Minireviews ChemPhotoChem doi.org/10.1002/cptc.202100001 1 Very Important Paper 2 3 The Issue of Tissue: Approaches and Challenges to the 4 5 Light Control of Drug Activity 6 [a] [a] 7 Mayank Sharma and Simon H. Friedman* 8 9 10 Many of the major challenges associated with drug delivery can modulate drug release. Because of these and other advantages, 11 potentially be addressed by linking drug action to light a range of mechanisms for using light to manipulate drug 12 irradiation. These challenges include the spacing, timing and activity has been developed, including photocleavage control, 13 amount of a drug’s activity. Once a drug’s activity is linked to photoconformational control, photothermal control and photo- 14 light, this activity can be more easily manipulated, because light degradation control. These major themes of light control will be 15 itself is easy to manipulate. One of the main issues that light described in this minireview, and illustrated with examples. In 16 control can address is off-target toxicity. This has the potential addition, the issue of tissue light permittivity, arguably the 17 to be limited if drugs are activated only in target tissues using major challenge for the discipline, will be described and 18 light. For drugs that are needed at varying concentrations analyzed. 19 through the day, varying light has the potential to temporally 20 21 22 1. Introduction larger community of researchers using light to manipulate 23 biological phenomena. 24 Light is a powerful chemical reagent: Where light goes, when it 25 is applied, and the amount of light delivered are all factors that 26 are relatively easy to regulate. Because of this, there has been a 2. The Dimensions that Light Can Control 27 significant interest in controlling biological phenomena using 28 light, since so much of biology is linked to the concentration of There are three principal aspects of a process that light can 29 key molecules, as well as the timing and location of their modulate: a) Its spacing, b) its timing and c) the degree to 30 appearance. The areas of study influenced by these factors are which it happens. This is because once a process is linked to 31 numerous and include gene expression, developmental biology light irradiation, you can control where light goes, when light 32 and neuroscience. The molecular tools developed for these irradiation is initiated and how much light is applied. Each of 33 studies have been wide ranging, and include light-activated these dimensions of control confers different potential advan- 34 nucleic acids, proteins and small molecules.[1] Within this larger tages. 35 category of light controlled biology has been the development The control of spacing has the potential to reduce a drug’s 36 of light controlled drug activity.[1b,k,2] The motivation behind toxicity, by limiting its activity to a specific site, for example a 37 light controlled drug activity has been similar to that of light tumor or a site of infection. Many chemotherapeutics have 38 controlled biology in general: There are multiple drug classes dose-limiting toxicities associated with healthy tissue, for 39 for which control of the timing, amount and location of activity example non-cancerous but rapidly dividing cells. Limiting a 40 is critical for optimal treatment of disease. drug’s activity only to target sites where they are activated by 41 This review will focus on the literature that deals with light light could allow them to be used for longer periods of time or 42 control of drugs, approved molecules that can be used to treat at higher doses. 43 human diseases. This is as opposed to the larger (and The control of the timing and amount of release can be 44 important) literature that deals with light control of biological useful for drugs where the required amount varies continuously 45 probes, used typically to understand biological phenomenon. throughout the day. The majority of drugs likely do not fall into 46 We have attempted to identify the broad themes in the this category, as all that is required for their effective 47 literature, and illustrated them with representative examples. In application is that the systemic concentration remains above a 48 addition we have highlighted the strengths and weaknesses of critical therapeutic threshold. Normally this can be achieved 49 the approaches. Needless to say, many of the issues that are through more conventional means, such as extended release 50 involved in the light control of drug release also apply to the formulations.