution outperformed the vascularization process by increasing new vessel formation in the irradiated sites. These results showed that the inclusion of strontium in the matrix-stimulated vascularization in a critical-size model of bone tissue regeneration after irradiation.

A Preclinical Validation of Iron Oxide Nanoparticles for Treatment of Perianal Fistulizing Crohn's Disease.

Fistulizing anoperineal lesions are severe complications of Crohn's disease (CD) that affect quality of life with a long-term risk of anal sphincter destruction, incontinence, permanent stoma, and anal cancer. Despite several surgical procedures, they relapse in about two-thirds of patients, mandating innovative treatments. Ultrasmall particles of iron oxide (USPIO) have been described to achieve in vivo rapid healing of deep wounds in the skin and liver of rats thanks to their nanobridging capability that could be adapted to fistula treatment. Our main purpose was to highlight preclinical data with USPIO for the treatment of perianal fistulizing CD. Twenty male Sprague Dawley rats with severe 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced proctitis were operated to generate two perianal fistulas per rat. At day 35, two inflammatory fistulas were obtained per rat and perineal magnetic resonance imaging (MRI) was performed. After a baseline MRI, a fistula tract was randomly drawn and topically treated either with saline or with USPIO for 1 min (n = 17 for each). The rats underwent a perineal MRI on postoperative days (POD) 1, 4, and 7 and were sacrificed for pathological examination. The primary outcome was the filling or closure of the fistula tract, including the external or internal openings. USPIO treatment allowed the closure and/or filling of all the treated fistulas from its application until POD 7 in comparison with the control fistulas (23%). The treatment with USPIO was safe, permanently closed the fistula along its entire length, including internal and external orifices, and paved new avenues for the treatment of perianal fistulizing Crohn's disease.

Roadmap on nanomedicine.

Since the launch of the Alliance for Nanotechnology in Cancer by the National Cancer Institute in late 2004, several similar initiatives have been promoted all over the globe with the intention of advancing the diagnosis, treatment and prevention of cancer in the wake of nanoscience and nanotechnology. All this has encouraged scientists with diverse backgrounds to team up with one another, learn from each other, and generate new knowledge at the interface between engineering, physics, chemistry and biomedical sciences. Importantly, this new knowledge has been wisely channeled towards the development of novel diagnostic, imaging and therapeutic nanosystems, many of which are currently at different stages of clinical development. This roadmap collects eight brief articles elaborating on the interaction of nanomedicines with human biology; the biomedical and clinical applications of nanomedicines; and the importance of patient stratification in the development of future nanomedicines. The first article reports on the role of geometry and mechanical properties in nanomedicine rational design; the second articulates on the interaction of nanomedicines with cells of the immune system; and the third deals with exploiting endogenous molecules, such as albumin, to carry therapeutic agents. The second group of articles highlights the successful application of nanomedicines in the treatment of cancer with the optimal delivery of nucleic acids, diabetes with the sustained and controlled release of insulin, stroke by using thrombolytic particles, and atherosclerosis with the development of targeted nanoparticles. Finally, the last contribution comments on how nanomedicine and theranostics could play a pivotal role in the development of personalized medicines. As this roadmap cannot cover the massive extent of development of nanomedicine over the past 15 years, only a few major achievements are highlighted as the field progressively matures from the initial hype to the consolidation phase.

Tuning Physicochemical Properties of a Macroporous Polysaccharide-Based Scaffold for 3D Neuronal Culture.

Central nervous system (CNS) lesions are a leading cause of death and disability worldwide. Three-dimensional neural cultures in biomaterials offer more physiologically relevant models for disease studies, toxicity screenings or in vivo transplantations. Herein, we describe the development and use of pullulan/dextran polysaccharide-based scaffolds for 3D neuronal culture. We first assessed scaffolding properties upon variation of the concentration (1%, 1.5%, 3% w/w) of the cross-linking agent, sodium trimetaphosphate (STMP). The lower STMP concentration (1%) allowed us to generate scaffolds with higher porosity (59.9 ± 4.6%), faster degradation rate (5.11 ± 0.14 mg/min) and lower elastic modulus (384 ± 26 Pa) compared with 3% STMP scaffolds (47 ± 2.1%, 1.39 ± 0.03 mg/min, 916 ± 44 Pa, respectively). Using primary cultures of embryonic neurons from PGKCre, Rosa26tdTomato embryos, we observed that in 3D culture, embryonic neurons remained in aggregates within the scaffolds and did not attach, spread or differentiate. To enhance neuronal adhesion and neurite outgrowth, we then functionalized the 1% STMP scaffolds with laminin. We found that treatment of the scaffold with a 100 µg/mL solution of laminin, combined with a subsequent freeze-drying step, created a laminin mesh network that significantly enhanced embryonic neuron adhesion, neurite outgrowth and survival. Such scaffold therefore constitutes a promising neuron-compatible and biodegradable biomaterial.

