Target, Treat, and Track: Superparamagnetic Iron Oxide Nanoparticles (SPION) Driven Theranostic Delivery of Antimicrobials to the Lungs

Technology advancements in synthesis and modification of nanoscale materials have advanced the development of different medical applications. Nanoparticles (NPs) have demonstrated promising potentials in diagnostic medicine especially for magnetic resonance imaging (MRI). Iron oxide, gold, and gadolinium NPs have been used in preclinical and clinical studies as contrast enhancing agents. Studies are ongoing to find the optimum parameters of these NPs as contrast agents (CAs) of MRI. This study aims to review the recent applications of iron oxide, gold, and gadolinium NPs as contrast enhancing agents in MRI for diagnosis of different disorders. The databases of PubMed (1980-2016), Web of Science (1980-2016), Scopus (1980-2016), and Google Scholar (1980-2016) were explored using the search terms “Nanoparticles,” “Contrast agents,” “Magnetic Resonance Imaging” and “disease.” The obtained results were screened for the title and abstract and comprehensively reviewed. MRI CAs are divided into T1 and T2 CAs, respectively, used for T1 and T2 weighted protocols in MRI. Iron oxide, gadolinium, and gold NPs are the most common CAs used in MRI. High magnetization values, small size, narrow particle size distribution are the main features of NPs as CAs in MRI. Gadolinium is the most common T1 CAs used in MRI. However, it is associated with toxicity which is a serious concern in patients with renal failure. Iron oxide NPs can be used for these patients. However, the main limitation of iron oxide NPs is limited relaxivity. The relaxivity strongly depends on the size of NP. Paramagnetic NPs serve as T1 CAs and super paramagnetic NPs as T2 CAs. Modulating the size of NPs is the main parameter to adjust different NPs for different MRI protocols. Recent years to overcome the problem of gadolinium and iron oxide NPs, different paramagnetic and super paramagnetic NPs are developed.

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

Nanotechnology provides a flexible platform for the development of effective therapeutic nanomaterials that can interact specifically with a target in a biological system and provoke a desired response. Of the nanomaterials studied, iron oxide nanoparticles have emerged as one of top candidates for cancer therapy. Their intrinsic superparamagnetism enables noninvasive magnetic resonance imaging (MRI), and their biodegradability is advantageous for in vivo applications. A therapeutic superparamagnetic iron oxide nanoparticle (SPION) typically consists of three primary components: an iron oxide nanoparticle core that serves as both a carrier for therapeutics and contrast agent for MRI, a coating on the iron oxide nanoparticle that promotes favorable interactions between the SPION and the biological system, and a therapeutic payload that performs the designated function in vivo. Often, the design may include a targeting ligand that recognizes the receptors over-expressed on the exterior surface of cancer cells. The body is a highly complex system that imposes multiple physiological and cellular barriers to foreign objects. Thus, the success of a therapeutic SPION largely relies on the design of the iron oxide core to ensure its detection in MRI and the coatings that allow the nanoparticles to bypass these barriers. Strategies to bypass the physiological barriers, such as liver, kidneys, and spleen, involve tuning the overall size and surface chemistry of the SPION to maximize blood half-life and facilitate the navigation in the body. Strategies to bypass cellular barriers include the use of targeting agents to maximize uptake of the SPION by cancer cells and the employment of materials that promote desired intracellular trafficking and enable controlled drug release. The payload can be genes, proteins, chemotherapy drugs, or a combination of these molecules. Each type of therapeutic molecule requires a specific coating design to maximize the loading and to achieve effective delivery and release. In this Account, we discuss the primary design parameters in developing therapeutic SPIONs with a focus on surface coating design to overcome the barriers imposed by the body's defense system. We provide examples of how these design parameters have been implemented to produce SPIONs for specific therapeutic applications. Although there are still challenges to be addressed, SPIONs show great promise in the successful diagnosis and treatment of the most devastating cancers. Once the critical design parameters have been optimized, these nanoparticles, combined with imaging modalities, can serve as truly multifunctional theranostic agents that not only perform a therapeutic function but also provide instant clinical feedback, allowing the physician to adjust the treatment plan.

