Octapod iron oxide nanoparticles as high-performance T2 contrast agents for magnetic resonance imaging

Colloidal polymer-coated Zn-doped iron oxide nanoparticles with high relaxivity and specific absorption rate for efficient magnetic resonance imaging and magnetic hyperthermia

This review highlights recent progress in utilizing iron oxide nanoparticles (IONPs) as a safer alternative to gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI). It consolidates findings from multiple studies, discussing current T1 contrast agents (CAs), the synthesis techniques for IONPs, the theoretical principles for designing IONP-based MRI CAs, and the key factors that impact their T1 contrast efficacy, such as nanoparticle size, morphology, surface modifications, valence states, and oxygen vacancies. Furthermore, we summarize current strategies to achieve IONP-based responsive CAs, including self-assembly/disassembly and distance adjustment. This review also evaluates the biocompatibility, organ accumulation, and clearance pathways of IONPs for clinical applications. Finally, the challenges associated with the clinical translation of IONP-based T1 CAs are included.

A magnetic resonance imaging contrast agent is proposed using iron oxide nanoparticles (IONPs) synthesized by a pulsed laser ablation technique. Experimentally, an Nd: YAG laser (1064 nm, 7 ns, 30 mJ) was directed and focused on a high-purity iron plate immersed in a liquid solution of deionized water and polyvinylpyrrolidone (PVP). After a few minutes of laser bombardment, iron oxide nanoparticles dispersed in the liquid were homogeneously produced. A reddish yellow color-colloidal IONPs are produced in the water, while its color changes to dark brown for the PVP solution. The characterization results demonstrated that IONPs in the form of Fe2O3 and Fe3O4 made in the PVP have an excellent dispersibility with a spherical shape that is significantly smaller than that of IONPs made in the deionized water at the same laser repetition rate. The produced IONPs are further applied as a contrast agent for the magnetic resonance imaging (MRI) modality by varying concentrations from 0.05 mM to 2.31 mM. The results demonstrated that images of the IONPs sample with a concentration of 2.31 mM showed the highest contrast enhancement (Cenh), with an enhancement factor of 221.875 % for T1-weighted images and 91.227 % for T2-weighted images. IONPs with a concentration of 2.31 mM had the highest signal-to-noise ratio (SNR) for a T1-weighted picture of 52.92, while IONPs with a concentration of 0.05 mM had the highest SNR for a T2-weighted image of 179.117.

We report the synthesis, from simple salts, and the physical characterization of superparamagnetic iron platinum nanoparticles (SIPPs) suitable for use as contrast agents in magnetic resonance imaging. The properties of these particles were determined by means of transmission electron microscopy (TEM), thermogravimetric analysis (TGA), inductively coupled plasma-optical emission spectroscopy (ICP-OES), superconducting quantum interference device (SQUID) magnetometry, and nuclear magnetic resonance (NMR) relaxivity at 4.7 Tesla. TEM showed that the diameters of the particles ranged from 9.3 nm to 10 nm, depending on the mole ratio of iron to platinum precursors, and on the concentration of Octadecylamine (ODA) used in their preparation. The iron to platinum stoichiometry determined by ICP-OES varied from 1.4:1 to 3.7:1 and was similarly dependant on the initial mole ratios of iron and platinum salts, as well as on the concentration of ODA in the reaction. SQUID magnetometry showed that the SIPPs were superparamagnetic and had magnetic moments that increased with increasing iron content from 62 to 72 A•m2/kg Fe. The measured relaxivities of the SIPPs at 4.7 Tesla were higher than commercially available superparamagnetic iron oxide nanoparticles (SPIONs), suggesting that these particles may be superior contrast agents in T2-weighted magnetic resonance imaging (MRI).

