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High-resolution, multiplexed experiments are a staple in cellular imaging. Analogous experiments in animals are challenging, however, due to substantial scattering and autofluorescence in tissue at visible (350–700 nm) and near-infrared (700–1,000 nm) wavelengths. Here, we enable real-time, non-invasive multicolour imaging experiments in animals through the design of optical contrast agents for the shortwave infrared (SWIR, 1,000–2,000 nm) region and complementary advances in imaging technologies. We developed tunable, SWIR-emissive flavylium polymethine dyes and established relationships between structure and photophysical properties for this class of bright SWIR contrast agents. In parallel, we designed an imaging system with variable near-infrared/SWIR excitation and single-channel detection, facilitating video-rate multicolour SWIR imaging for optically guided surgery and imaging of awake and moving mice with multiplexed detection. Optimized dyes matched to 980 nm and 1,064 nm lasers, combined with the clinically approved indocyanine green, enabled real-time, three-colour imaging with high temporal and spatial resolutions.Conducting high-resolution, multiplexed imaging in living mammals is challenging because of considerable scattering and autofluorescence in tissue at visible and near-infrared wavelengths. Now, real-time, non-invasive multicolour imaging experiments in live animals have been achieved through the design of optical contrast agents for the shortwave infrared (SWIR, 1,000–2,000 nm) region and the introduction of excitation multiplexing with single-channel SWIR detection.

Key Points Ligand targeting allows selective delivery of therapeutic and imaging agents to cancer cells while avoiding collateral damage to healthy tissues. Small-molecule–ligand conjugates more readily penetrate dense solid tumours than do high-molecular-weight conjugates. Following the delivery of cytotoxic drug conjugates to their target cells, cleavage of the ligand from its therapeutic cargo and release from endosomes into the cytoplasm are necessary for optimal killing of the targeted cell. Typically, cytotoxic agents with nanomolar potencies are required in an effective ligand-targeted strategy, as receptor-mediated delivery may limit the maximum intracellular concentration of drug to 100 nM or less. One strategy for treating cancer while limiting off-target effects on healthy cells is to conjugate cytotoxic agents to small-molecule ligands for receptors that are upregulated in tumours. Low and colleagues explain the key aspects to be considered when designing ligand–drug conjugates, and summarize the ligand–drug and ligand–imaging agent conjugates that are currently in clinical trials. Most cancer drugs are designed to interfere with one or more events in cell proliferation or survival. As healthy cells may also need to proliferate and avoid apoptosis, anticancer agents can be toxic to such cells. To minimize these toxicities, strategies have been developed wherein the therapeutic agent is targeted to tumour cells through conjugation to a tumour-cell-specific small-molecule ligand, thereby reducing delivery to normal cells and the associated collateral toxicity. This Review describes the major principles in the design of ligand-targeted drugs and provides an overview of ligand–drug conjugates and ligand–imaging-agent conjugates that are currently in development.

Purpose Ultrasmall silver sulfide nanoparticles (Ag 2 S-NP) have been identified as promising contrast agents for a number of modalities and in particular for dual-energy mammography. These Ag 2 S-NP have demonstrated marked advantages over clinically available agents with the ability to generate higher contrast with high biocompatibility. However, current synthesis methods for inorganic nanoparticles are low-throughput and highly time-intensive, limiting the possibility of large animal studies or eventual clinical use of this potential imaging agent. Methods We herein report the use of a scalable silicon microfluidic system (SSMS) for the large-scale synthesis of Ag 2 S-NP. Ag 2 S-NP produced using this system were compared to bulk synthesis and a commercially available microfluidic device through characterization, contrast generation, in vivo imaging, and clearance profiles. Results Using SSMS chips with 1 channel, 10 parallelized channels, and 256 parallelized channels, we determined that the Ag 2 S-NP produced were of similar quality as measured by core size, concentration, UV–visible spectrometry, and in vitro contrast generation. Moreover, by combining parallelized chips with increasing reagent concentration, we were able to increase output by an overall factor of 5,100. We also found that in vivo imaging contrast generation was consistent across synthesis methods and confirmed renal clearance of the ultrasmall nanoparticles. Finally, we found best-in-class clearance of the Ag 2 S-NP occurred within 24 h. Conclusions These studies have identified a promising method for the large-scale production of Ag 2 S-NP, paving the way for eventual clinical translation.