Mouse Wnt1-CRE-RosaTomato Dental Pulp Stem Cells Directly Contribute to the Calvarial Bone Regeneration Process.

Stem cells endowed with skeletogenic potentials seeded in specific scaffolds are considered attractive tissue engineering strategies for treating large bone defects. In the context of craniofacial bone, mesenchymal stromal/stem cells derived from the dental pulp (DPSCs) have demonstrated significant osteogenic properties. Their neural crest embryonic origin further makes them a potential accessible therapeutic tool to repair craniofacial bone. The stem cells' direct involvement in the repair process versus a paracrine effect is however still discussed. To clarify this question, we have followed the fate of fluorescent murine DPSCs derived from PN3 Wnt1-CRE- RosaTomato mouse molar (T-mDPSCs) during the repair process of calvaria bone defects. Two symmetrical critical defects created on each parietal region were filled with (a) dense collagen scaffolds seeded with T-mDPSCs, (b) noncellularized scaffolds, or (c) no scaffold. Mice were imaged over a 3-month period by microcomputed tomography to evaluate the extent of repair and by biphotonic microscopy to track T-mDPSCs. Histological and immunocytochemical analyses were performed in parallel to characterize the nature of the repaired tissue. We show that T-mDPSCs are present up to 3 months postimplantation in the healing defect and that they rapidly differentiate in chondrocyte-like cells expressing all the expected characteristic markers. T-mDPSCs further maturate into hypertrophic chondrocytes and likely signal to host progenitors that form new bone tissue. This demonstrates that implanted T-mDPSCs are able to survive in the defect microenvironment and to participate directly in repair via an endochondral bone ossification-like process. Stem Cells 2019;37:701-711.

Nanostructured lipid carriers accumulate in atherosclerotic plaques of ApoE-/- mice.

Nanostructured lipid carriers (NLC) might represent an interesting approach for the identification and targeting of rupture-prone atherosclerotic plaques. In this study, we evaluated the biodistribution, targeting ability and safety of 64Cu-fonctionalized NLC in atherosclerotic mice. 64Cu-chelating-NLC (51.8±3.1 nm diameter) with low dispersity index (0.066±0.016) were produced by high pressure homogenization at tens-of-grams scale. 24 h after injection of 64Cu-chelated particles in ApoE-/- mice, focal regions of the aorta showed accumulation of particles on autoradiography that colocalized with Oil Red O lipid mapping. Signal intensity was significantly greater in aortas isolated from ApoE-/- mice compared to wild type (WT) control (8.95 [7.58, 10.16]×108 vs 4.59 [3.11, 5.03]×108 QL/mm2, P < 0.05). Moreover, NLC seemed safe in relevant biocompatibility studies. NLC could constitute an interesting platform with high clinical translation potential for targeted delivery and imaging purposes in atherosclerosis.

Impact of Astaxanthin on Diabetes Pathogenesis and Chronic Complications.

Oxidative stress (OS) plays a pivotal role in diabetes mellitus (DM) onset, progression, and chronic complications. Hyperglycemia-induced reactive oxygen species (ROS) have been shown to reduce insulin secretion from pancreatic ß-cells, to impair insulin sensitivity and signaling in insulin-responsive tissues, and to alter endothelial cells function in both type 1 and type 2 DM. As a powerful antioxidant without side effects, astaxanthin (ASX), a xanthophyll carotenoid, has been suggested to contribute to the prevention and treatment of DM-associated pathologies. ASX reduces inflammation, OS, and apoptosis by regulating different OS pathways though the exact mechanism remains elusive. Based on several studies conducted on type 1 and type 2 DM animal models, orally or parenterally administrated ASX improves insulin resistance and insulin secretion; reduces hyperglycemia; and exerts protective effects against retinopathy, nephropathy, and neuropathy. However, more experimental support is needed to define conditions for its use. Moreover, its efficacy in diabetic patients is poorly explored. In the present review, we aimed to identify the up-to-date biological effects and underlying mechanisms of ASX on the ROS-induced DM-associated metabolic disorders and subsequent complications. The development of an in-depth research to better understand the biological mechanisms involved and to identify the most effective ASX dosage and route of administration is deemed necessary.

