Supramolecular Pharmacy
12. Photopharmacology
Ondřej Jurček
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Photopharmacology
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• Emerging approach in medicine using activation and deactivation of photoswitchable
molecules with light for targeted drug delivery
• Photopharmacology refers to bioactive molecular systems that undergo reversible
photochemical transformation that alter their pharmacokinetics and pharmacodynamics
• Allows to achieve control of when and where drugs are active in a reversible manner
and to prevent side effects
• Switching drugs "on" and "off" is achieved by introducing photoswitches such as
azobenzene, spiropyran, diarylethene, anthracene, or stilbene into a drug
• Photomediated reactive oxygen generation, small molecule activation, micelle,
nanoparticle disruption, and material degradation (e.g., gels) are the most common
Spectral range
3DeForest et al. Adv. Drug Del. Rev. 2021, 171, 94–107.
• Light is uniquely powerful tool for controlling molecular events in biology
• No other external input (e.g., heat, ultrasound, magnetic field) can be so tightly
focused or so highly regulated as a clinical laser
Light sources
4DeForest et al. Adv. Drug Del. Rev. 2021, 171, 94–107.
• Mercury Arc lamps (250-600 nm) broad-spectrum of light which can be refined to
desired wavelengths with bandpass filters (typically 254, 365, 405, 436, 546, and 579
nm) – relatively cheap and high power
• LEDs (250-700 nm) wide variety of wavelengths and intensities – the full-width half
maximum value might extend ± 10-20 nm beyond the reported wavelength
• Lasers (250-900 nm) have highly focused beam and narrow bandwidth (centered to
±1 nm), laser pointers cannot readily change intensity
Challenges of photopharmacology
5DeForest et al. Adv. Drug Del. Rev. 2021, 171, 94–107.
• X-rays or radio waves may pass through the body with relative ease, visible, UV, and
infrared (IR) light experience variable and high levels of absorption/scattering by living
tissue
• Poor penetration depth of low-energy electromagnetic radiation
• The greatest depth of penetration is achieved by low-energy IR light, with 750 nm light
penetrating ~5 mm below the skin’s surface
• High amounts of light scattering as well as high absorption
of hemoglobin and melanin
• Selectively using different wavelengths of light allows
researchers to potentially trigger multiple events
separately and/or sequentially
• Facile control over the intensity and wavelength of the
light could allow dosing of the active drug
Properties of photoactive molecules (photoswitches)
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• Molar absorptivity = refers to capacity of compound to absorb light of a specific
wavelength
• Excitation wavelengths
• Quantum yield = the ratio of the number of photons emitted to the number of
photons absorbed (describes how efficiently a fluorophore converts the excitation
light into fluorescence)
• Photostationary state = equilibrium chemical composition under a specific kind of
electromagnetic irradiation
• Stability (thermo-, solvato-, acido-, mechano-)
Challenges of photopharmacology
7DeForest et al. Adv. Drug Del. Rev. 2021, 171, 94–107.
• The most effectively penetrating wavelengths are in the visible-IR regions, generally
accepted to be between 650–900 nm (near-infrared phototherapeutic window) (λ<650
nm – absorption by hemoglobin, λ>900 nm water)
• The most organic and inorganic chromophores have molar absorptivities (104–105 M−1
cm−1 at 500 nm) that exceed those of biological chromophores such as human
rhodopsin in the eye (~104 M−1 cm−1 at 500 nm), the comparatively high concentration
of the latter can necessitate fairly large light dosages to phototrigger engineered
material changes
• Since quantum yields are often lower than desired for many traditional photochemical
reactions, the flux of light required may near the range of thermal tissue damage,
especially in the use of high-energy light
Photopharmacology
8Feringa et al. Angew. Chem. Int. Ed. 2016, 55, 10978–10999.
1. Photodynamic therapy
2. Optogenetics
3. Photopharmacology
1. Photodynamic therapy (PDT)
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• Uses dyes that relax from their light-induced excited
state by converting available triplet oxygen (3O2) into
highly toxic singlet oxygen (1O2) (reactive oxygen
species – ROS) – tissue ablation
• Singlet oxygen is short-lived, its toxicity can be
contained in a small volume, thereby leading to spatial
selectivity of the therapy
• Several PDT drugs are in clinical trials and some
underwent FDA approval
• This goes hand in hand with innovations in light
application devices in the clinic, enabling light to be
delivered to any region in the body with varying levels of
invasiveness
DeForest et al. Adv. Drug Del. Rev. 2021, 171, 94–107.
2. Optogenetics
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• Biological technique to control the activity of neurons and
other cell types with light
• Achieved by expression of light-sensitive ion channels,
pumps or enzymes in target cells
• Using the optogenetic technology scientist could map
functional connectivity of the brain as well as to understand
neural contribution to decision making, learning, fear
memory, addiction, locomotion, etc.
• It led to first medical application where vision was restored
to a blind patient
2.