Stimuli-responsive multimodality imaging agents have broad potential in medical diagnostics. Herein, we report the development of a new class of branched-bottlebrush polymer dual-modality organic radical contrast agents—ORCAFluors—for combined magnetic resonance and near-infrared fluorescence imaging in vivo . These nitroxide radical-based nanostructures have longitudinal and transverse relaxation times that are on par with commonly used heavy-metal-based magnetic resonance imaging (MRI) contrast agents. Furthermore, these materials display a unique compensatory redox response: fluorescence is partially quenched by surrounding nitroxides in the native state; exposure to ascorbate or ascorbate/glutathione leads to nitroxide reduction and a concomitant 2- to 3.5-fold increase in fluorescence emission. This behaviour enables correlation of MRI contrast, fluorescence intensity and spin concentration with tissues known to possess high concentrations of ascorbate in mice. Our in vitro and in vivo results, along with our modular synthetic approach, make ORCAFluors a promising new platform for multimodality molecular imaging. Multimodal and stimuli-responsive imaging agents can yield more biological information than more typical single-mode or inert imaging probes. Here, the authors have made a dual-modal MRI-fluorescence probe and demonstrate its ability to image redox status in vivo .

Fluorescence imaging in the second near-infrared window (NIR-II, 1,000–1,700 nm) features deep tissue penetration, reduced tissue scattering, and diminishing tissue autofluorescence. Here, NIR-II fluorescent probes, including down-conversion nanoparticles, quantum dots, single-walled carbon nanotubes, and organic dyes, are constructed into biocompatible nanoparticles using the layer-by-layer (LbL) platform due to its modular and versatile nature. The LbL platform has previously been demonstrated to enable incorporation of diagnostic agents, drugs, and nucleic acids such as siRNA while providing enhanced blood plasma half-life and tumor targeting. This work carries out head-to-head comparisons of currently available NIR-II probes with identical LbL coatings with regard to their biodistribution, pharmacokinetics, and toxicities. Overall, rare-earth-based down-conversion nanoparticles demonstrate optimal biological and optical performance and are evaluated as a diagnostic probe for high-grade serous ovarian cancer, typically diagnosed at late stage. Successful detection of orthotopic ovarian tumors is achieved by in vivo NIR-II imaging and confirmed by ex vivo microscopic imaging. Collectively, these results indicate that LbL-based NIR-II probes can serve as a promising theranostic platform to effectively and noninvasively monitor the progression and treatment of serous ovarian cancer.

Copper ferrite nanoparticles for use as MRI contrast agents were synthesized using two different methods. A novel microwave-assisted (MW) solvothermal method was developed and compared to a conventional 12-hour synthesis (Reflux) as an eco-friendlier approach. This innovative synthesis method successfully produced nanoparticles with enhanced properties compared to traditional ferrite materials. The nanoparticles’ morphological and magnetic properties were evaluated and tested in in-vivo MRI studies. The results revealed both similarities and differences between the amine-functionalized copper ferrite nanoparticles. FTIR, XRD, HRTEM, and VSM analyses indicated improved properties in the CuFe 2 O 4 -NH 2 MW particles, while AFM confirmed successful polymer encapsulation of the nanoparticles. For the CuFe 2 O 4 -NH 2 MW sample, 76.8 wt% copper ferrite and 23.2 wt% magnetite were detected, with crystallite sizes of 8 ± 2 nm and 13 ± 2 nm, respectively. In the CuFe 2 O 4 -NH 2 Refl. sample, in addition to these two magnetic phases, larger copper particles (31.6 wt%) were also formed. DLS analysis demonstrated that the CuFe 2 O 4 -NH 2 MW sample exhibited excellent colloidal stability, maintaining its size distribution in aqueous media for 3 hours without aggregation, unlike the CuFe 2 O 4 -NH 2 Refl. sample, which showed slight aggregation. The CuFe 2 O 4 -NH 2 MW sample displayed superparamagnetic behavior (Ms: 15 emu/g, Mr: 0 emu/g, Hc: 0 Oe), while the CuFe 2 O 4 -NH 2 Refl. sample exhibited ferromagnetic characteristics (Ms: 40 emu/g, Mr: 1.35 emu/g, Hc: 30 Oe). Both samples produced comparable results during in vitro MRI measurements, showing similar T2* relaxation and signal characteristics. Further in vivo studies demonstrated that both samples induced significant hypointense changes. The study provides valuable insights into the synthesis, properties, and potential applications of these materials, emphasizing the importance of eco-friendly methods and the optimization of ferrite-based MRI contrast agents.