Development of 3D Hepatic Constructs Within Polysaccharide-Based Scaffolds with Tunable Properties.

Organoids production is a key tool for in vitro studies of physiopathological conditions, drug-induced toxicity assays, and for a potential use in regenerative medicine. Hence, it prompted studies on hepatic organoids and liver regeneration. Numerous attempts to produce hepatic constructs had often limited success due to a lack of viability or functionality. Moreover, most products could not be translated for clinical studies. The aim of this study was to develop functional and viable hepatic constructs using a 3D porous scaffold with an adjustable structure, devoid of any animal component, that could also be used as an in vivo implantable system. We used a combination of pharmaceutical grade pullulan and dextran with different porogen formulations to form crosslinked scaffolds with macroporosity ranging from 30 µm to several hundreds of microns. Polysaccharide scaffolds were easy to prepare and to handle, and allowed confocal observations thanks to their transparency. A simple seeding method allowed a rapid impregnation of the scaffolds with HepG2 cells and a homogeneous cell distribution within the scaffolds. Cells were viable over seven days and form spheroids of various geometries and sizes. Cells in 3D express hepatic markers albumin, HNF4α and CYP3A4, start to polarize and were sensitive to acetaminophen in a concentration-dependant manner. Therefore, this study depicts a proof of concept for organoid production in 3D scaffolds that could be prepared under GMP conditions for reliable drug-induced toxicity studies and for liver tissue engineering.

Astaxanthin Complexes to Attenuate Muscle Damage after In Vivo Femoral Ischemia-Reperfusion.

(1) Background: Reperfusion injury refers to the cell and tissue damage induced, when blood flow is restored after an ischemic period. While reperfusion reestablishes oxygen supply, it generates a high concentration of radicals, resulting in tissue dysfunction and damage. Here, we aimed to challenge and achieve the potential of a delivery system based on astaxanthin, a natural antioxidant, in attenuating the muscle damage in an animal model of femoral hind-limb ischemia and reperfusion. (2) Methods: The antioxidant capacity and non-toxicity of astaxanthin was validated before and after loading into a polysaccharide scaffold. The capacity of astaxanthin to compensate stress damages was also studied after ischemia induced by femoral artery clamping and followed by varied periods of reperfusion. (3) Results: Histological evaluation showed a positive labeling for CD68 and CD163 macrophage markers, indicating a remodeling process. In addition, higher levels of Nrf2 and NQO1 expression in the sham group compared to the antioxidant group could reflect a reduction of the oxidative damage after 15 days of reperfusion. Furthermore, non-significant differences were observed in non-heme iron deposition in both groups, reflecting a cell population susceptible to free radical damage. (4) Conclusions: Our results suggest that the in situ release of an antioxidant molecule could be effective in improving the antioxidant defenses of ischemia/reperfusion (I/R)-damaged muscles.

Pharmaceutical Development and Safety Evaluation of a GMP-Grade Fucoidan for Molecular Diagnosis of Cardiovascular Diseases.

The adhesion molecule P-selectin is present on the cell surface of both activated endothelium and activated platelets. The present study describes the pharmaceutical development, safety evaluation, and preclinical efficacy of a micro-dosed radiotracer. The macromolecular nanoscale assembly consisted of a natural compound made of a sulfated fucose-rich polysaccharides (fucoidan) and a radionuclide (technetium-99m) for the detection of P-selectin expression in cardiovascular diseases. After extraction and fractionation from brown seaweeds, the good manufacturing practice (GMP) production of a low molecular weight (LMW) fucoidan of 7 kDa was achieved and full physicochemical characterization was performed. The regulatory toxicology study in rats of the GMP batch of LMW fucoidan revealed no adverse effects up to 400 µg/kg (×500 higher than the expected human dose) and pseudoallergy was not seen as well. In a myocardial ischemia-reperfusion model in rats, the GMP-grade LMW fucoidan labeled with technetium-99m detected P-selectin upregulation in vivo. The present study supports the potential of using 99mTc-fucoidan as an imaging agent to detect activated endothelium in humans.