Recent advances in engineering iron oxide nanoparticles for effective magnetic resonance imaging

Stimuli‐Responsive Nanotheranostics

Introduction: Contrast-enhanced magnetic resonance (MR) imaging is a powerful tool for diagnosing atherosclerosis; however, its ability to assess plaque inflammation remains limited. Here, we developed a highly sensitive, plaque-targeted biomimetic MR contrast agent for precise inflammation assessment, aiming to enhance early diagnosis and treatment monitoring in atherosclerosis. Hypothesis: We recently developed a monocyte membrane-cloaked nanoparticle platform (MoNP) as a targeted delivery vehicle for atherosclerosis. Building on this, we hypothesize that MoNP-mediated delivery of MR contrast agents will enhance their accumulation in plaques, enabling precise spatial and temporal monitoring of inflammation status during plaque progression via MRI. Methods: Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used as T2 contrast agents for MR imaging but suffer from non-specific biodistribution and low plaque-site bioavailability, limiting their clinical utility. To address these limitations, SPIONs were encapsulated in polymeric nanoparticles (NP) via a double emulsion approach and subsequently cloaked with monocyte plasma membranes, forming MoNP-SPION. MoNP-SPION were evaluated in vitro and in mouse models using a 7-Tesla MRI. Results: Our physicochemical characterization confirmed the successful formation of MoNP-SPION, with a hydrodynamic size of approximately 271 nm, an SPION loading capacity of 8.5%, and a high T2 relaxivity of 400 mM -1 s -1 . In vitro studies showed that MoNP-SPION exhibited significantly enhanced targeting efficiency toward TNFα-activated endothelial cells (ECs), increasing intracellular iron content 2.98-fold compared to 1.42- and 1.51-fold increases with NP-SPION and standalone SPION, respectively. MR phantom imaging further validated these findings, showing a 0.76-fold decrease in T2* signal in TNFα-activated ECs with MoNP-SPION. In vivo MR imaging of atherosclerotic mice revealed that MoNP-SPION, but not NP-SPION or SPION, induced strong T2* signal reductions in plaques at the aortic root and carotid bifurcation while sparing lesion-free areas, confirming MoNP-SPION’s capability in selective targeting and detection of plaque inflammation. Conclusion: Our findings demonstrate that MoNP-SPION is a promising biomimetic contrast agent that enables precise MR imaging-based detection of inflammation and monitoring of plaque progression.

Nanoparticle-based magnetic resonance imaging (MRI) contrast agents have received much attention over the past decade. By virtue of a high payload of magnetic moieties, enhanced accumulation at disease sites, and a large surface area for additional modification with targeting ligands, nanoparticle-based contrast agents offer promising new platforms to further enhance the high resolution and sensitivity of MRI for various biomedical applications. T 2 * superparamagnetic iron oxide nanoparticles (SPIONs) first demonstrated superior improvement on MRI sensitivity. The prevailing SPION attracted growing interest in the development of refined nanoscale versions of MRI contrast agents. Afterwards, T 1 -based contrast agents were developed, and became the most studied subject in MRI due to the positive contrast they provide that avoids the susceptibility associated with MRI signal reduction. Recently, chemical exchange saturation transfer (CEST) contrast agents have emerged and rapidly gained popularity. The unique aspect of CEST contrast agents is that their contrast can be selectively turned 'on' and 'off' by radiofrequency saturation. Their performance can be further enhanced by incorporating a large number of exchangeable protons into well-defined nanostructures. Besides activatable CEST contrast agents, there is growing interest in developing nanoparticle-based activatable MRI contrast agents responsive to stimuli (pH, enzyme, etc.), which improves sensitivity and specificity. In this review, we summarize the recent development of various types of nanoparticle-based MRI contrast agents, and have focused our discussions on the key advantages of introducing nanoparticles in MRI. WIREs Nanomed Nanobiotechnol 2016, 8:814-841. doi: 10.1002/wnan.1400 For further resources related to this article, please visit the WIREs website.