Superparamagnetic iron oxide nanoparticles (SPIONs) can be used as efficient transverse relaxivity (T2 ) contrast agents in magnetic resonance imaging (MRI). Organizing small (D<10 nm) SPIONs into large assemblies can considerably enhance their relaxivity. However, this assembly process is difficult to control and can easily result in unwanted aggregation and precipitation, which might further lead to lower contrast agent performance. Herein, we present highly stable protein-polymer double-stabilized SPIONs for improving contrast in MRI. We used a cationic-neutral double hydrophilic poly(N-methyl-2-vinyl pyridinium iodide-block-poly(ethylene oxide) diblock copolymer (P2QVP-b-PEO) to mediate the self-assembly of protein-cage-encapsulated iron oxide (γ-Fe2 O3 ) nanoparticles (magnetoferritin) into stable PEO-coated clusters. This approach relies on electrostatic interactions between the cationic N-methyl-2-vinylpyridinium iodide block and magnetoferritin protein cage surface (pI≈4.5) to form a dense core, whereas the neutral ethylene oxide block provides a stabilizing biocompatible shell. Formation of the complexes was studied in aqueous solvent medium with dynamic light scattering (DLS) and cryogenic transmission electron microcopy (cryo-TEM). DLS results indicated that the hydrodynamic diameter (Dh ) of the clusters is approximately 200 nm, and cryo-TEM showed that the clusters have an anisotropic stringlike morphology. MRI studies showed that in the clusters the longitudinal relaxivity (r1 ) is decreased and the transverse relaxivity (r2 ) is increased relative to free magnetoferritin (MF), thus indicating that clusters can provide considerable contrast enhancement.

After injury of the central and peripheral nervous systems, functional recovery is impaired by axon regeneration failure. Various approaches for promoting axon growth have been attempted but their low efficacy has prevented them from being clinically applicable. It is possible that in spite of all the research that has been performed regarding axon growth, we are still missing key aspects of axon growth biology that are essential in order to design effective treatments for axon regeneration. Most of what we know about how an axon grows has been discovered by using tools that delete, add, block, or activate macromolecules in the whole cell and by looking at its corresponding effect on axon growth. Less is known about the spatiotemporal actions of macromolecules and organelles at the growth cone and its relation with axon growth. Macromolecules and organelles are heterogeneously distributed in the cell and their resulting function depends heavily on when and where they exert their actions. We need tools that allow us to manipulate these macromolecules and organelles in a temporal window during which axon growth events are taking place. The development of such tools will provide enhanced knowledge of how an axon grows and lead to design more effective therapies to promote axon growth.

Gadolinium-based chelates are a mainstay of contrast agents for magnetic resonance imaging (MRI) in the clinic. However, their toxicity elicits severe side effects and the Food and Drug Administration has issued many warnings about their potential retention in patients' bodies, which causes safety concerns. Iron oxide nanoparticles (IONPs) are a potentially attractive alternative, because of their nontoxic and biodegradable nature. Studies in developing IONPs as T1 contrast agents have generated promising results, but the complex, interrelated parameters influencing contrast enhancement make the development difficult, and IONPs suitable for T1 contrast enhancement have yet to make their way to clinical use. Here, the fundamental principles of MRI contrast agents are discussed, and the current status of MRI contrast agents is reviewed with a focus on the advantages and limitations of current T1 contrast agents and the potential of IONPs to serve as safe and improved alternative to gadolinium-based chelates. The past advances and current challenges in developing IONPs as a T1 contrast agent from a materials science perspective are presented, and how each of the key material properties and environment variables affects the performance of IONPs is assessed. Finally, some potential approaches to develop high-performance and clinically relevant T1 contrast agents are discussed.

BackgroundCoronaviruses usually cause mild respiratory disease in humans but as seen recently, some human coronaviruses can cause more severe diseases, such as the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the global spread of which has resulted in the ongoing coronavirus pandemic.ResultsIn this study we analyzed the potential of using iron oxide nanoparticles (IONPs) coated with biocompatible molecules like dimercaptosuccinic acid (DMSA), 3-aminopropyl triethoxysilane (APS) or carboxydextran (FeraSpin™ R), as well as iron oxyhydroxide nanoparticles (IOHNPs) coated with sucrose (Venofer®), or iron salts (ferric ammonium citrate -FAC), to treat and/or prevent SARS-CoV-2 infection. At non-cytotoxic doses, IONPs and IOHNPs impaired virus replication and transcription, and the production of infectious viruses in vitro, either when the cells were treated prior to or after infection, although with different efficiencies. Moreover, our data suggest that SARS-CoV-2 infection affects the expression of genes involved in cellular iron metabolism. Furthermore, the treatment of cells with IONPs and IOHNPs affects oxidative stress and iron metabolism to different extents, likely influencing virus replication and production. Interestingly, some of the nanoparticles used in this work have already been approved for their use in humans as anti-anemic treatments, such as the IOHNP Venofer®, and as contrast agents for magnetic resonance imaging in small animals like mice, such as the FeraSpin™ R IONP.ConclusionsTherefore, our results suggest that IONPs and IOHNPs may be repurposed to be used as prophylactic or therapeutic treatments in order to combat SARS-CoV-2 infection.Graphical

