Epithelial HMGB1 delays skin wound healing and drives tumor initiation by priming neutrophils for NET formation

Regenerative responses predispose tissues to tumor formation by largely unknown mechanisms. High-mobility group box 1 (HMGB1) is a danger-associated molecular pattern contributing to inflammatory pathologies. We show that HMGB1 derived from keratinocytes, but not myeloid cells, delays cutaneous wound healing and drives tumor formation. In wounds of mice lacking HMGB1 selectively in keratinocytes, a marked reduction in neutrophil extracellular trap (NET) formation is observed. Pharmacological targeting of HMGB1 or NETs prevents skin tumorigenesis and accelerates wound regeneration. HMGB1-dependent NET formation and skin tumorigenesis is orchestrated by tumor necrosis factor (TNF) and requires RIPK1 kinase activity. NETs are present in the microenvironment of keratinocyte-derived tumors in mice and lesional and tumor skin of patients suffering from recessive dystrophic epidermolysis bullosa, a disease in which skin blistering predisposes to tumorigenesis. We conclude that tumorigenicity of the wound microenvironment depends on epithelial-derived HMGB1 regulating NET formation, thereby establishing a mechanism linking reparative inflammation to tumor initiation

Paramagnetic and fluorescent liposomes for target-specific imaging and therapy of tumor angiogenesis

Angiogenesis is essential for tumor growth and metastatic potential and for that reason considered an important target for tumor treatment. Noninvasive imaging technologies, capable of visualizing tumor angiogenesis and evaluating the efficacy of angiostatic therapies, are therefore becoming increasingly important. Among the various imaging modalities, magnetic resonance imaging (MRI) is characterized by a superb spatial resolution and anatomical soft-tissue contrast. Revolutionary advances in contrast agent chemistry have delivered versatile angiogenesis-specific molecular MRI contrast agents. In this paper, we review recent advances in the preclinical application of paramagnetic and fluorescent liposomes for noninvasive visualization of the molecular processes involved in tumor angiogenesis. This liposomal contrast agent platform can be prepared with a high payload of contrast generating material, thereby facilitating its detection, and is equipped with one or more types of targeting ligands for binding to specific molecules expressed at the angiogenic site. Multimodal liposomes endowed with contrast material for complementary imaging technologies, e.g., MRI and optical, can be exploited to gain important preclinical insights into the mechanisms of binding and accumulation at angiogenic vascular endothelium and to corroborate the in vivo findings. Interestingly, liposomes can be designed to contain angiostatic therapeutics, allowing for image-supervised drug delivery and subsequent monitoring of therapeutic efficacy

MRI contrast agents : current status and future perspectives

A review. Magnetic Resonance Imaging (MRI) is increasingly used in clin. diagnostics, for a rapidly growing no. of indications. The MRI technique is non-invasive and can provide information on the anatomy, function and metab. of tissues in vivo. MRI scans of tissue anatomy and function make use of the two hydrogen atoms in water to generate the image. Apart from differences in the local water content, the basic contrast in the MR image mainly results from regional differences in the intrinsic relaxation times T1 and T2, each of which can be independently chosen to dominate image contrast. However, the intrinsic contrast provided by the water T1 and T2 and changes in their values brought about by tissue pathol. are often too limited to enable a sensitive and specific diagnosis. For that reason increasing use is made of MRI contrast agents that alter the image contrast following i.v. injection. The degree and location of the contrast changes provide substantial diagnostic information. Certain contrast agents are predominantly used to shorten the T1 relaxation time and these are mainly based on low-mol. wt. chelates of the gadolinium ion (Gd3+). The most widely used T2 shortening agents are based on iron oxide (FeO) particles. Depending on their chem. compn., mol. structure and overall size, the in vivo distribution vol. and pharmacokinetic properties vary widely between different contrast agents and these largely det. their use in specific diagnostic tests. This review describes the current status, as well as recent and future developments of MRI contrast agents with focus on applications in oncol. First the basis of MR image contrast and how it is altered by contrast agents will be discussed. After some considerations on bioavailability and pharmacokinetics, specific applications of contrast agents will be presented according to their specific purposes, starting with non-specific contrast agents used in classical contrast enhanced magnetic resonance angiog. (MRA) and dynamic contrast enhanced MRI. Next targeted contrast agents, which are actively directed towards a specific mol. target using an appropriate ligand, functional contrast agents, mainly used for functional brain and heart imaging, smart contrast agents, which generate contrast as a response to a change in their phys. environment as a consequence of some biol. process, and finally cell labeling agents will be presented. To conclude some future perspectives are discussed

Magnetic quantum dots for multimodal imaging

Multimodal contrast agents based on highly luminescent quantum dots (QDs) combined with magnetic nanoparticles (MNPs) or ions form an exciting class of new materials for bioimaging. With two functionalities integrated in a single nanoparticle, a sensitive contrast agent for two very powerful and highly complementary imaging techniques [fluorescence imaging and magnetic resonance imaging (MRI)] is obtained. In this review, the state of the art in this rapidly developing field is given. This is done by describing the developments for four different approaches to integrate the fluorescence and magnetic properties in a single nanoparticle. The first type of particles is created by the growth of heterostructures in which a QD is either overgrown with a layer of a magnetic material or linked to a (superpara, or ferro) MNP. The second approach involves doping of paramagnetic ions into QDs. A third option is to use silica or polymer nanoparticles as a matrix for the incorporation of both QDs and MNPs. Finally, it is possible to introduce chelating molecules with paramagnetic ions (e.g., Gd-DTPA) into the coordination shell of the QDs. All different approaches have resulted in recent breakthroughs and the demonstration of the capability of bioimaging using both functionalities. In addition to giving an overview of the most exciting recent developments, the pros and cons of the four different classes of bimodal contrast agents are discussed, ending with an outlook on the future of this emerging new fiel

