The Development of a Smart Magnetic Resonance Imaging and Chemical Exchange Saturation Transfer Contrast Agent for the Imaging of Sulfatase Activity.

The molecular imaging of biomarkers plays an increasing role in medical diagnostics. In particular, the imaging of enzyme activity is a promising approach, as it enables the use of its inherent catalytic activity for the amplification of an imaging signal. The increased activity of a sulfatase enzyme has been observed in several types of cancers. We describe the development and in vitro evaluation of molecular imaging agents that allow for the detection of sulfatase activity using the whole-body, non-invasive MRI and CEST imaging methods. This approach relies on a responsive ligand that features a sulfate ester moiety, which upon sulfatase-catalyzed hydrolysis undergoes an elimination process that changes the functional group, coordinating with the metal ion. When Gd3+ is used as the metal, the complex can be used for MRI, showing a 25% decrease at 0.23T and a 42% decrease at 4.7T in magnetic relaxivity after enzymatic conversion, thus providing a "switch-off" contrast agent. Conversely, the use of Yb3+ as the metal leads to a "switch-on" effect in the CEST imaging of sulfatase activity. Altogether, the results presented here provide a molecular basis and a proof-of-principle for the magnetic imaging of the activity of a key cancer biomarker.

A Photocleavable Contrast Agent for Light-Responsive MRI.

Thanks to its innocuousness and high spatiotemporal resolution, light is used in several established and emerging applications in biomedicine. Among them is the modulation of magnetic resonance imaging (MRI) contrast agents' relaxivity with the aim to increase the sensitivity, selectivity and amount of functional information obtained from this outstanding whole-body medical imaging technique. This approach requires the development of molecular contrast agents that show high relaxivity and strongly pronounced photo-responsiveness. To this end, we report here the design and synthesis of a light-activated MRI contrast agent, together with its evaluation using UV-vis spectroscopy, Fast Field Cycling (FFC) relaxometry and relaxometric measurements on clinical MRI scanners. The high relaxivity of the reported agent changes substantially upon irradiation with light, showing a 17% decrease in relaxivity at 0.23T upon irradiation with λ = 400 nm (violet) light for 60 min. On clinical MRI scanners (1.5T and 3.0T), irradiation leads to a decrease in relaxivity of 9% and 19% after 3 and 60 min, respectively. The molecular design presents an important blueprint for the development of light-activatable MRI contrast agents.

A Facile and Reproducible Synthesis of Near-Infrared Fluorescent Conjugates with Small Targeting Molecules for Microbial Infection Imaging.

Optical imaging of microbial infections, based on the detection of targeted fluorescent probes, offers high sensitivity and resolution with a relatively simple and portable setup. As the absorbance of near-infrared (NIR) light by human tissues is minimal, using respective tracers, such as IRdye800CW, enables imaging deeper target sites in the body. Herein, we present a general strategy for the conjugation of IRdye800CW and IRdye700DX to small molecules (vancomycin and amphotericin B) to provide conjugates targeted toward bacterial and fungal infections for optical imaging and photodynamic therapy. In particular, we present how the use of coupling agents (such as HBTU or HATU) leads to high yields (over 50%) in the reactions of amines and IRDye-NHS esters and how precipitation can be used as a convenient purification strategy to remove excess of the targeting molecule after the reaction. The high selectivity of the synthesized model compound Vanco-800CW has been proven in vitro, and the development of analogous agents opens up new possibilities for diagnostic and theranostic purposes. In times of increasing microbial resistance, this research gives us access to a platform of new fluorescent tracers for the imaging of infections, enabling early diagnosis and respective treatment.

Modular Medical Imaging Agents Based on Azide-Alkyne Huisgen Cycloadditions: Synthesis and Pre-Clinical Evaluation of 18 F-Labeled PSMA-Tracers for Prostate Cancer Imaging.

Since the seminal contribution of Rolf Huisgen to develop the [3+2] cycloaddition of 1,3-dipolar compounds, its azide-alkyne variant has established itself as the key step in numerous organic syntheses and bioorthogonal processes in materials science and chemical biology. In the present study, the copper(I)-catalyzed azide-alkyne cycloaddition was applied for the development of a modular molecular platform for medical imaging of the prostate-specific membrane antigen (PSMA), using positron emission tomography. This process is shown from molecular design, through synthesis automation and in vitro studies, all the way to pre-clinical in vivo evaluation of fluorine-18- labeled PSMA-targeting 'F-PSMA-MIC' radiotracers (t1/2 =109.7 min). Pre-clinical data indicate that the modular PSMA-scaffold has similar binding affinity and imaging properties to the clinically used [68 Ga]PSMA-11. Furthermore, we demonstrated that targeting the arene-binding in PSMA, facilitated through the [3+2]cycloaddition, can improve binding affinity, which was rationalized by molecular modeling. The here presented PSMA-binding scaffold potentially facilitates easy coupling to other medical imaging moieties, enabling future developments of new modular imaging agents.

Following nanomedicine activation with magnetic resonance imaging: why, how, and what's next?

Nanomedicines, such as liposomal formulations, play an important role in cancer therapy. To support their development, medical imaging modalities are employed for following the drug delivery. Encapsulation of MRI contrast agents, which change their relaxivity upon co-release with the drug, is a promising strategy for monitoring both the biodistribution and payload release from a nanocarrier. This approach is successfully applied in preclinical settings to image the activation of liposomes responsive to heat, pH changes or sonication. Recent advances include combination with different treatments and the implementation of chemical exchange saturation transfer imaging to gain spectral resolution over different contrast agents. However, this field still faces challenges, such as matching the pharmacokinetic profiles of the contrast agents and the liberated drugs.

Beyond Photodynamic Therapy: Light-Activated Cancer Chemotherapy.

BACKGROUND: Cancer chemotherapy is limited by severe side effects due to unspecific cytotoxic activity of currently used therapeutics. In order to minimize these unwanted effects, several approaches have been taken, relying on the use of light to activate drugs. As light can be delivered with a very high spatiotemporal resolution, this technique is a promising strategy to selectively activate cytotoxic drugs at their site of action and thus to improve the tolerability and safety of chemotherapy. OBJECTIVE: This review summarizes different approaches towards photoactivated chemotherapy and identifies its challenges and opportunities. RESULTS: The respective papers were summarized and evaluated in terms of their phototherapeutic indices and the wavelength needed for activation. First, the design, synthesis and/or evaluation of photoactivated metal complexes including platinum- , ruthenium-, and rhodium-complexes is described. Next, photocaged metal complexes and photoacaged organic chemotherapeutics are reported, with a wide range of cytotoxicity mechanisms. The final part includes, examples of photoswitchable drugs for cancer therapy. Some designs, especially metal complexes, stand out due to their very high phototherapeutic index (> 1880) but the common drawback of light-responsive metal complexes and organic chemotherapeutics is the irreversibility of activation. Photoswitchable drugs, however, address this challenge. Nevertheless, the need of UV light for their activation still limits their application. CONCLUSION: The field of photoactivated cancer chemotherapy is rapidly growing and already includes very promising approaches with designs providing high phototherapeutic indices and also NIR or visible light-activatable drugs.