Myocardial infarction and gut microbiota: An incidental connection.

Myocardial infarction (MI) is the main cause of cardiovascular crises that entails serious concerns in mortality, morbidity, and cost to the society. The main therapeutic goal of modern cardiology is to develop novel approaches to minimize inflammation, myocardial necrosis/apoptosis, and enhance cardiac repair after MI. Though MI can be affected by genetic and environmental factors, the search for targeting lifestyle factors has been of greater interest. One such potential factor is the microbiota, the human intestinal microbial community. Although the fundamental data on the role of microbiome on MI is more limited, the disruption of intestinal flora structure provokes MI and poor prognosis. Since gut microbiota is readily modifiable through a variety of interventions, it can be targeted to modulate the host signaling pathways involved in inflammation and MI pathogenesis. Symbiosis bacteria can reduce ischemia/reperfusion injury and inflammation; moreover, they can regulate lipid metabolism, blood pressure, apoptosis, MI size, and overall cardiac survival. In this review, we provide an overview of the development of MI following the dysbiosis microbiota and give an update on a microbiota-based therapeutic strategy to delay or prevent MI.

Effect of cross-linking on the physicochemical and in vitro properties of pullulan/dextran microbeads.

Hydrogels are very promising for tissue engineering as they provide scaffolds and a suitable microenvironment to control cell behavior and tissue regeneration. We used a patented method to obtain beads of pullulan/dextran cross-linked with sodium trimetaphosphate (STMP), that were already described for in vivo bone repair. The aim of this study was to provide a comparative analysis of microbeads made of polysaccharides prepared using three different STMP feeding ratio of 1.5, 2.25 or 3 % w/w. The morphology, swelling and biodegradability of these structures were assessed. Mesenchymal stem cells were also seeded to evaluate the cell organization onto the beads. We found that the amount of phosphorus resulting from the cross-linking was proportional to the introduced STMP concentration. An increase of cross-linking decreased the in vitro enzymatic degradability, and also decreased the swelling in PBS or water. The microstructures observed by SEM and confocal microscopy indicated that homogeneous spherical microbeads were obtained, except for the lower cross-linking ratio where the shapes were altered. Beads hydrated in PBS exhibited a mean diameter ranging from 400 to 550 µm with the decrease of STMP ratio. Cells adhered to the surface of microbeads even in the absence of protein coating. Cell viability studies revealed an increase in cell numbers over two weeks for the highest cross-linked beads, whereas the two lowest STMP concentrations induced a decrease of cell viability. Overall, this study demonstrated that pullulan/dextran hydrogels can be designed as microbeads with adjustable physicochemical and biological properties to fulfill requirements for tissue engineering approaches.

Astaxanthin-Loaded Nanostructured Lipid Carriers for Preservation of Antioxidant Activity.

Astaxanthin is a xanthophyll carotenoid showing efficient scavenging ability and represents an interesting candidate in the development of new therapies for preventing and treating oxidative stress-related pathologies. However, its high lipophilicity and thermolability often limits its antioxidant efficacy in human applications. Here, we developed a formulation of lipid carriers to protect astaxanthin's antioxidant activity. The synthesis of natural astaxanthin-loaded nanostructured lipid carriers using a green process with sunflower oil as liquid lipid is presented. Their antioxidant activity was measured by α-Tocopherol Equivalent Antioxidant Capacity assay and was compared to those of both natural astaxanthin and α-tocopherol. Characterizations by dynamic light scattering, atomic force microscopy, and scattering electron microscopy techniques were carried out and showed spherical and surface negative charged particles with z-average and polydispersity values of ~60 nm and ~0.3, respectively. Astaxanthin loading was also investigated showing an astaxanthin recovery of more than 90% after synthesis of nanostructured lipid carriers. These results demonstrate the capability of the formulation to stabilize astaxanthin molecule and preserve and enhance the antioxidant activity.

Abiotic Sequence-Coded Oligomers as Efficient In†Vivo Taggants for the Identification of Implanted Materials.