Superparamagnetic iron oxide (SPIO) and ultra small superparamagnetic iron oxide (USPIO) nanoparticles have been developed as magnetic resonance imaging (MRI) contrast agents. Iron oxide nanoparticles, that become superparamagnetic if the core particle diameter is ~ 30nm or less, present R1 and R2 relaxivities which are much higher than those of conventional paramagnetic gadolinium chelates. Generally, these magnetic particles are coated with biocompatible polymers that prevent the agglomeration of the colloidal suspension and improve their blood distribution profile. In spite of their potential as MRI blood contrast agents, the biomedical application of iron oxide nanoparticles is still limited because of their intravascular half-life of only few hours; such nanoparticles are rapidly cleared from the bloodstream by macrophages of the reticulo-endothelial system (RES). To increase the life span of these MRI contrast agents in the bloodstream we proposed the encapsulation of SPIO nanoparticles in red blood cells (RBCs) through the transient opening of cell membrane pores. We have recently reported results obtained by applying our loading procedure to several SPIO nanoparticles with different chemical physical characteristics such as size and coating agent. In the current investigation we showed that the life span of iron-based contrast agents in the mice bloodstream was prolonged to 12 days after the intravenous injection of murine SPIO-loaded RBCs. Furthermore, we developed an animal model that implicates the pretreatment of animals with clodronate to induce a transient suppression of tissue macrophages, followed by the injection of human SPIO-loaded RBCs which make it possible to encapsulate nanoparticle concentrations (5.3-16.7mM Fe) higher than murine SPIO-loaded RBCs (1.4-3.55mM Fe). The data showed that, when human RBCs are used as more capable SPIO nanoparticle containers combined with a depletion of tissue macrophages, Fe concentration in animal blood is 2-3 times higher than iron concentration obtained by the use of murine SPIO-loaded RBCs.

Various inorganic nanoparticles have been used as magnetic resonance imaging (MRI) contrast agents due to their unique properties, such as large surface area and efficient contrasting effect. Since the first use of superparamagnetic iron oxide (SPIO) as a liver contrast agent, nanoparticulate MRI contrast agents have attracted a lot of attention. Magnetic iron oxide nanoparticles have been extensively used as MRI contrast agents due to their ability to shorten T2* relaxation times in the liver, spleen, and bone marrow. More recently, uniform ferrite nanoparticles with high crystallinity have been successfully employed as new T2 MRI contrast agents with improved relaxation properties. Iron oxide nanoparticles functionalized with targeting agents have been used for targeted imaging via the site‐specific accumulation of nanoparticles at the targets of interest. Recently, extensive research has been conducted to develop nanoparticle‐based T1 contrast agents to overcome the drawbacks of iron oxide nanoparticle‐based negative T2 contrast agents. In this report, we summarize the recent progress in inorganic nanoparticle‐based MRI contrast agents.

Magnetic resonance imaging (MRI) is a powerful technique for tumor diagnostics. Iron oxide nanoparticles (IONPs) are safe and biocompatible tools that can be used for further enhancing MR tumor contrasting. Although numerous IONPs have been proposed as MRI contrast agents, low delivery rates to tumor site limit its application. IONPs accumulation in malignancies depends on both IONPs characteristics and tumor properties. In the current paper, three differently shaped Pluronic F-127-modified IONPs (nanocubes, nanoclusters, and nanorods) were compared side by side in three murine tumor models (4T1 breast cancer, B16 melanoma, and CT26 colon cancer). Orthotopic B16 tumors demonstrated more efficient IONPs uptake than heterotopic implants. Magnetic nanocubes (MNCb) had the highest r2-relaxivity in vitro (300 mM−1·s−1) compared with magnetic nanoclusters (MNCl, 104 mM−1·s−1) and magnetic nanorods (MNRd, 51 mM−1·s−1). As measured by atomic emission spectroscopy, MNCb also demonstrated better delivery efficiency to tumors (3.79% ID) than MNCl (2.94% ID) and MNRd (1.21% ID). Nevertheless, MNCl overperformed its counterparts in tumor imaging, providing contrast enhancement in 96% of studied malignancies, whereas MNCb and MNRd were detected by MRI in 73% and 63% of tumors, respectively. Maximum MR contrasting efficiency for MNCb and MNCl was around 6-24 hours after systemic administration, whereas for MNRd maximum contrast enhancement was found within first 30 minutes upon treatment. Presumably, MNRd poor MRI performance was due to low r2-relaxivity and rapid clearance by lungs (17.3% ID) immediately after injection. MNCb and MNCl were mainly captured by the liver and spleen without significant accumulation in the lungs, kidneys, and heart. High biocompatibility and profound accumulation in tumor tissues make MNCb and MNCl the promising platforms for MRI-based tumor diagnostics and drug delivery.

