Inorganic nanocrystals as contrast agents in MRI: synthesis, coating and introduction of multifunctionality

Inorganic nanocrystals have myriad applications in medicine, including their use as drug or gene delivery complexes, therapeutic hyperthermia agents, in diagnostic systems and as contrast agents in a wide range of medical imaging techniques. In MRI, nanocrystals can produce contrast themselves, with iron oxides having been the most extensively explored, or can be given a coating that generates MR contrast, for example gold nanoparticles coated with gadolinium chelates. These MR-active nanocrystals can be used for imaging of the vasculature, liver and other organs, as well as molecular imaging, cell tracking and theranostics. As a result of these exciting applications, the synthesis and rendering of these nanocrystals as water soluble and biocompatible are therefore highly desirable. We discuss aqueous phase and organic phase methods for the synthesis of inorganic nanocrystals, such as gold, iron oxides and quantum dots. The pros and cons of the various methods are highlighted. We explore various methods for making nanocrystals biocompatible, i.e. direct synthesis of nanocrystals coated with biocompatible coatings, ligand substitution, amphiphile coating and embedding in carrier matrices that can be made biocompatible. Various examples are highlighted and their applications explained. These examples signify that the synthesis of biocompatible nanocrystals with controlled properties has been achieved by numerous research groups and can be applied to a wide range of applications. Therefore, we expect to see reports of preclinical applications of ever more complex MRI-active nanoparticles and their wider exploitation, as well as in novel clinical setting

Nanocrystal Core Lipoprotein Biomimetics for Imaging of Lipoproteins and Associated Diseases

Lipoproteins are natural nanoparticles composed of phospholipids and apolipoproteins that transport lipids throughout the body. As key effectors of lipid homeostasis, the functions of lipoproteins have been demonstrated to be crucial during the development of cardiovascular diseases. Therefore various strategies have been used to study their biology and detect them in vivo. A recent approach has been the production of lipoprotein biomimetic particles loaded with diagnostically active nanocrystals in their core. These include, but are not limited to: quantum dots, iron oxide or gold nanocrystals. Inclusion of these nanocrystals enables the utilization of lipoproteins as probes for a variety of imaging modalities (computed tomography, magnetic resonance imaging, fluorescence) while preserving their biological activity. Furthermore as some lipoproteins naturally accumulate in atherosclerotic plaque or specific tumor tissues, nanocrystal core lipoprotein biomimetics have been developed as contrast agents for early diagnosis of these disease

Controlling the Topography and Surface Plasmon Resonance of Gold Nanoshells by a Templated Surfactant-Assisted Seed Growth Method

Gold nanoshells with varying surface topographies and tunable SPR bands were synthesized in high yields by the templated surfactant-assisted seed growth method. By changing the types and amounts of surfactants and ionic additives in the growth solution, the nanoshell topography was controlled from smooth shells to highly structured nanoshells composed of spherical nanoparticles or sharp spikes of varying aspect ratios. The SPR band of the nanoshells could be tuned over a wide range of wavelengths by varying the nanoshell topography, without significantly changing the amount of gold. Finite-difference time-domain (FDTD) modeling was used to predict and understand the optical properties of nanoshells composed of various subparticles, providing insight into the origins of the tunable SPR band

Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance

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Hydrolyzed Polyacrylamide as an In Situ Assistant in the Nucleation and Growth of Gold Nanoparticles

The modulation of nanoparticles’ size, shape, and dispersion by polymers has attracted particular attention in different fields. Nevertheless, there is a lack of information regarding the use of charged macromolecules as assistants in the nanostructures’ nucleation and growth processes. Prompted by this, the in situ synthesis of gold nanoparticles (AuNPs) aided by hydrolyzed polyacrylamides (HPAM), with different chemical structures, was developed. In contrast to the conventional synthesis of nanostructures assisted by polyacrylamide, here, the polymerization, hydrolysis, and nanostructure formation processes were carried out simultaneously in the same milieu. Likewise, the growing chains acted as a template for the nanoparticles’ growth, so their conformations and chemical structure, especially the amount of charges along the chain, played an important role in the AuNPs’ morphology, size, and some of the final composite features. The nanocomposite was thoroughly characterized with appropriate techniques, including ATR–FTIR, GPC, UV–Vis, and SEM

Conformational Changes in High-Density Lipoprotein Nanoparticles Induced by High Payloads of Paramagnetic Lipids

