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

Dynamic changes in 1H-MR relaxometric properties of cell-internalized paramagnetic liposomes, as studied over a properties of cell-internalized paramagnetic liposomes, as studied over a five-day period

Molecular imaging based on MRI requires the use of amplification strategies in order to achieve sufficient sensitivity for the detection of low-level molecular markers. Recently, we described a combination of two amplification methods: (i) the use of paramagnetic liposomes that can be prepared with a high payload of Gd3+-containing lipid; and (ii) targeting to a cell-surface receptor that can undergo multiple rounds of nanoparticle delivery in the cell, followed by recycling to the cell membrane. Liposome uptake was monitored over a period of 24¿h and was found to lead to massive delivery in subcellular compartments. The present study aimed to monitor the longer-term fate of the cell-internalized contrast material by studying its relaxometric properties over 5 days, following an initial 24¿h loading period. Circa 25% of the Gd3+-content delivered to the cells via integrin-targeted liposomes was lost in the first 24¿h, which led to 65 and 77% reductions in R1 and R2, respectively, as compared with the original R1 and R2 enhancements. This implies that the remaining cell-associated gadolinium had relatively low effective r1 and r2 relaxivities. It is proposed that this is due to gradual release of Gd3+ from the chelate in the cell, followed by sequestration in an MR silent state. Most of the gadolinium internalized by cells following incubation with non-targeted liposomes was released in the 5-day follow-up perio

Myoglobin and troponin concentrations are increased in early stage deep tissue injury

\u3cp\u3e Pressure-induced deep tissue injury is a form of pressure ulcer which is difficult to detect and diagnose at an early stage, before the wound has severely progressed and becomes visible at the skin surface. At the present time, no such detection technique is available. To test the hypothesis that muscle damage biomarkers can be indicative of the development of deep tissue injury after sustained mechanical loading, an indentation test was performed for 2 h on the tibialis anterior muscle of rats. Myoglobin and troponin were analysed in blood plasma and urine over a period of 5 days. The damage as detected by the biomarkers was compared to damage as observed with T \u3csub\u3e2\u3c/sub\u3e MRI to validate the response. We found that myoglobin and troponin levels in blood increased due to the damage. Myoglobin was also increased in urine. The amount of damage observed with MRI immediately after loading had a strong correlation with the maximal biomarker levels: troponin in blood r \u3csub\u3es\u3c/sub\u3e = 0.94; myoglobin in blood r \u3csub\u3es\u3c/sub\u3e = 0.75; and myoglobin in urine r \u3csub\u3es\u3c/sub\u3e = 0.57. This study suggests that muscle damage markers measured in blood and urine could serve as early diagnosis for pressure induced deep tissue injury. \u3c/p\u3

Cancer-specific ligand-receptor interactions

\u3cp\u3eThe concept of cancer targeting, which exploits the abundance of specific molecular epitopes on cancer cells, has been proposed as a strategy to enhance the efficacy and specificity of cancer therapy and diagnostics. Although many promising results have been obtained with this approach, the research experience of the last decades demonstrates clearly the challenges that the clinical application of cancer-targeted approaches faces. This can be attributed to both the complexity of targeted probe-cell interactions as well as the multitude of additional factors, which influence the efficacy of the targeting process. The aim of this chapter is to address the key steps involved in the cellular pathway of ligand-functionalized probes for cancer targeting. Special attention is given to nanoparticulate delivery systems as the most commonly exploited formulations for cancer targeting. Their interaction with target cells is initiated by ligand binding to the cell surface receptor, which is frequently followed by endocytosis of ligand-receptor complex and, in the final phase, by lysosomal degradation. All the aforementioned processes are presented in view of the pathophysiological and molecular features of the biological system as well as the physicochemical and biological properties of targeted probes. Importantly, we discuss the implications of these intracellular events for the therapeutic activity and diagnostic capabilities of targeted agents.\u3c/p\u3

Automatic segmentation of subcutaneous mouse tumors by multiparametric MR analysis based on endogenous contrast

\u3cp\u3eObject: Contrast-enhanced T\u3csub\u3e1\u3c/sub\u3e-weighted imaging is usually included in MRI procedures for automatic tumor segmentation. Use of an MR contrast agent may not be appropriate for some applications, however. We assessed the feasability of automatic tumor segmentation by multiparametric cluster analysis that uses intrinsic MRI contrast only. Materials and methods: Multiparametric MRI consisting of quantitative T\u3csub\u3e1\u3c/sub\u3e, T\u3csub\u3e2\u3c/sub\u3e, and apparent diffusion coefficient (ADC) mapping was performed in mice bearing subcutaneous tumors (n = 21). k-means and fuzzy c-means clustering with all possible combinations of MRI parameters, i.e. feature vectors, and 2–7 clusters were performed on the multiparametric data. Clusters associated with tumor tissue were selected on the basis of the relative signal intensity of tumor tissue in T\u3csub\u3e2\u3c/sub\u3e-weighted images. The optimum segmentation method was determined by quantitative comparison of automatic segmentation with manual segmentation performed by three observers. In addition, the automatically segmented tumor volumes from seven separate tumor data sets were quantitatively compared with histology-derived tumor volumes. Results: The highest similarity index between manual and automatic segmentation (SI\u3csub\u3emanual,automatic\u3c/sub\u3e = 0.82 ± 0.06) was observed for k-means clustering with feature vector {T\u3csub\u3e2\u3c/sub\u3e, ADC} and four clusters. A strong linear correlation between automatically and manually segmented tumor volumes (R\u3csup\u3e2\u3c/sup\u3e = 0.99) was observed for this segmentation method. Automatically segmented tumor volumes also correlated strongly with histology-derived tumor volumes (R\u3csup\u3e2\u3c/sup\u3e = 0.96). Conclusion: Automatic segmentation of mouse subcutaneous tumors can be achieved on the basis of endogenous MR contrast only.\u3c/p\u3

