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The use of photolabile protecting groups has been growing in emphasis for decades, in particular because of their numerous applications ranging from organic synthesis to neurosciences. More recently, two-photon sensitive photolabile protecting groups were developed, bringing the advantages (e.g. finer spatial resolution with a deeper tissue penetration) of this nonlinear excitation technique to a photostimulation method. However, the widespread photolabile protecting groups developed for classical one-photon excitation exhibited low two-photon sensitivity. Therefore, the rules of molecular engineering pointed out for the optimization of nonlinear properties of molecular systems for material sciences were applied to this specific field. Consequently, efficient two-photon photolabile protecting groups have been developed. We describe here the recent developments in molecular engineering of two-photon sensitive photolabile protecting groups as well as their application in neurobiology, physiology and biomaterials.
© 2016 Optical Society of America
1. Introduction
Biological processes are very complex phenomena ruled by series of precise spatio-temporal events. To reveal intimate mechanism of these phenomena, cellular activity needs to be precisely controlled and tuned with the help of orthogonal tools. During the last decade, light has become one of the major orthogonal triggers; it was initially developed in neuroscience and is today used in many fields of biology, such as genetics or embryology [1–4]. Photoactivation has also been recently applied for the development of light-responsive drug release using nanocarriers since clinical applications of nanomedicines require precise spatial and temporal control of the release of the therapeutic agent (e.g. drugs, proteins, gene/siRNA) [5].
Photolabile protecting groups, also known as “cages”, are minimally invasive and very powerful tools to control physiological processes at cellular level by controlled light triggered releases of biologically relevant molecules. The principle of caged compounds is to start from a biologically inert assembly composed of a biological effector for which the biological activity was hidden by a linked photolabile protecting group. Light irradiation induces a photochemical reaction, leading to the release of the biologically active compound, now available for triggering a specific biological function, Fig. 1.
Ortho-nitrobenzyl photolabile groups are among the most popular caging groups, but many different chromophores, such as coumarin, indoline, ortho-nitrophenethyl or quinoline derivatives have been more recently engineered to be efficient as photolabile protecting group for more sophisticated applications, Fig. 2 [6]. In particular, much work has been performed in order to overcome the most severe limitations for in vivo applications of these ortho-nitrobenzyl photolabile groups, which require UV light for excitation.
The diversification of photolabile protecting groups allows now for a fine tuning of the excitation wavelength, leading to a higher versatility to control a given biological response in various fields, as diverse as in vivo neurosciences or plant physiology. In particular, now it’s possible to have in one system several photoremovable groups which could be addressed individually with light of different wavelengths (multiplexing) [1].
A higher and outstanding 3D spatial resolution can be reached using nonlinear optical phenomena, known as two-photon absorption [7,8]. In this case, due to the nonlinear response of the molecule upon irradiation (with a quadratic dependence of the probability of absorption P versus the light intensity I), the excitation can occur only where the light intensity is maximum, typically at the focal point of the optical system used for irradiation (Eq. (1), Fig. 3). The two-photon absorption cross section (σ2, also called δa) is generally expressed in GM (1 GM = 10−50 cm4 s photon−1) in honor of Maria Goeppert-Mayer which described theoretically the phenomena in 1931 [9].
Fig. 3 Fluorescent compound upon one (up) and two-photon (down) excitation showing fluorescence upon the whole optical pathway in the case of one-photon excitation which is restricted to the focal point in the case of two-photon excitation.
The simultaneous absorption of two photons of half the energy required for the transition towards the excited state implies the use of a less energetic light vs. the classical absorption of one photon, typically in the IR instead of the UV or blue region of the electromagnetic spectrum. Due to the low energy of IR light, two-photon excitation shows less photo-toxicity than the corresponding one-photon excitation [7]. In addition, the use of IR wavelengths provides a deep penetration in biological samples because of the low absorption and scattering of living material in this region of the electromagnetic spectrum (700-1000 nm, known as the relative transparency window of live tissue) and allows imaging or triggering deeper than with UV light [7]. The efficiency of a caging group towards two-photon excitation is defined in a similar way to the efficiency of a one-photon cage (ε.Φu) by the two-photon uncaging action cross-section δu expressed by the product of the two-photon absorption cross-section δa times the quantum yield of the photochemical reaction Φu (Eq. (2).
During the last decade many caging groups were developed and described in extensive reviews [1,10,11]. Here, we would like to provide an update on the recently described two-photon sensitive platforms which appeared in the last 4 years for various applications, ranging from neurophysiological studies to material sciences and light-triggered drug delivery systems.
2. Cage compound history, design and engineering
Initially photolabile protecting groups were used mainly in organic synthesis [12]. Hoffman and associates, Schlaeger and associates have given a new prospect to this particular class of protecting groups by developing the first caged compounds for respectively in vitro light controlled release of Adenosine Tri-Phosphate (ATP) and cyclic 3′,5′-Adenosine Mono-Phosphate (cAMP) [13,14]. Their works were followed by an extensive development of new caging platforms for various biologically active molecules [6]. In 2001, a new step was crossed by Kasai and associates who used two-photon excitation with a pulsed laser at 720 nm on 1 (4-Metoxy-7-NitroIndolinyl or MNI caged glutamate, Fig. 4) and mimicked a neurotransmitter’s release at single synapse resolution with a δu = 0.06 GM for the first time [15].
