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

Controlling drug activity with light:developments in photopharmacology

For millennia, humanity has been fascinated by the prospect of using visible light in medical applications. Nowadays, light is used in the clinic for intraoperative imaging and photodynamic therapy, among others. However, the precision of light delivery has also the potential to enable safe and targeted pharmacological treatments. This is the dream behind the emerging field of photopharmacology, which develops drugs whose activity can be regulated with light irradiation. Those photopharmacological drugs can be designed in two ways. Firstly, the drug can be "silenced" by attachment of a group that can be locally removed with light. Secondly, a molecular photoswitch can be inserted into a drug molecule to enable it switching on and off with different colours of light. In this article, a perspective is given on the basic principles and future of photopharmacology on its way to clinical applications.</p

Controlling drug activity with light:developments in photopharmacology

For millennia, humanity has been fascinated by the prospect of using visible light in medical applications. Nowadays, light is used in the clinic for intraoperative imaging and photodynamic therapy, among others. However, the precision of light delivery has also the potential to enable safe and targeted pharmacological treatments. This is the dream behind the emerging field of photopharmacology, which develops drugs whose activity can be regulated with light irradiation. Those photopharmacological drugs can be designed in two ways. Firstly, the drug can be "silenced" by attachment of a group that can be locally removed with light. Secondly, a molecular photoswitch can be inserted into a drug molecule to enable it switching on and off with different colours of light. In this article, a perspective is given on the basic principles and future of photopharmacology on its way to clinical applications.</p

Rational Design in Photopharmacology with Molecular Photoswitches

Photopharmacology is an attractive approach for achieving targeted drug action with the use of light. In photopharmacology, molecular photoswitches are introduced into the structure of biologically active small molecules to allow for the optical control of their potency. Going beyond trial and error, photopharmacology has progressively applied rational drug design methodologies to devise light-controlled bioactive ligands. In this review, we categorize photopharmacological efforts from the standpoint of medicinal chemistry strategies, focusing on diffusible photochromic ligands modified with photoswitches that operate through E-Z bond isomerization. In the vast majority of cases, photoswitchable ligands are designed as analogs of existing compounds, through a variety of approaches. By analyzing in detail a comprehensive list of instructive examples, we describe the state of the art and discuss future opportunities for rational design in photopharmacology.</p

Molecular photoswitches in aqueous environments

Molecular photoswitches enable dynamic control of processes with high spatiotemporal precision, using light as external stimulus, and hence are ideal tools for different research areas spanning from chemical biology to smart materials. Photoswitches are typically organic molecules that feature extended aromatic systems to make them responsive to (visible) light. However, this renders them inherently lipophilic, while water-solubility is of crucial importance to apply photoswitchable organic molecules in biological systems, like in the rapidly emerging field of photopharmacology. Several strategies for solubilizing organic molecules in water are known, but there are not yet clear rules for applying them to photoswitchable molecules. Importantly, rendering photoswitches water-soluble has a serious impact on both their photophysical and biological properties, which must be taken into consideration when designing new systems. Altogether, these aspects pose considerable challenges for successfully applying molecular photoswitches in aqueous systems, and in particular in biologically relevant media. In this review, we focus on fully water-soluble photoswitches, such as those used in biological environments, in both in vitro and in vivo studies. We discuss the design principles and prospects for water-soluble photoswitches to inspire and enable their future applications

Controlling drug activity with light:developments in photopharmacology

For millennia, humanity has been fascinated by the prospect of using visible light in medical applications. Nowadays, light is used in the clinic for intraoperative imaging and photodynamic therapy, among others. However, the precision of light delivery has also the potential to enable safe and targeted pharmacological treatments. This is the dream behind the emerging field of photopharmacology, which develops drugs whose activity can be regulated with light irradiation. Those photopharmacological drugs can be designed in two ways. Firstly, the drug can be "silenced" by attachment of a group that can be locally removed with light. Secondly, a molecular photoswitch can be inserted into a drug molecule to enable it switching on and off with different colours of light. In this article, a perspective is given on the basic principles and future of photopharmacology on its way to clinical applications.</p

Multivalent Probes in Molecular Imaging:Reality or Future?