Iron oxide superparamagnetic nanoparticles have been extensively studied as T2 contrast agents in magnetic resonance imaging. The theory of nuclear magnetic relaxation induced by superparamagnetic nanoparticles has been validated by numerous experimental studies in the case of spherical particles. Recently, several studies focused on the synthesis of cubic nanoparticles. Some of them reported significantly higher relaxivities compared to their spherical counterpart and attributed this increase to their specific shapes. This work investigates the impact of cube-shaped nanoparticles on nuclear magnetic relaxation through Monte Carlo methods. Transverse relaxation at high static magnetic field is simulated by modeling the proton diffusion in the magnetic field generated by a cubic or a spherical nanoparticle. The results indicate that, in the case of magnetite nanoparticles, there is no significant difference between both shapes for sizes above 30nm when particles are compared at equal volumes and magnetization. Below this size, a -40%-15% variation of the relaxation rates is predicted for the cubic case compared to the spherical case. These results are explained using general relaxation models that incorporate the distribution of the magnetic field generated by the nanoparticles. The simulation predictions are compared to some experimental results from the literature, revealing that, in some cases, the magnetic field specific to the nanoparticle shape alone cannot explain the observed increase in the relaxation rate of cubic nanoparticles.

Nanomedicine has emerged as a transformative field in medical diagnostics, particularly in cancer detection. Superparamagnetic iron oxide nanoparticles (SPIONs) and ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) have garnered significant attention due to their remarkable properties, making them suitable for use in molecular imaging. These nanoparticles can serve as effective contrast agents for magnetic resonance imaging (MRI) and can also be radiolabeled with various radioisotopes for use in nuclear medicine modalities such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). Recent advancements in multimodal imaging systems, such as PET/MRI and SPECT/MRI, have demonstrated the potential of these nanoparticles to combine the strengths of different imaging techniques, allowing for more accurate cancer detection at early stages. MRI provides high spatial and temporal resolution but lacks sensitivity, while PET and SPECT offer high sensitivity with lower resolution. The integration of these modalities allows for enhanced imaging of cancerous tissues. This review discusses the application of radiolabeled SPIONs and USPIONs in dual-modality imaging systems, highlighting their advantages and limitations as contrast agents. The continued development of targeted nanoprobes and the exploration of new multimodal imaging systems offer promising avenues for improving early cancer diagnosis and treatment.

Purpose: Despite significant advancements in dendritic cell (DC)-based cancer immunotherapy, the approach remains challenging, especially with regard to developing a simple yet robust method for activating the immune system against cancer in the context of using tumor antigen-activated DCs. To improve the feasibility of this immunotherapy approach, we sought to develop a robust vaccine that utilizes nanotechnology to activate endogenous DCs in the host. Method: Using a superparamagnetic iron oxide (SPIO) nanoparticle as the carrier for this therapy, two immune system activating molecules were conjugated to the nanoparticle. The dextran-coated SPIO nanoparticles were reacted with an epoxyamine linker to produce amine groups on the surface of the nanoparticle. Next, a potent Natural Killer T (NKT) cell activating glycolipid, was conjugated to the SPIO nanoparticle via a disulfide-containing crosslinker. For in vivo studies, an MUC-1 derived antigenic peptide was conjugated as well to the same nanoparticles. Here, adult MUC-1 transgenic C57BL/6 mice were implanted with MUC-1 transfected C57G tumors. The protein and adjuvant conjugated nanoparticle was delivered to mice via subcutaneous injection. Tumor growth in the treated and untreated groups of mice was measured by ultrasound over a 5-week period. Results: Using a mouse model, the effectiveness of a nanovaccine was determined. The nanoparticle conjugated with the NKT cell agonist induced robust IFN-γ and IL-4 response in wild-type mice while no response was elicited in NKT cell- or DC-deficient mice probed with the same nanovaccine. In a different mouse model group, treatment of tumor-bearing MUC-1 animals with the nanovaccine resulted in markedly diminished tumor growth compared to the untreated group. Conclusion: The results indicate that the nanoparticle delivery vehicle can induce a robust immune response in mice. Beyond this vehicular capability, the SPIO nanoparticles can be used as contrast agents for magnetic resonance imaging. As a result, this multimodal and multivalent nanovaccine, achieved through nanotechnology, has the potential to provide microanatomical and functional imaging feedback of the DC-targeted anti-cancer immunotherapy, thus leading to longitudinal treatment and monitoring. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1964. doi:1538-7445.AM2012-1964