Nanoparticulate assemblies of amphiphiles and diagnostically active materials for multimodality imaging

No abstract

Magnetic resonance molecular imaging contrast agents and their application in atherosclerosis

Heart disease is the most prevalent cause of mortality in the Western world and is most frequently caused by rupture of lesions in the arteries, which are formed by atherosclerosis. Atherosclerosis is a progressive disease, and therefore, there is a strong motivation to be able to image the stages of this disease in vivo. The pathogenesis of this disease is now well established, and a number of markers such as macrophages, vascular adhesion molecules, fibrin, and the alphanubeta3-integrin have been identified that are of particular interest for imaging. Furthermore, the differentiation between the stable and unstable plaque with imaging is a central goal of the field. Contrast can be generated in magnetic resonance imaging through the application of several types of agents such as T1, T2, chemical exchange saturation transfer or 19F-based imaging agents. Subsequent to the discussion of the above topics, we will describe some examples of molecular imaging agents that successfully detect specific markers in atherosclerotic plaques that are of interest in several stages of this diseas

Magnetic and fluorescent nanoparticles for multimodality imaging

The development of nanoparticulate contrast agents is providing an increasing contribution to the field of diagnostic and molecular imaging. Such agents provide several advantages over traditional compounds. First, they may contain a high payload of the contrast-generating material, which greatly improves their detectability. Second, multiple properties may be easily integrated within one nanoparticle to allow its detection with several imaging techniques or to include therapeutic qualities. Finally, the surface of such nanoparticles may be modified to improve circulation half-lives or to attach targeting groups. Magnetic resonance imaging and optical techniques are highly complementary imaging methods. Combining these techniques would therefore have significant advantages and may be realized through the use of nanoparticulate contrast agents. This review gives a survey of the different types of fluorescent and magnetic nanoparticles that have been employed for both magnetic resonance and optical imaging studie

A liposomal system for contrast-enhanced magnetic resonance imaging of molecular targets

Pegylated paramagnetic and fluorescent immunoliposomes were designed to enable the parallel detection of the induced expression of molecular markers on endothelial cells with magnetic resonance imaging (MRI) and fluorescence microscopy. MRI is capable of three-dimensional noninvasive imaging of opaque tissues at near cellular resolution, while fluorescence microscopy can be used to investigate processes at the subcellular level. As a model for the expression of a molecular marker, human umbilical vein endothelial cells (HUVEC) were treated with the pro-inflammatory cytokine tumor necrosis factor (TNF) to upregulate the expression of the adhesion molecule E-selectin/CD62E. E-selectin-expressing HUVEC were incubated with pegylated paramagnetic fluorescently labeled liposomes carrying anti-E-selectin monoclonal antibody as a targeting ligand. Both MRI and fluorescence microscopy revealed the specific association of the liposomal MR contrast agent with stimulated HUVEC. This study suggests that this newly developed system may serve as a useful diagnostic tool to investigate pathological processes in vivo with MRI

Liposome-enhanced MRI of neointimal lesions in the ApoE-KO mouse

Conventional high-resolution MRI is capable of detecting lipid-rich atherosclerotic plaques in both human atherosclerosis and animal models of atherosclerosis. In this study we induced neointimal lesions in ApoE-KO mice by placing a constrictive collar around the right carotid artery. The model was imaged with conventional multispectral MRI, and the thickened wall could not be distinguished from surrounding tissue. We then tested paramagnetic liposomes (mean size = 90 nm) for their ability to improve MRI visualization of induced thickening, using Gd-DTPA as a control. T-1-weighted (T-1-w), black-blood MRI of the neck area of the mice was performed before and 15 min, 45 min, and 24 hr after intravenous injection of either paramagnetic liposomes or Gd-DTPA. The collared vessel wall of mice that were injected with liposomes showed a pronounced signal enhancement of similar to 100% immediately after injection, which was sustained largely until 24 hr postinjection. In contrast, the vessel wall of all controls (left carotid artery and animals injected with Gd-DTPA) did not show significant contrast enhancement at those time points. This study demonstrates that intimal thickening in ApoE-KO mice can be effectively detected by contrast-enhanced (CE)-MRI upon injection of paramagnetic liposome

Annexin A5-functionalized bimodal lipid-based contrast agents for the detection of apoptosis

Apoptosis, or programmed cell death, plays an important role in the etiology of a variety of diseases, including cancer and myocardial infarction. Visualization of apoptosis would allow both early detection of therapy efficiency and evaluation of disease progression. To that aim, we synthesized two types of lipid-based bimodal contrast agents that enable the detection of apoptotic cells with both MRI and optical techniques. MR contrast was provided either by entrapment of iron oxide particles within pegylated micelles or by incorporation of Gd-DTPA-bis(stearylamide) (Gd-DTPA-BSA) lipids within the lipid bilayer of pegylated liposomes. The resulting contrast agents were approximately 10 and 100 nm in diameter, respectively. Additional fluorescent lipids were incorporated in the lipid (bi)layer of the contrast agents to allow parallel detection with optical methods. Multiple human recombinant annexin A5 molecules were covalently coupled to introduce specificity for apoptotic cells. Both annexin A5-conjugated contrast agents were shown to significantly increase the relaxation rates of apoptotic cell pellets compared to untreated control cells and apoptotic cells that were treated with nonfunctionalized nanoparticles. Increased relaxation rates were confirmed to originate from association of the contrast agents to apoptotic cells by confocal microscopy. The targeted nanoparticles presented in this study, which differ both in size and in magnetic properties, may have applications for the in vivo detection of apoptosi