High-density lipoprotein (HDL) nanoparticles doped with gadolinium lipids can be used as magnetic resonance imaging diagnostic agents for atherosclerosis. In this study, HDL nanoparticles with different molar fractions of gadolinium lipids (0 < <i>x</i>_Gd‑lipids < 0.33) were prepared, and the MR relaxivity values (<i>r</i>1 and <i>r</i>2) for all compositions were measured. Both <i>r</i>1 and <i>r</i>2 parameters reached a maximal value at a molar fraction of approximately <i>x</i>_Gd‑lipids = 0.2. Higher payloads of gadolinium did not significantly increase relaxivity values but induced changes in the structure of HDL, increasing the size of the particles from <i>d</i>_H = 8.2 ± 1.6 to 51.7 ± 7.3 nm. High payloads of gadolinium lipids trigger conformational changes in HDL, with potential effects on the in vivo behavior of the nanoparticles

Spiky Gold Nanoshells: Synthesis and Enhanced Scattering Properties

Gold nanoshells covered with sharp rods called “spiky gold nanoshells” are synthesized by employing a silver-assisted seed-growth method for heterogeneous nanoparticle syntheses at polymer/water interfaces. It is found that silver ions in the growth solution play an important role in forming uniform gold shells as well as regulating the surface morphology. The optical properties of spiky gold nanoshells are investigated by single-particle scattering measurements, single-particle surface-enhanced Raman scattering measurements, and finite-difference time-domain modeling. The scattering intensities from isolated spiky nanoshells are significantly enhanced compared to those of conventional smooth shells. Moreover, due to the abundant hot spots on spiky nanoshells, the SERS signal is readily observed from single spiky shells with a very small intensity variation (35%), whereas there is no detectable signal from isolated smooth shells. These results demonstrate that our synthetic method provides a straightforward way to organize metal nanoparticles into well-defined assemblies with enhanced scattering properties

Single Step Reconstitution of Multifunctional High-Density Lipoprotein-Derived Nanomaterials Using Microfluidics

High-density lipoprotein (HDL) is a natural nanoparticle that transports peripheral cholesterol to the liver. Reconstituted high-density lipoprotein (rHDL) exhibits antiatherothrombotic properties and is being considered as a natural treatment for cardiovascular diseases. Furthermore, HDL nanoparticle platforms have been created for targeted delivery of therapeutic and diagnostic agents. The current methods for HDL reconstitution involve lengthy procedures that are challenging to scale up. A central need in the synthesis of rHDL, and multifunctional nanomaterials in general, is to establish large-scale production of reproducible and homogeneous batches in a simple and efficient fashion. Here, we present a large-scale microfluidics-based manufacturing method for single-step synthesis of HDL-mimicking nanomaterials (μHDL). μHDL is shown to have the same properties (e.g., size, morphology, bioactivity) as conventionally reconstituted HDL and native HDL. In addition, we were able to incorporate simvastatin (a hydrophobic drug) into μHDL, as well as gold, iron oxide, quantum dot nanocrystals or fluorophores to enable its detection by computed tomography (CT), magnetic resonance imaging (MRI), or fluorescence microscopy, respectively. Our approach may contribute to effective development and optimization of lipoprotein-based nanomaterials for medical imaging and drug delivery. © 2013 American Chemical Society

Single step reconstitution of multifunctional high-density lipoprotein-derived nanomaterials using microfluidics

High-density lipoprotein (HDL) is a natural nanoparticle that transports peripheral cholesterol to the liver. Reconstituted high-density lipoprotein (rHDL) exhibits antiatherothrombotic properties and is being considered as a natural treatment for cardiovascular diseases. Furthermore, HDL nanoparticle platforms have been created for targeted delivery of therapeutic and diagnostic agents. The current methods for HDL reconstitution involve lengthy procedures that are challenging to scale up. A central need in the synthesis of rHDL, and multifunctional nanomaterials in general, is to establish large-scale production of reproducible and homogeneous batches in a simple and efficient fashion. Here, we present a large-scale microfluidics-based manufacturing method for single-step synthesis of HDL-mimicking nanomaterials (μHDL). μHDL is shown to have the same properties (e.g., size, morphology, bioactivity) as conventionally reconstituted HDL and native HDL. In addition, we were able to incorporate simvastatin (a hydrophobic drug) into μHDL, as well as gold, iron oxide, quantum dot nanocrystals or fluorophores to enable its detection by computed tomography (CT), magnetic resonance imaging (MRI), or fluorescence microscopy, respectively. Our approach may contribute to effective development and optimization of lipoprotein-based nanomaterials for medical imaging and drug deliver