Nanoparticle-based materials, such as drug delivery vehicles and diagnostic probes, currently under evaluation in oncology clinical trials are largely not tumor selective. To be clinically successful, the next generation of nanoparticle agents should be tumor selective, nontoxic, and exhibit favorable targeting and clearance profiles. Developing probes meeting these criteria is challenging, requiring comprehensive in vivo evaluations. Here, we describe our full characterization of an approximately 7-nm diameter multimodal silica nanoparticle, exhibiting what we believe to be a unique combination of structural, optical, and biological properties. This ultrasmall cancer-selective silica particle was recently approved for a first-in-human clinical trial. Optimized for efficient renal clearance, it concurrently achieved specific tumor targeting. Dye-encapsulating particles, surface functionalized with cyclic arginine-glycine-aspartic acid peptide ligands and radioiodine, exhibited high-affinity/avidity binding, favorable tumor-to-blood residence time ratios, and enhanced tumor-selective accumulation in α v β 3 integrin-expressing melanoma xenografts in mice. Further, the sensitive, real-time detection and imaging of lymphatic drainage patterns, particle clearance rates, nodal metastases, and differential tumor burden in a large-animal model of melanoma highlighted the distinct potential advantage of this multimodal platform for staging metastatic disease in the clinical setting.

Restoration of coronary blood flow after a heart attack can cause reperfusion injury potentially leading to impaired cardiac function, adverse tissue remodeling and heart failure. Iron is an essential biometal that may have a pathologic role in this process. There is a clinical need for a precise noninvasive method to detect iron for risk stratification of patients and therapy evaluation. Here, we report that magnetic susceptibility imaging in a large animal model shows an infarct paramagnetic shift associated with duration of coronary artery occlusion and the presence of iron. Iron validation techniques used include histology, immunohistochemistry, spectrometry and spectroscopy. Further mRNA analysis shows upregulation of ferritin and heme oxygenase. While conventional imaging corroborates the findings of iron deposition, magnetic susceptibility imaging has improved sensitivity to iron and mitigates confounding factors such as edema and fibrosis. Myocardial infarction patients receiving reperfusion therapy show magnetic susceptibility changes associated with hypokinetic myocardial wall motion and microvascular obstruction, demonstrating potential for clinical translation.

Understanding the parameters that control the intermolecular interactions of chromophores encapsulated within nanoparticles is of fundamental importance to various fields of nanoscience. Employing single-molecule time and spectral domains, we studied a red-absorbing hemicyanine analogue (DY-630) covalently encapsulated in the core of ∼20 and ∼30 nm core–shell silica nanoparticles. We find that on average 4 and 7 dyes are encapsulated within these particles, respectively. Steady state and fluorescence correlation spectroscopy show unusually strong enhancements (up to 16 times) in the relative fluorescence efficiency of the nanoparticles as compared to the free dye in aqueous solution. This increase is explained in terms of restriction of the trans–cis isomerization process due to the more rigid local environment provided by the silica, and protection from the solute–solvent interaction, while preserving the spectral characteristics of the constituent dye. Single molecule measurements reveal that the majority of the nanoparticles behave as systems of independently emitting chromophores. Two subpopulations of molecules are identified and assigned to molecules embedded within and on the surface of the core, respectively. Fluorescence lifetime and polarization trajectories of single molecules provide evidence that under certain conditions intermolecular interactions between several encapsulated molecules, such as energy hopping and singlet–singlet annihilation, can occur within single nanoparticles. We find that the energy transfer processes are more efficient in the smaller nanoparticles (∼11%), probably due to the limited space provided by the core and the shorter distance between the trapped molecules (4 nm). In the bigger nanoparticles energy hopping is present only in 5% of the studied cases.