3. Photopharmacology
11Klán et al. Chem. Rev. 2020, 120, 13135-13272.
3.
3. Photopharmacology
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Circulating drug carriers: small-molecule prodrugs, micelles, and liposomes
• Small molecule prodrugs
• Photocaged small molecules for in vitro discovery
• Caged prodrugs for targeted delivery
• Transition-metal complexes as photocages and dual-action prodrugs
• Small-molecule light-activated theranostic approaches
• Photoregulating gene expression
• Nanoparticle delivery vehicles: micelles, liposomes, and nanoparticles
• Disrupting nanostructures with organic photosensitizers
• Disrupting nanostructures with inorganic photosensitizers
Drug-loaded depots: soft biomaterials as drug delivery platforms
• Phototriggered drug release from hydrogels
• Photodegradable hydrogels for drug delivery
• Photocleavable linkers to release tethered cargo
• Directing cell growth in vitro with light
• Light-responsive living hydrogels
DeForest et al. Adv. Drug Del. Rev. 2021, 171, 94–107.
Photopharmacology selected mechanisms
13DeForest et al. Adv. Drug Del. Rev. 2021, 171, 94–107.
Photocleavable groups
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Coumarin
Ortho-nitrobenzyl
a) DeForest et al. Adv. Drug Del. Rev. 2021, 171, 94–107, b) Klán et al. Chem. Rev. 2020, 120, 13135-13272.
Molecular photoswitches
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360 nm
470 nm
550 nm
350 nm
Azobenzen switches
StilbenesAnthracenes
DithienylethenesSpiropyrans
Molecular photoswitches
16Feringa et al. Nanoscale Adv. 2021, 3, 24–40.
• Azobenzene photoswitches
• the most common used photoswitches (simple
synthesis, photostability, reliability)
• the planar E isomer goes into bulkier Z isomer
• azobenzenes show high quantum yields for both Z/E
and E/Z photoisomerizations, and high photostationary
state ratios
• nearly all the photophysical and photochemical
properties of azobenzenes, in particular quantum yield,
thermal stability of Z-isomer, photostationary state
ratios, excitation wavelengths, can be tuned easily by
introducing appropriate substituents at the azobenzene
core
• well-described in literature
360 nm
470 nm
Molecular photoswitches
17Feringa et al. Nanoscale Adv. 2021, 3, 24–40.
• Azobenzene photoswitches
Molecular photoswitches
18Feringa et al. Nanoscale Adv. 2021, 3, 24–40.
• Spiropyrans
Colorless spiropyrans undergo UV light induced
isomerization to the zwitterionic, colored merocyanine
form
Spiropyran form can be regenerated by irradiation
at longer wavelengths or by heating and the transoid
merocyanine form can be stabilized by protonation
Compounds are photo- and often thermo-, acido-,
solvato-, and mechano-chromic
• Dithienylethens (DTEs)
ring-opened isomer (colorless) under UV-light leads to
colored, ring-closed, isomer
some derivatives show half-lives at RT reaching 400 000
years and a remarkably high photostability even over 10 000
isomerization cycles
550 nm
350 nm
Molecular photoswitches
19Feringa et al. Nanoscale Adv. 2021, 3, 24–40.
• Anthracenes
• Undergo a formal [4 + 4] photocycloaddition dimerization
upon exposure to UV light, while the monomerization of
the photodimer can be achieved thermally
• Requires proper stacking (intermolecular
distance between reactive carbons <4.5 Å)
• Stilbenes
• Substitution patterns around the olefinic bond in these
compounds precludes the competitive photodegradation
pathways characteristic for stilbene derivatives and
controls the rate of the rotary motion, thus providing a
possibility to fine-tune the rate of rotation by synthetic
modification
Nanoparticles in pharmacy
20Mitchell et al. Nature Reviews: Drug Discovery 2021, 20, 101–124.
Photoswitchable lipids and amphiphiles
21Trauner et al. Acc. Chem. Res. 2015, 48, 1947−1960
• Effect on the biophysical properties of a biological membrane, such as fluidity,
curvature, raft formation, impedance, and capacitance
• Photolipids can operate at the interface of the lipid bilayer and a membrane protein
(surrounding membrane is known to have a large influence on the dynamics of
transmembrane proteins)
• Can function as more conventional ligands that bind deeply within a protein or at the
protein−cytosol interface (transmembrane, membrane-associated, and cytosolic
proteins, such as TRP channels, protein kinase C, or nuclear hormone receptors)
Photoswitchable polymers, micelles, and vesicles
22Klán et al. Chem. Rev. 2020, 120, 13135-13272.
Polymersome – photosolvolysis Polymer NPs releasing anticancer Ru(II)
• Cleavage of perylene-3-yl protecting group
Photoswitchable polymers, micelles, and vesicles
23Klán et al. Chem. Rev. 2020, 120, 13135-13272.