Sequence-defined oligourethanes were tested as in vivo taggants for implant identification. The oligomers were prepared in an orthogonal solid-phase iterative approach and thus contained a coded monomer sequence that can be unequivocally identified by tandem mass spectrometry (MS/MS). The oligomers were then included in small amounts (1 wt %) in square-centimeter-sized crosslinked poly(vinyl alcohol) (PVA) model films, which were intramuscularly and subcutaneously implanted in the abdomen of rats. After one week, one month, or three months of implantation, the PVA films were explanted. The rat tissues exposed to the implants did not exhibit any adverse reactions, which suggested that the taggants are not harmful and probably not leaching out from the films. Furthermore, the explanted films were immersed in methanol, as a solvent for oligourethanes, and the liquid extract was analyzed by mass spectrometry. In all cases, the oligourethane taggant was detected, and its sequence was identified by MS/MS.

Bioreactivity of stent material: Activation of platelets, coagulation, leukocytes and endothelial cell dysfunction in vitro.

Outcome of patients with coronary artery disease has been significantly improved by percutaneous coronary interventions with stent implantation. However, despite progress made on devices and antithrombotic treatments, stent thrombosis remains an important issue because of serious adverse consequences. Several mechanisms are assumed to favor stent thrombosis as platelet aggregation, fibrin formation, defective healing and local inflammation. The objective of this study was to evaluate in vitro the thrombogenicity, proinflammatory properties and healing capacities of cobalt-chromium (CoCr), an alloy commonly used for cardiovascular implants. Platelet adhesion was quantified in static and flow conditions. Thrombin generation was performed using the calibrated automated thrombogram. Neutrophil adhesion and formation of extracellular traps were visualized by scanning electron microscopy and by immunofluorescence. The phenotype of endothelial cells grown on CoCr was analyzed using specific antibodies, whereas the procoagulant potential was analyzed by measuring thrombin generation and protein C activation. Our results show that human blood platelets adhere to and are activated on CoCr in static and flow conditions. Overall, CoCr significantly induced thrombin generation in the presence or absence of platelets by 1.5- and 4.8-fold, respectively, involving activation of the contact pathway and activation of platelets. CoCr triggered leukocyte adhesion and behaved as a scaffold for the formation of neutrophil extracellular traps in the presence of platelets. Endothelial cells adhered and formed a monolayer covering CoCr. However, they switched from an anticoagulant phenotype to a procoagulant one with a significant 2.2-fold increase in thrombin generation due to a combined 30% reduced capacity to trigger protein C activation and 30% increased expression of tissue factor. Moreover, endothelial cells grown on CoCr acquired an inflammatory phenotype as indicated by the increased expression of ICAM-1 and VCAM-1. These data show that bare CoCr is prothrombotic and proinflammatory due to its capacity to activate platelets and coagulation and to induce leukocyte adhesion and activation. More importantly, even if endothelialization is achievable, the switch in endothelial phenotype prevents effective healing. Furthermore, we propose our methodology for future preclinical in vitro evaluation of the thrombogenicity of stent materials.

Calcium-phosphate ceramics and polysaccharide-based hydrogel scaffolds combined with mesenchymal stem cell differently support bone repair in rats.

Research in bone tissue engineering is focused on the development of alternatives to autologous bone grafts for bone reconstruction. Although multiple stem cell-based products and biomaterials are currently being investigated, comparative studies are rarely achieved to evaluate the most appropriate approach in this context. Here, we aimed to compare different clinically relevant bone tissue engineering methods and evaluated the kinetic repair and the bone healing efficiency supported by mesenchymal stem cells and two different biomaterials, a new hydrogel scaffold and a commercial hydroxyapatite/tricalcium phosphate ceramic, alone or in combination.Syngeneic mesenchymal stem cells (5 × 105) and macroporous biphasic calcium phosphate ceramic granules (Calciresorb C35®, Ceraver) or porous pullulan/dextran-based hydrogel scaffold were implanted alone or combined in a drilled-hole bone defect in rats. Using quantitative microtomography measurements and qualitative histological examinations, their osteogenic properties were evaluated 7, 30, and 90 days after implantation. Three months after surgery, only minimal repair was evidenced in control rats while newly mineralized bone was massively observed in animals treated with either hydrogels (bone volume/tissue volume = 20%) or ceramics (bone volume/tissue volume = 26%). Repair mechanism and resorption kinetics were strikingly different: rapidly-resorbed hydrogels induced a dense bone mineralization from the edges of the defect while ceramics triggered newly woven bone formation in close contact with the ceramic surface that remained unresorbed. Delivery of mesenchymal stem cells in combination with these biomaterials enhanced both bone healing (>20%) and neovascularization after 1 month, mainly in hydrogel.Osteogenic and angiogenic properties combined with rapid resorption make hydrogels a promising alternative to ceramics for bone repair by cell therapy.

