Medical imaging is routine in the diagnosis and staging of a wide range of medical conditions. In particular, magnetic resonance imaging (MRI) is critical for visualizing soft tissue and organs, with over 60 million MRI procedures performed each year worldwide. About one-third of these procedures are contrast-enhanced MRI, and gadolinium-based contrast agents (GBCAs) are the mainstream MRI contrast agents used in the clinic. GBCAs have shown efficacy and are safe to use with most patients; however, some GBCAs have a small risk of adverse effects, including nephrogenic systemic fibrosis (NSF), the untreatable condition recently linked to gadolinium (Gd) exposure during MRI with contrast. In addition, Gd deposition in the human brain has been reported following contrast, and this is now under investigation by the US Food and Drug Administration (FDA). To address a perceived need for a Gdfree contrast agent with pharmacokinetic and imaging properties comparable to GBCAs, we have designed and developed zwitterioncoated exceedingly small superparamagnetic iron oxide nanoparticles (ZES-SPIONs) consisting of ∼3-nm inorganic cores and ∼1-nm ultrathin hydrophilic shell. These ZES-SPIONs are free of Gd and show a high T 1 contrast power. We demonstrate the potential of ZES-SPIONs in preclinical MRI and magnetic resonance angiography. exceedingly small iron oxide nanoparticles | renal clearance | gadoliniumfree positive MR contrast agent | preclinical magnetic resonance imaging M RI signal arises from the excitation of low-energy nuclear spins, which are formed in a permanent magnetic field, by applying radiofrequency pulses followed by the measurement of the spin relaxation processes (i.e
From magnetic resonance imaging to cancer hyperthermia and wireless control of cell signaling, ferrite nanoparticles produced by thermal decomposition methods are ubiquitous across biomedical applications. While well-established synthetic protocols allow for precise control over the size and shape of the magnetic nanoparticles, structural defects within seemingly single-crystalline materials contribute to variability in the reported magnetic properties. We found that stabilization of metastable wüstite in commonly used hydrocarbon solvents contributed to significant cation disorder, leading to nanoparticles with poor hyperthermic efficiencies and transverse relaxivities. By introducing aromatic ethers that undergo radical decomposition upon thermolysis, the electrochemical potential of the solvent environment was tuned to favor the ferrimagnetic phase. Structural and magnetic characterization identified hallmark features of nearly defect-free ferrite nanoparticles that could not be demonstrated through postsynthesis oxidation with nearly 500% increase in the specific loss powers and transverse relaxivity times compared to similarly sized nanoparticles containing defects. The improved crystallinity of the nanoparticles enabled rapid wireless control of intracellular calcium. Our work demonstrates that redox tuning during solvent thermolysis can generate potent theranostic agents through selective phase control in ferrites and can be extended to other transition metal oxides relevant to memory and electrochemical storage devices.
Calcium ions are ubiquitous signaling molecules in all multicellular organisms, where they mediate diverse aspects of intracellular and extracellular communication over widely varying temporal and spatial scales1. Although techniques for mapping calcium-related activity at high resolution by optical means are well established, there is currently no reliable method to measure calcium dynamics over large volumes in intact tissue2. Here we address this need by introducing a family of magnetic calcium-responsive nanoparticles (MaCaReNas) that can be detected by magnetic resonance imaging (MRI). MaCaReNas respond within seconds to [Ca2+] changes in the 0.1-1.0 mM range, suitable for monitoring extracellular calcium signaling processes in the brain. We show that the probes permit repeated detection of brain activation in response to diverse stimuli in vivo. MaCaReNas thus provide a tool for calcium activity mapping in deep tissue and offer a precedent for development of further nanoparticle-based sensors for dynamic molecular imaging with MRI.
The physiological roles of free Zn(2+) have attracted great attention. To clarify those roles, there has been a need for ratiometric fluorescent Zn(2+) probes for practical use. We report the rational design and synthesis of a series of ratiometric fluorescent Zn(2+) probes. The structures of the probes are based on the 7-hydroxycoumarin structure. We focused on the relationship between the electron-donating ability of the 7-hydroxy group and the excitation spectra of 7-hydroxycoumarins, and exploited that relationship in the design of the ratiometric probes; as a result, most of the synthesized probes showed ratiometric Zn(2+)-sensing properties. Then, we designed and synthesized ratiometric Zn(2+) probes that can be excited with visible light, by choosing adequate substituents on coumarin dyes. Since one of the probes could permeate living cell membranes, we introduced the probe to living RAW264 cells and observed the intracellular Zn(2+) concentration via ratiometric fluorescence microscopy. As a result, the ratio value of the probe changed quickly in response to intracellular Zn(2+) concentration.
A novel photocontrolled compound release system using liposomes and a caged antimicrobial peptide was developed. The caged antimicrobial peptide was activated by UV irradiation, resulting in the formation of pores on the liposome surface to release the contained fluorophores. The compound release could be observed using fluorescence measurements and time-lapse fluorescence microscopy. UV irradiation resulted in a quick release of the inclusion compounds (within 1 min in most cases) under simulated physiological conditions. The proposed system is expected to be applicable in a wide range of fields from cell biology to clinical sciences.
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