DTI of human skeletal muscle: the effects of diffusion encoding parameters, signal-to-noise ratio and T-2 on tensor indices and fiber tracts

In this study, we have performed simulations to address the effects of diffusion encoding parameters, signal-to-noise ratio (SNR) and T-2 on skeletal muscle diffusion tensor indices and fiber tracts. Where appropriate, simulations were corroborated and validated by in vivo diffusion tensor imaging (DTI) of human skeletal muscle. Specifically, we have addressed: (i) the accuracy and precision of the diffusion parameters and eigenvectors at different SNR levels; (ii) the effects of the diffusion gradient direction encoding scheme; (iii) the optimal b value for diffusion tensor estimation; (iv) the effects of changes in skeletal muscle T-2; and, finally, the influence of SNR on fiber tractography and derived (v) fiber lengths, (vi) pennation angles and (vii) fiber curvatures. We conclude that accurate DTI of skeletal muscle requires an SNR of at least 25, a b value of between 400 and 500 s/mm(2), and data acquired with at least 12 diffusion gradient directions homogeneously distributed on half a sphere. Furthermore, for DTI studies focusing on skeletal muscle injury or pathology, apparent changes in the diffusion parameters need to be interpreted with great care in view of the confounding effects of T-2, particularly for moderate to low SNR values. Copyright (c) 2013 John Wiley & Sons, Ltd

Implementation of a semiautomatic method to design patient-specific instruments for corrective osteotomy of the radius

\u3cp\u3ePurpose: 3D-printed patient-specific instruments (PSIs), such as surgical guides and implants, show great promise for accurate navigation in surgical correction of post-traumatic deformities of the distal radius. However, existing costs of computer-aided design and manufacturing process prevent everyday surgical use. In this paper, we propose an innovative semiautomatic methodology to streamline the PSIs design. Methods: The new method was implemented as an extension of our existing 3D planning software. It facilitates the design of a regular and smooth implant and a companion guide starting from a user-selected surface on the affected bone. We evaluated the software by designing PSIs starting from preoperative virtual 3D plans of five patients previously treated at our institute for corrective osteotomy. We repeated the design for the same cases also with commercially available software, with and without dedicated customization. We measured design time and tracked user activity during the design process of implants, guides and subsequent modifications. Results: All the designed shapes were considered valid. Median design times (t~) were reduced for implants ((t~ \u3csub\u3eI\u3c/sub\u3e) = 2.2 min) and guides ((t~ \u3csub\u3eG\u3c/sub\u3e) = 1.0 min) compared to the standard ((t~ \u3csub\u3eI\u3c/sub\u3e) = 13 min and (t~ \u3csub\u3eG\u3c/sub\u3e) = 8 min) and the partially customized ((t~ \u3csub\u3eI\u3c/sub\u3e) = 6.5 min and (t~ \u3csub\u3eG\u3c/sub\u3e) = 6.0 min) commercially available alternatives. Mouse and keyboard activities were reduced (median count of strokes and clicks during implant design ((s~ \u3csub\u3eI\u3c/sub\u3e) = 53, and guide design ((s~ \u3csub\u3eG\u3c/sub\u3e) = 27) compared to using standard software ((s~ \u3csub\u3eI\u3c/sub\u3e) = 559 and (s~ \u3csub\u3eG\u3c/sub\u3e) = 380) and customized commercial software ((s~ \u3csub\u3eI\u3c/sub\u3e) = 217 and (s~ \u3csub\u3eG\u3c/sub\u3e) = 180). Conclusion: Our software solution efficiently streamlines the design of PSIs for distal radius malunion. It represents a first step in making 3D-printed PSIs technology more accessible.\u3c/p\u3

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

Biquadratic interlayer exchange coupling in epitaxial Fe/Si/Fe

\u3cp\u3eWe have studied the biquadratic exchange coupling in epitaxially grown Fe/Si/Fe. The temperature and thickness dependence of the biquadratic coupling strength were determined unambiguously by fitting the easy- and hard-axis magneto-optical Kerr effect loops. The origin of the biquadratic coupling can be fully understood in terms of Slonczewski's loose spins mechanism.\u3c/p\u3

Origin of biquadratic exchange in Fe/Si/Fe

The thickness and temperature dependences of the interlayer exchange coupling in well-defined molecular beam epitaxy-grown Fe/Si/Fe sandwich structures have been studied. The biquadratic coupling shows a strong temperature dependence in contrast to the bilinear coupling. Both depend exponentially on thickness. These observations can be well understood in the framework of Slonczewski's loose spins model [J. Appl. Phys. 73, 5957 (1993)]. No bilinear contribution of the loose spins to the coupling was observed