Purpose To evaluate the use of three different pre-reconstruction interpolation methods to convert non-Cartesian k-space data to Cartesian samples such that iterative reconstructions can be performed more simply and more rapidly. Methods Phantom as well as cardiac perfusion radial datasets were reconstructed by four different methods. Three of the methods used pre-reconstruction interpolation once followed by a fast Fourier transform (FFT) at each iteration. The methods were: bilinear interpolation of nearest-neighbor points (BINN), 3-point interpolation, and a multi-coil interpolator called GRAPPA Operator Gridding (GROG). The fourth method performed a full non-Uniform FFT (NUFFT) at each iteration. An iterative reconstruction with spatiotemporal total variation constraints was used with each method. Differences in the images were quantified and compared. Results The GROG multi-coil interpolation, the 3-point interpolation, and the NUFFT-at-each-iteration approaches produced high quality images compared to BINN, with the GROG-derived images having the fewest streaks among the three pre-interpolation approaches. However, all reconstruction methods produced approximately equal results when applied to perfusion quantitation tasks. Pre-reconstruction interpolation gave approximately an 83% reduction in reconstruction time. Conclusion Image quality suffers little from using a pre-reconstruction interpolation approach compared to the more accurate NUFFT-based approach. GROG-based pre-reconstruction interpolation appears to offer the best compromise by using multi-coil information to perform the interpolation to Cartesian sample points prior to image reconstruction. Speed gains depend on the implementation and relatively standard optimizations on a MATLAB platform result in pre-interpolation speedups of ~6 compared to using NUFFT at every iteration, reducing the reconstruction time from around 42 minutes to 7 minutes.

BackgroundEndogenous contrast T1ρ cardiovascular magnetic resonance (CMR) can detect scar or infiltrative fibrosis in patients with ischemic or non-ischemic cardiomyopathy. Existing 2D T1ρ techniques have limited spatial coverage or require multiple breath-holds. The purpose of this project was to develop an accelerated, free-breathing 3D T1ρ mapping sequence with whole left ventricle coverage using a multicoil, compressed sensing (CS) reconstruction technique for rapid reconstruction of undersampled k-space data.MethodsWe developed a cardiac- and respiratory-gated, free-breathing 3D T1ρ sequence and acquired data using a variable-density k-space sampling pattern (A = 3). The effect of the transient magnetization trajectory, incomplete recovery of magnetization between T1ρ-preparations (heart rate dependence), and k-space sampling pattern on T1ρ relaxation time error and edge blurring was analyzed using Bloch simulations for normal and chronically infarcted myocardium. Sequence accuracy and repeatability was evaluated using MnCl2 phantoms with different T1ρ relaxation times and compared to 2D measurements. We further assessed accuracy and repeatability in healthy subjects and compared these results to 2D breath-held measurements.ResultsThe error in T1ρ due to incomplete recovery of magnetization between T1ρ-preparations was T1ρhealthy = 6.1% and T1ρinfarct = 10.8% at 60 bpm and T1ρhealthy = 13.2% and T1ρinfarct = 19.6% at 90 bpm. At a heart rate of 60 bpm, error from the combined effects of readout-dependent magnetization transients, k-space undersampling and reordering was T1ρhealthy = 12.6% and T1ρinfarct = 5.8%. CS reconstructions had improved edge sharpness (blur metric = 0.15) compared to inverse Fourier transform reconstructions (blur metric = 0.48). There was strong agreement between the mean T1ρ estimated from the 2D and accelerated 3D data (R2 = 0.99; P < 0.05) acquired on the MnCl2 phantoms. The mean R1ρ estimated from the accelerated 3D sequence was highly correlated with MnCl2 concentration (R2 = 0.99; P < 0.05). 3D T1ρ acquisitions were successful in all human subjects. There was no significant bias between undersampled 3D T1ρ and breath-held 2D T1ρ (mean bias = 0.87) and the measurements had good repeatability (COV2D = 6.4% and COV3D = 7.1%).ConclusionsThis is the first report of an accelerated, free-breathing 3D T1ρ mapping of the left ventricle. This technique may improve non-contrast myocardial tissue characterization in patients with heart disease in a scan time appropriate for patients.Electronic supplementary materialThe online version of this article (10.1186/s12968-018-0507-2) contains supplementary material, which is available to authorized users.