SY20-02: Theranostic nanoparticles for targeted therapy of pancreatic and triple-negative breast cancers

Iron oxide nanoparticles (IONPs) have garnered significant interest as magnetic resonance imaging (MRI) contrast agents due to their exceptional magnetic properties and biocompatibility. Toward more precise diagnosis of diseases, the relaxometric properties of IONPs have become a key research focus. Despite extensive studies on structural factors such as size, morphology, surface modification, crystalline phase, and aggregation state, the correlation between the intrinsic structure and relaxometric behavior remains unclear, particularly for ultrasmall IONPs. To address this issue, we carefully compared IONPs with identical size, shape, and surface modification and found out strong correlations among the content of Fe2+ ions, oxygen vacancies, and the relaxometric properties. By optimizing the reaction system, ultrasmall IONPs showing outstanding relaxometric performance, with longitudinal relaxivity up to 9.0 mM-1 s-1 and transverse relaxivity up to 28.5 mM-1 s-1, were successfully obtained. These results underscore the pivotal role of Fe2+ in the relaxometric properties of IONP-based MRI contrast agents.

We report on the fabrication of organic/inorganic hybrid micelles of amphiphilic block copolymers physically encapsulated with hydrophobic drugs within micellar cores and stably embedded with superparamagnetic iron oxide (SPIO) nanoparticles within hydrophilic coronas, which possess integrated functions of chemotherapeutic drug delivery and magnetic resonance (MR) imaging contrast enhancement. Poly(ε-caprolactone)-b-poly(glycerol monomethacrylate), PCL-b-PGMA, and PCL-b-P(OEGMA-co-FA) amphiphilic block copolymers were synthesized at first by combining ring-opening polymerization (ROP), atom transfer radical polymerization (ATRP), and post- modification techniques, where OEGMA and FA are oligo(ethylene glycol) monomethyl ether methacrylate and folic acid-bearing moieties, respectively. A model hydrophobic anticancer drug, paclitaxel (PTX), and 4 nm SPIO nanoparticles were then loaded into micellar cores and hydrophilic coronas, respectively, of mixed micelles fabricated from PCL-b-PGMA and PCL-b-P(OEGMA-co-FA) diblock copolymers by taking advantage of the hydrophobicity of micellar cores and strong affinity between 1,2-diol moieties in PGMA and Fe atoms at the surface of SPIO nanoparticles. The controlled and sustained release of PTX from hybrid micelles was achieved, exhibiting a cumulative release of ~61% encapsulated drugs (loading content, 8.5 w/w%) over ~130 h. Compared to that of surfactant-stabilized single SPIO nanoparticles (r(2) = 28.3 s(-1) mM(-1) Fe), the clustering of SPIO nanoparticles within micellar coronas led to considerably enhanced T(2) relaxivity (r(2) = 121.1 s(-1) mM(-1) Fe), suggesting that hybrid micelles can serve as a T(2)-weighted MR imaging contrast enhancer with improved performance. Moreover, preliminary experiments of in vivo MR imaging were also conducted. These results indicate that amphiphilic block copolymer micelles surface embedded with SPIO nanoparticles at the hydrophilic corona can act as a new generation of nanoplatform integrating targeted drug delivery, controlled release, and disease diagnostic functions.

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.

Using RGD10-NGR9 dual-targeting superparamagnetic iron oxide nanoparticles to evaluate their potential value in tumor angiogenesis magnetic resonance imaging (MRI) and the biodistribution in vitro and in vivo. Dual-targeting RGD10-NGR9 ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles were designed and synthesized in our previous study. In vitro, prussian blue staining and phenanthroline colorimetry were conducted to evaluate binding affinity and adsorption of dual-targeting USPIO nanoparticles to αvβ3-integrin/APN positive cells. In vivo, a xenograft mouse tumor model was used to evaluate the potential of the dual-targeting nanoparticles as an MRI contrast agent. After intravenous injection, the contrast-to-noise ratio (CNR) values of MR images obtained were calculated at predetermined time-points. The iron level was detected to access the biodistribution and plasma half-time. In vitro, dual-targeting USPIO nanoparticles bound to proliferating human umbilical vein endothelia cells with high specificity. In vivo, contrast MRI of xenograft mice using dual-targeting nanoparticles demonstrated a significant decrease in signal intensity and a greater increase in CNR than standard MRI and facilitated the imaging of tumor angiogenesis in T2*WI. In terms of biodistribution, dual-targeting USPIO nanoparticles increased to 1.83 times in tumor lesions as compared to the control. And the plasma half-time was about 6.2h. A novel RGD10-NGR9 dual-targeting USPIO has a great potential value as a contrast agent for the identification of tumor angiogenesis on MRI, according to the high specific affinity in vitro and in vivo.