Superparamagnetic iron oxide (SPIO) nanoparticles are a relatively large class of contrast agents for magnetic resonance imaging. According to their biodistribution, distinct classes of SPIO nanoparticles have been investigated for clinical applications either as macrophage imaging agents or blood pool agents. Contrast agents which are pharmaceutics followed the same development rules as therapeutic drugs. Several drawbacks such as clinical development difficulties, organization of market access and imaging technological developments have limited the widespread use of these products. SPIO nanoparticles that are composed of thousands iron atoms providing large T2* effects are particularly suitable for theranostic. Stem cell migration and immune cell trafficking, as well as targeted SPIO nanoparticles for molecular imaging studies are mainly at the stage of proof of concept. A major economic challenge in the development of molecular imaging associated with a therapeutic treatment/procedure is to define innovative business models compatible with the needs of all players taking into account that theranostic solutions are promising to optimize resource allocation and ensure that expensive treatments are prescribed to responding patients.

We have investigated the efficacy of superparamagnetic iron oxide nanoparticles (SPIONs) as positive T1 contrast agents for low-field magnetic resonance imaging (MRI) at 64 millitesla (mT). Iron oxide-based agents, such as the FDA-approved ferumoxytol, were measured using a variety of techniques to evaluate T1 contrast at 64 mT. Additionally, we characterized monodispersed carboxylic acid-coated SPIONs with a range of diameters (4.9–15.7 nm) in order to understand size-dependent properties of T1 contrast at low-field. MRI contrast properties were measured using 64 mT MRI, magnetometry, and nuclear magnetic resonance dispersion (NMRD). We also measured MRI contrast at 3 T to provide comparison to a standard clinical field strength. SPIONs have the capacity to perform well as T1 contrast agents at 64 mT, with measured longitudinal relaxivity (r1) values of up to 67 L mmol−1 s−1, more than an order of magnitude higher than corresponding r1 values at 3 T. The particles exhibit size-dependent longitudinal relaxivities and outperform a commercial Gd-based agent (gadobenate dimeglumine) by more than eight-fold at physiological temperatures. Additionally, we characterize the ratio of transverse to longitudinal relaxivity, r2/r1 and find that it is ~ 1 for the SPION based agents at 64 mT, indicating a favorable balance of relaxivities for T1-weighted contrast imaging. We also correlate the magnetic and structural properties of the particles with models of nanoparticle relaxivity to understand generation of T1 contrast. These experiments show that SPIONs, at low fields being targeted for point-of-care low-field MRI systems, have a unique combination of magnetic and structural properties that produce large T1 relaxivities.

Iron oxide nanoparticles (IONPs) extensively employed beyond regenerative medicines to imaging disciplines because of their great constituents for magneto-responsive nano-systems. The unique superparamagnetic behavior makes IONPs very suitable for hyperthermia and imaging applications. From the last decade, versatile functionalization with surface capabilities, efficient contrast properties and biocompatibilities make IONPs an essential imaging contrast agent for magnetic resonance imaging (MRI). IONPs have shown signals for both longitudinal relaxation and transverse relaxation; therefore, negative contrast as well as dual contrast can be used for imaging in MRI. In the current review, we have focused on different oxidation state of iron oxides, i.e., magnetite, maghemite and hematite for their T1 and T2 contrast enhancement properties. We have also discussed different factors (synthesis protocols, biocompatibility, toxicity, architecture, etc.) that can affect the contrast properties of the IONPs.

Ultrasmall superparamagnetic iron oxides (USPIOs): a future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)?