[3] However, there is a subset of applications where 51 timing and amount is critical, such as with hormones and other 52 [a] M. Sharma, Prof. S. H. Friedman signaling molecules where the requirements vary continuously 53 Division of Pharmacology and Pharmaceutical Sciences throughout the day. Light in this context has the potential to 54 School of Pharmacy confer a much needed level of timing and degree control. University of Missouri-Kansas City 55 Kansas City, MO 64108 (USA) 56 E-mail: [email protected] 57 An invited contribution to a Special Collection on Photopharmacology ChemPhotoChem 2021, 5, 1–9 1 © 2021 Wiley-VCH GmbH These are not the final page numbers! �� Wiley VCH Mittwoch, 10.03.2021 2199 / 197084 [S. 1/9] 1 Minireviews ChemPhotoChem doi.org/10.1002/cptc.202100001 1 3. The Ways In Which Light Has Been Used To control of the activity of a biomolecule is the caging of ATP by 2 Control Drug Activity Hoffman and co-workers using an ortho-nitro benzyl group 3 that was capable of blocking the activity of ATP until 365 nm 4 irradiation released native ATP.[6] In the subsequent years, many 5 We can classify light controlled drug activity into four broad actual drugs have been modified with photocleavable (PC) 6 categories, which are linked to the mechanism of light control. groups and showed modulation of activity, although primarily 7 These are 1) Photocleavage control 2) Photoconformational in in-vitro settings. 8 control 3) Photothermal control and 4) Photodegradation The two photocleavable groups that have been most 9 control (Figure 1). With all four of these mechanisms, there are investigated for light activated drug control are the ortho-nitro 10 two principle characteristics of the photoactivated group that benzylic derivatives[7] and coumarin derivatives,[8] although a 11 determine the ultimate performance: The wavelength required wide range of other PC groups have also been explored. The 12 of the photoactivation, and the quantum yield for this process. ortho-nitro benzylic derivatives have absorption maxima in the 13 The wavelength strongly influences the depth that light can far UV (~365 nm). This is not an ionizing wavelength of UV 14 penetrate through tissue, with UV and short visible wave- light, but being shorter than visible light still suffers from lower 15 lengths penetrating a millimeter or less, and infrared having tissue penetration. For example, Nishimoto and co-workers 16 the potential to penetrate on the order of centimeters.[4] This used an ortho-nitro benzylic PC group to act as a linker 17 determines the ultimate number of photons that can reach the between the drug, 5 fluoro uracil, and a cyclic peptide targeting 18 desired target and photoactivated group, based on the amount moiety.[9] Lin and co-workers linked a porphyrin, itself capable 19 of light the body is irradiated with. In addition to wavelength, a of potential photodynamic therapy to 5 fluoro-uracil, via a light 20 critical descriptor of the photoactivated group is the quantum cleaved ortho-nitro benzylic group, showing light dependent 21 yield, the ratio of photostimulated events (e.g. photolysis) per cell toxicity.[10] The coumarin system has also been extensively 22 photon absorbed by the group. The ultimate nature of the examined, in studies of light activated drug and biological 23 photoactivation mechanism also influences the specific photo- probe release. This has resulted in the synthesis of derivatives 24 activated group that can be used. The photochemistry of with increasingly higher wavelengths of deprotection that now 25 specific photoactivatable groups has been recently described stretch to 500 nm and above.[8a,c,e] For example Feringa and co- 26 and reviewed in detail.[1k,2c,5] workers used two different coumarins with different depro- 27 Photocleavage: In photocleavage, irradiation is accompa- tection wavelengths to inhibit two separate strains of 28 nied by the breaking of a covalent bond between the drug and bacteria.[11] This was accomplished through the caging of two 29 a moiety that is responsible for modulating the activity of the different classes of antibiotics, a penicillin and a fluoroquino- 30 drug. Although not a drug, the earliest example of photo- lone. The coumarin system has also shown the potential for 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Figure 1. Four main approaches to the light control of drug action. ChemPhotoChem 2021, 5, 1–9 www.chemphotochem.org 2 © 2021 Wiley-VCH GmbH These are not the final page numbers! �� Wiley VCH Mittwoch, 10.03.2021 2199 / 197084 [S. 2/9] 1 Minireviews ChemPhotoChem doi.org/10.1002/cptc.202100001 1 radical recombination, resulting in undesired products. This is The rationale behind this approach is to switch the drug from 2 dependent on the nature of the linker. Multiple groups are an inactive state, unable to bind to the target of interest, to an 3 examining approaches to avoid this problem, including spacers active state after light is applied. The purpose of this, like much 4 to prevent unproductive recombination events.[12] of photocleavage activation, is to spatially trigger activity only 5 Outside of these two main PC groups, there have been in the target tissue, for example a site of bacterial infection or 6 multiple other photocleavable groups explored.