Gadolinium-based contrast agents are widely used in clinical magnetic resonance imaging (MRI) due to their strong paramagnetic properties and ability to enhance image contrast. Despite their diagnostic value, concerns remain regarding gadolinium toxicity and long-term tissue retention, particularly for less stable linear chelates. In this study, we report preliminary results on a newly synthesized gadolinium-based compound (L-Gd), in which the Gd3+ ion is coordinated to a specific ligand designed to improve biocompatibility. To evaluate the feasibility of L-Gd encapsulation within human RBCs (hRBCs) for drug delivery, its biocompatibility and cellular interactions were thoroughly investigated. RBCs represent an attractive biomimetic carrier system capable of limiting the direct exposure of tissues to paramagnetic agents while potentially improving circulation time and safety. In vitro assays demonstrated that L-Gd maintains high compatibility with hRBCs within specific concentration ranges, showing no significant hemolysis or morphological alterations. Furthermore, preliminary encapsulation studies indicate that L-Gd can be successfully associated with RBCs, supporting the potential of this approach for contrast agent delivery. These findings suggest that RBC-mediated transport of gadolinium complexes may represent a promising strategy to reduce toxicity and mitigate gadolinium retention. Further investigations will focus on optimizing encapsulation efficiency, relaxometric properties, and in vivo behavior of the L-Gd system.

While nanoparticles are usually designed for targeted drug delivery, they can also simultaneously provide diagnostic information by a variety of in vivo imaging methods. These diagnostic capabilities make use of specific properties of nanoparticle core materials. Near-infrared fluorescent probes provide optical detection of cells targeted by real-time nanoparticle-distribution studies within the organ compartments of live, anesthetized animals. By combining different imaging modalities, we can start with deep-body imaging by magnetic resonance imaging or computed tomography, and by using optical imaging, get down to the resolution required for real-time fluorescence-guided surgery.

In recent years, several synthetic strategies aiming at the peripheral functionalization of porphyrins were developed. Particularly interesting are those involving the modification of β-pyrrolic positions leading to pyrrole-modified porphyrins containing four-, five-, six- or seven-membered heterocycles. Azeteoporphyrins, porpholactones and morpholinoporphyrins are representative examples of such porphyrinoids. These porphyrin derivatives have recently gained an increasing interest due to their potential application in PDT, as multimodal imaging contrast agents, NIR-absorbing dyes, optical sensors for oxygen, cyanide, hypochlorite and pH, and in catalysis.

One way to image the molecular pathology in Alzheimer's disease is by positron emission tomography using probes that target amyloid fibrils. However, these fibrils are not closely linked to the development of the disease. It is now thought that early-stage biomarkers that instigate memory loss are composed of Aβ oligomers. Here, we report a sensitive molecular magnetic resonance imaging contrast probe that is specific for Aβ oligomers. We attach oligomer-specific antibodies onto magnetic nanostructures and show that the complex is stable and binds to Aβ oligomers on cells and brain tissues to give a magnetic resonance imaging signal. When intranasally administered to an Alzheimer's disease mouse model, the probe readily reached hippocampal Aβ oligomers. In isolated samples of human brain tissue, we observed a magnetic resonance imaging signal that distinguished Alzheimer's disease from controls. Such nanostructures that target neurotoxic Aβ oligomers are potentially useful for evaluating the efficacy of new drugs and ultimately for early-stage Alzheimer's disease diagnosis and disease management. A magnetic resonance imaging probe that binds specifically to neurotoxic amyloid-beta oligomers can potentially be used for early detection of Alzheimer's disease.