Beyond Photodynamic Therapy: Light-Activated Cancer Chemotherapy

Reeßing, Friederike; Szymański, Wiktor

doi:10.2174/0929867323666160906103223

Cited by 43 publications

(67 citation statements)

References 118 publications

(281 reference statements)

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“…Lastly, we show that SBTs can also be straightforwardly integrated inside a bioactive scaffold avoiding penalties of compound complexity, in contrast to photouncaging strategies that increase synthetic cost and molecular weight, often penalising biodistribution. 53,54 We consider these as promising features for SBT applications to high-precision, reproducible, "clean" phototriggered biological control.…”

Section: Discussion and Outlookmentioning

confidence: 99%

Photoswitchable microtubule inhibitors enabling robust, GFP-orthogonal optical control over the tubulin cytoskeleton

Gao

Kraus

Wranik

et al. 2019

Preprint

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Here we present GFP-orthogonal optically controlled reagents for reliable and repetitive in cellulo modulation of microtubule dynamics and its dependent processes. Optically controlled reagents ("photopharmaceuticals") have developed into powerful tools for high-spatiotemporal-precision control of endogenous biology, with numerous applications in neuroscience, embryology, and cytoskeleton research. However, the restricted chemical domain of photopharmaceutical scaffolds has constrained their properties and range of applications. Styrylbenzothiazoles are an as-yet unexplored scaffold for photopharmaceuticals, which we now rationally design to feature potent photocontrol, switching microtubule cytoskeleton function off and on according to illumination conditions. We show more broadly that this scaffold is exceptionally chemically and biochemically robust as well as substituent-tolerant, and offers particular advantages for intracellular biology through a range of desirable photopharmaceutical and drug-like properties not accessible to the current classes of photoswitches. We expect that these reagents will find powerful applications enabling robust, high precision, optically controlled cell biological experimentation in cytoskeleton research and beyond. Introduction:Molecular photoswitches have been used to install optical control over a broad range of phenomena, with applications from material sciences 1,2 through to reversible photocontrol of ligand binding affinities 3 and manipulation of diverse cellular processes in chemical biology 4,5 . For studies of temporally-regulated and spatially anisotropic biological systems, particularly those that simultaneously support several cellular functions, photoswitchable inhibitors conceptually enable a range of powerful studies not accessible with other tool systems. [6][7][8] A prime example of such spatiotemporally regulated, multifunctional systems is the microtubule (MT) cytoskeleton. This complex cellular network plays central roles in nearly all directed mechanical processes, such as intracellular transport and cell motility; its crucial function in cell proliferation has also made it a central anticancer drug target. 9-11 Yet, whereas cytoskeleton research typically aims to study a subset of MT-dependent processes that are spatially and/or temporally localised, nearly all MT inhibitors reported as tool compounds for biological research are drugs that are active wherever they are distributed, including at sites and at times where drug activity is not desired. 12 This restricts the scope of applications and utility of these inhibitors for selective research into the various, highly dynamic, anisotropic processes dependent on MTs. 13 The structure of the colchicine site MT inhibitor combretastatin A-4 (CA4; Fig 1a) 14 has recently inspired photoswitchable solutions to the problem of achieving spatiotemporal control over MT inhibition. CA4 is a stilbene whose Z-isomer (cis) binds tubulin, acts as a low nanomolar cytotoxin in cellulo, and reached Phase III trials as an ...

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Section: Discussion and Outlookmentioning

confidence: 99%

Photoswitchable microtubule inhibitors enabling robust, GFP-orthogonal optical control over the tubulin cytoskeleton

Gao

Kraus

Wranik

et al. 2019

Preprint

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“…11,12,13,14,15 Several cancer treatments relying on the use of light have emerged during the last decades. 8 One of those, known as photodynamic therapy (PDT), is already well established and clinically applied. The procedure involves administration of a photosensitizer that forms reactive oxygen species (ROS) upon irradiation with light at a specific wavelength, leading to direct tumor cell death, damage to the microvasculature and induction of an inflammatory reaction.…”

Section: Introductionmentioning

confidence: 99%

Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy

et al. 2018

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The efficacy and tolerability of systemically administered anticancer agents are limited by their off-target effects. Precise spatiotemporal control over their cytotoxic activity would allow improving chemotherapy treatments, and light-regulated drugs are well suited to this purpose. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase (DHFR), as a photochromic analog of methotrexate, a widely prescribed chemotherapeutic drug to treat cancer and psoriasis. Quantification of the light-regulated DHFR enzymatic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent antifolate in its photoactivated cis configuration, and that it is nearly inactive in its darkrelaxed trans form. Thus, phototrexate constitutes a proof-of-concept to design light-regulated cytotoxic small molecules, and a step forward to develop targeted anticancer photochemotherapies with localized efficacy and reduced adverse effects.

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“…Photoresponsive molecules and materials are transforming multiple areas of research, from drug delivery, [1][2][3][4][5][6] to materials engineering, [7][8][9][10][11][12][13][14][15] and biology. [16][17][18][19][20][21][22][23][24][25][26] Many natural biological processes are not photoresponsive, making light a versatile trigger for controlling complex biological systems.…”

Section: Introductionmentioning

confidence: 99%

Designing photolabile ruthenium polypyridyl crosslinkers for hydrogel formation and multiplexed, visible-light degradation

et al. 2019

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Beyond Photodynamic Therapy: Light-Activated Cancer Chemotherapy

Abstract: 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.

Cited by 43 publications

References 118 publications

Photoswitchable microtubule inhibitors enabling robust, GFP-orthogonal optical control over the tubulin cytoskeleton

Photoswitchable microtubule inhibitors enabling robust, GFP-orthogonal optical control over the tubulin cytoskeleton

Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy

Designing photolabile ruthenium polypyridyl crosslinkers for hydrogel formation and multiplexed, visible-light degradation

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