Mesoporous silica nanoparticles (MSNs)
• 420 or 800 nm light was used to release chlorambucil from 7-amino-coumarin derivative grafted onto surface of MSN
24
• AuNPs capable of treating acne (Sebashells)
are being developed by Sebacia Inc
• ~150 nm silica-gold nanoshells, coated
with PEG
• treat acne by disrupting overactive
sebaceous glands in the skin
Gold nanoparticles as drugs
Anselmo et al. Am. Assoc. Pharm. Sci. 2015, 17(5), 1041.
• AuroLase® is being developed by
Nanospectra, are silica-gold nanoshells
coated with (poly)ethylene glycol (PEG)
designed to thermally ablate solid tumors
following stimulation with a near-infrared
energy source
Photocontrol over host-guest chemistry of cyclodextrins
25Klán et al. Chem. Rev. 2020, 120, 13135-13272.
Cyclodextrin host-guest chemistry
Osa et al. J. Am. Chem. Soc. 1979, 101, 2779-2780.
Wang and Wu constructed supramolecular valves from tetra-o-methoxy-substituted
azobenzene and β-CD to control release of doxorubicin from nanopores of MSC
using red light (Langmuir 2016, 32 (2), 632-636).
Metal-organic frameworks – MOFs (MOF-5)
26O. Yaghi, ch. 9: Macrocyclic and Supramolecular Chemistry: How Izatt–Christensen Award Winners Shaped the Field
Photoswitchable MOFs
27Feringa et al. Nanoscale Adv. 2021, 3, 24–40.
Azobenzen switches
Spiropyran switches
Dithienylethene switches
pendant backboneguest
Photoswitchable MOFs
28a) Feringa et al. Nanoscale Adv. 2021, 3, 24–40. b) Stoddart and Yaghi et al. Chem. Sci. 2013, 4, 2858–2864
• The geometrical change E/Z can be used to release cargo from microporous
materials
• The first ever, isoreticular MOF-74, having a one-dimensional hexagonal
microchannels functionalized with evenly separated azobenzene pendants pointing
towards the center of the pore
• Challenges are mode of linker incorporation, local heating, bulk isomerization
Photoswitches
29Feringa et al. Nanoscale Adv. 2021, 3, 24–40.
Anthracene switches Stilbene switches and molecular motors
Photodruggability
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• Druggability = possibility for a disease-related receptor/enzyme to be targeted by a
drug (usually a small molecule) that can bind to it with high affinity and change its
activity/properties
• Photodruggability = the above and:
• target should be responsive to the light-induced changes
• target must be related to a localized disease, such as a solid tumor or local
inflammation
• target should be accessible by light
Feringa et al. Angew. Chem. Int. Ed. 2016, 55, 10978–10999.
Photodruggability
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• This can lead to division by accessibility of light to organs:
• Class 1 – easily accessible, skin, eyes
• Class 2 – accessible by endoscopy, GI tract, mouth and throat, sinuses, respiratory
system, cervix, biliary tract, urine bladder
• Class 3 – accessible through the skin without incision (lying just below the skin):
thyroid, testicles, lymph nodes, muscles, and bones close to skin
• Class 4 – accessible through minor incision: peritoneum, including pancreas, liver,
ovaries, stomach, intestines, kidneys, and spleen; also prostate, most blood
vessels, glands, lymph nodes, muscles, and bones
• Class 5 – accessible through major incision or intraoperatively: brain and bone
marrow
Feringa et al. Angew. Chem. Int. Ed. 2016, 55, 10978–10999.
Photodruggability – Class 1
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• Light-gating process: formation of the (zwitterionic) merocyanine isomer leads to
localized build-up of charges and, thus, opening of the channel
Feringa et al. Angew. Chem. Int. Ed. 2016, 55, 10978–10999.
• KV channel photoswitches that enable control
of neuron excitation (blind mice vision)
Photodruggability – Class 2
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• Treatment of tuberculosis, Mycobacterium tuberculosis, phosphoribosyl isomerase A
(mtPriA)
Feringa et al. Angew. Chem. Int. Ed. 2016, 55, 10978–10999.
Photodruggability – Class 3
420 nm (10 fold difference)
• Microtubule dynamics are essential in
intracellular transport, motility, and cell
proliferation
• Combretastatin A4 phosphate has shown
potency against anaplastic thyroid
carcinoma (inhibits polymerization of
tubulins)
250 fold difference
Photodruggability – Class 4
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• Diabetes research – sulfonylurea 9 allows
control over insulin release and pancreatic
beta cell function with UV light
Feringa et al. Angew. Chem. Int. Ed. 2016, 55, 10978–10999.
Photodruggability – Class 5
Stimulates production of insulin
400 nm
• Photocontrol of β-amyloid aggregation
associated with Alzheimer‘s disease
Acetylcholin esterase inhibitor
(hepatotoxic)
In the next class…
Molecular machines
Thank you for your attention!