The rapidly developing field of molecular medical imaging focuses on specific visualization of (patho)physiological processes through the application of imaging agents (IAs) in multiple clinical modalities. Although our understanding of the principles underlying efficient IAs design has increased tremendously, many IAs still show poor in vivo imaging performance because of low binding affinity and/or specificity. These limitations can be addressed by taking advantage of multivalency, in which multiple copies of a ligand are employed to strengthen the interaction. We critically address specific challenges associated with the application of multivalent compounds in molecular imaging, and we give directions for a stepwise approach to the design of multivalent imaging probes to improve their target binding and pharmacokinetics (PK) for improved diagnostic potential. The rapidly developing field of molecular medical imaging focuses on specific visualization of (patho)physiological processes through the application of imaging agents (IAs) in multiple clinical modalities. Although our understanding of the principles underlying efficient IAs design has increased tremendously, many IAs still show poor in vivo imaging performance because of low binding affinity and/or specificity. These limitations can be addressed by taking advantage of multivalency, in which multiple copies of a ligand are employed to strengthen the interaction. We critically address specific challenges associated with the application of multivalent compounds in molecular imaging, and we give directions for a stepwise approach to the design of multivalent imaging probes to improve their target binding and pharmacokinetics (PK) for improved diagnostic potential. Challenges and Applications of Molecular Imaging in Medicine Medical imaging enables the visualization of anatomical structures and physiological processes for diagnostic purposes [1,2], and is commonly subcategorized into structural, functional, and molecular imaging [3]. Molecular imaging reveals diagnostically relevant biochemical information [4,5] at cellular and molecular levels in vivo [6,7]. Therefore, in addition to diagnostic applications

Reversible, Spatial and Temporal Control over Protein Activity Using Light

In biomedical sciences, the function of a protein of interest is investigated by altering its net activity and assessing the consequences for the cell or organism. To change the activity of a protein, a wide variety of chemical and genetic tools have been developed. The drawback of most of these tools is that they do not allow for reversible, spatial and temporal control. Here, we describe selected developments in photopharmacology that aim at establishing such control over protein activity through bioactive molecules with photo-controlled potency. We also discuss why such control is desired and what challenges still need to be overcome for photopharmacology to reach its maturity as a chemical biology research tool

Reversible Photocontrolled Nanopore Assembly

Self-assembly is a fundamental feature of biological systems, and control of such processes offers fascinating opportunities to regulate function. Fragaceatoxin C (FraC) is a toxin that upon binding to the surface of sphingomyelin-rich cells undergoes a structural metamorphosis, leading to the assembly of nanopores at the cell membrane and causing cell death. In this study we attached photoswitchable azobenzene pendants to various locations near the sphingomyelin binding pocket of FraC with the aim of remote controlling the nanopore assembly using light. We found several constructs in which the affinity of the toxin for biological membranes could be activated or deactivated by irradiation, thus enabling reversible photocontrol of pore formation. Notably, one construct was completely inactive in the thermally adapted state; it however induced full lysis of cultured cancer cells upon light irradiation. Selective irradiation also allowed isolation of individual nanopores in artificial lipid membranes. Photocontrolled FraC might find applications in photopharmacology for cancer therapeutics and has potential to be used for the fabrication of nanopore arrays in nanopore sensing devices, where the reconstitution, with high spatiotemporal precision, of single nanopores must be controlled

Computational Design, Synthesis, and Photochemistry of Cy7-PPG, an Efficient NIR-Activated Photolabile Protecting Group for Therapeutic Applications

Photolabile Protecting Groups (PPGs) are molecular tools used, for example, in photopharmacology for the activation of drugs with light, enabling spatiotemporal control over their potency. Yet, red-shifting of PPG activation wavelengths into the NIR range, which penetrates the deepest in tissue, has often yielded inefficient or insoluble molecules, hindering the use of PPGs in the clinic. To solve this problem, we report herein a novel concept in PPG design, by transforming clinically-applied NIR-dyes with suitable molecular orbital configurations into new NIR-PPGs using computational approaches. Using this method, we demonstrate how Cy7, a class of NIR dyes possessing ideal properties (NIR-absorption, high molecular absorptivity, excellent aqueous solubility) can be successfully converted into Cy7-PPG. We report a facile synthesis towards Cy7-PPG from accessible precursors and confirm its excellent properties as the most redshifted oxygen-independent NIR-PPG to date (λmax=746 nm)