Radical Copolymerization of Vinyl Ethers and Cyclic Ketene Acetals as a Versatile Platform to Design Functional Polyesters.

Free-radical copolymerization of cyclic ketene acetals (CKAs) and vinyl ethers (VEs) was investigated as an efficient yet simple approach for the preparation of functional aliphatic polyesters. The copolymerization of CKA and VE was first predicted to be quasi-ideal by DFT calculations. The theoretical prediction was experimentally confirmed by the copolymerization of 2-methylene-1,3-dioxepane (MDO) and butyl vinyl ether (BVE), leading to rMDO =0.73 and rBVE =1.61. We then illustrated the versatility of this approach by preparing different functional polyesters: 1) copolymers functionalized by fluorescent probes; 2) amphiphilic copolymers grafted with poly(ethylene glycol) (PEG) side chains able to self-assemble into PEGylated nanoparticles; 3) antibacterial films active against Gram-positive and Gram-negative bacteria (including a multiresistant strain); and 4) cross-linked bioelastomers with suitable properties for tissue engineering applications.

Fucoidans in Nanomedicine.

Fucoidans are widespread cost-effective sulfated marine polysaccharides which have raised interest in the scientific community over last decades for their wide spectrum of bioactivities. Unsurprisingly, nanomedicine has grasped these compounds to develop innovative therapeutic and diagnostic nanosystems. The applications of fucoidans in nanomedicine as imaging agents, drug carriers or for their intrinsic properties are reviewed here after a short presentation of the main structural data and biological properties of fucoidans. The origin and the physicochemical specifications of fucoidans are summarized in order to discuss the strategy of fucoidan-containing nanosystems in Human health. Currently, there is a need for reproducible, well characterized fucoidan fractions to ensure significant progress.

Nanomedicine for the molecular diagnosis of cardiovascular pathologies.

Predicting acute clinical events caused by atherosclerotic plaque rupture remains a clinical challenge. Anatomic mapping of the vascular tree provided by standard imaging technologies is not always sufficient for a robust diagnosis. Yet biological mechanisms leading to unstable plaques have been identified and corresponding biomarkers have been described. Nanosystems charged with contrast agents and targeted towards these specific biomarkers have been developed for several types of imaging modalities. The first systems that have reached the clinic are ultrasmall superparamagnetic iron oxides for Magnetic Resonance Imaging. Their potential relies on their passive accumulation by predominant physiological mechanisms in rupture-prone plaques. Active targeting strategies are under development to improve their specificity and set up other types of nanoplatforms. Preclinical results show a huge potential of nanomedicine for cardiovascular diagnosis, as long as the safety of these nanosystems in the body is studied in depth.

The leukotriene B4 receptor (BLT) antagonist BIIL284 decreases atherosclerosis in ApoE-/- mice.

Leukotriene B4 (LTB4) induces proinflammatory signaling through BLT receptors expressed in atherosclerotic lesions. Either genetic or pharmacological targeting of the high affinity LTB4 receptor, BLT1, reduces atherosclerosis in different mouse models. The low affinity BLT2 receptor for LTB4 may transduce additional pro-atherogenic signaling, but combined BLT1 and BLT2 receptor antagonism has not previously been explored in atherosclerosis. The aim of the present study was to unravel the effects of the BLT receptor antagonist BIIL284 in apolipoprotein E deficient mice in terms of atherosclerotic lesion size and composition, as well as on arterial matrixmetalloproteinase (MMP) activity and plasma cytokines. Oral administration of BIIL284 (0.3-3mg/kg) dose-dependently decreased atherosclerotic lesion size after 12 weeks. In addition, significantly smaller aortic lesions were observed in mice treated with BIIL284 (3mg/kg) for 24 weeks. The reduced atherosclerosis was associated with less lesion smooth muscle cells, less arterial MMP activities and lower plasma levels of TNF-α and IL-6. Taken together, these results suggest a therapeutic value of BLT receptor antagonism in atherosclerosis.