This marks the beginning of the design of a second generation of cages with improved two-photon absorption properties (Fig. 4). Thus, Dore’s team developed in 2006 the quinoline platform 2 (8-Bromo-7-HydroxyQuinoline-2-ylmethyl or BHQ, Fig. 4) with two-photon uncaging action cross-section from 0.40 GM to 0.9 GM (depending on the nature of the released compound) [16,17]. Later on, in 2007, Jullien et al. explored trans-cinnamate derivatives 3 and 4 Fig. 4 with two-photon uncaging action cross-sections of 1.6 and 4.7 GM respectively for ethanol uncaging [18,19]. Our team has worked on the engineering of nitro-aromatic compounds, first with 5 (3-(4,5-DiMethoxy-2-NitroPhenyl)-2-Butyl or DMNPB, Fig. 4) and biphenyl based groups 6a-b with δu = 0.17 GM and δu = 3.2 GM [20] at 720 nm respectively. In a second step, a conjugated dimeric system, 7 (2,7-Bis-{4-Nitro-8-[3-(2-propyl)-Styryl]}-9,9-bis-[1-(3,6-dioxaheptyl)]-Fluorene BNSF, Fig. 4) was explored with δu = 5.0 GM [21]. This nitro-phenethyl series was further improved in 2012 with 6c-d (4’-(bis(Carboxymeth-yl)Amino)-4-Nitro-[1,1’-Biphenyl]-3-yl)Propan-1-ol or CANBP) and 2-(4’-(bis((2-methoxyethoxy)Ethyl)Amino)-4-Nitro-[1,1’-Biphenyl]-3-yl)Propan-1-ol or EANBP, Fig. 4) which reached 11 GM at 800 nm due to an extensive aromatic system and an efficient electron donating group [22].
Starting from these major contributions we will focus then on the recent developments from the last four years. The structures of the recently developed two-photon sensitive photoremovable groups are summarized in Fig. 5. The extension of the aromatic system is one of the rational ways to upgrade two-photon properties of a compound. Zhu et al. have synthetized two new derivatives 8 and 9 based on coumarin [23] and nitrobenzyl [24] moieties with an extended styryl group, Fig. 5. They obtained promising δu = 0.25 GM and 0.014 GM for the release of adenosine and prodrugs respectively. Engineering electron withdrawing and/or electron donating group is often decisive to reach a red shifted absorption. Jullien et al. [25] developed three new coumarins 10a-c (7-diethylamino-4-substituted methylcoumarin or NdiEt-R, Fig. 5) derivatives with significant action cross-sections for uncaging upon a blue-cyan light (beyond 450 nm) and a low light absorption in classical range 350-400 nm region. In the same way, a very recent study presented a new series of meso-substitued BODIPY dyes 11a-b, Fig. 5 with good photochemical properties and low cytotoxicity for which the irradiation wavelength was beyond 500 nm [26]. This trend to shift the irradiation wavelength to NIR emerged with the multichromic optical techniques that will be discussed further in this review. A successful strategy used by Goeldner and associates [21,22] for nitro aromatic series, based on multipolar derivatives, has been also investigated in quinoline series by two additional teams. First, in 2013, Blanchard-Desce et al. [27] prepared dipolar and octupolar derivatives based on triphenylamino group 12 and 13 Fig. 5, with an interesting enhancement from the dipole to the octupole from 0.002 GM to 0.04 GM. A quadrupolar compound based on a fluorenyl core was also explored but revealed a low two-photon absorption response in the NIR region. New quadrupolar species 14 Fig. 5, appeared one year later [28] where two quinolines moieties 15 were directly linked in two different positions and reached δu = 0.07 GM and 0.40 GM (for (8,8′-Bis(dimethylamino)-[6,6′-biquinoline]-2,2′-diyl)bis-(methylene)diacetate 6-(8-DMAQ) and (8,8′-Bis(dimethylamino)-[5,5′-biquinoline]-2,2′-diyl)bis-(methylene)-diacetate) 5-(8-DMAQ), Fig. 5). Recently, the group of Dalko reached GM by identifying the C5-substituted isomer as a privileged isomer to increase the two-photon sensitivity of 8-dimethylaminoquinoline derivatives [29].
Another approach to increase the NIR two-photon sensitivity of one-photon sensitive protecting group was recently described and relays on the use of two-photon sensitive moieties as an antenna to transfer the light energy to the photoremovable group. A classical nitro aromatic compound, such as 16 (3,4-dimethoxy-6-nitrobenzyl acetate (NVOAc, Fig. 7), showed an enhancement of its sensitivity to 800 nm two-photon excitation by a factor of 5 due to its covalent bond and proximity with a fluorenyl dyad [30]. A detailed study on the photoinduced electron transfer (PeT) phenomena based on two-photon sensitive fluorenyl antenna cores has recently been published [31]. Up to now, to the best of our knowledge, this technique didn’t allow to reach high photolysis quantum yields yet, however the compound 17 (bis-ethynyl fluorene BEF-pyr-GABA), described in the next section, exhibited a very high two-photon absorption cross-section and an acceptable photolysis quantum yield leading to a excellent two-photon uncaging efficiency [32].
Overall, despite the number of photoremovable group already reported in literature, it’s still very difficult to predict the effect of any modification on a given photoremovable group (generally done in order to improve the TPA cross-section) on the efficiency of the photolytical reaction. On the other hand, the use of classical theoretical methods as well as the development of new approaches to TPA cross section calculations can be used to estimate the effect of small modifications or conformation changes on TPA efficiency [33] and will be of great interest in molecular engineering of new two-photon sensitive caging platforms .
3. Photoprotecting group for investigations in neurobiology and physiology
Glutamate and Gamma-Amino Butyric Acid (GABA) are the two major neurotransmitters in mammalian brains. They are always balanced together during most neuronal processes. To reach a complete understanding of a given neuronal network activity, high spatio-temporal control of the local concentration of these two compounds is required. Therefore, photolabile protecting group and in particular the use of caged glutamate and/or GABA have had a favorable relationship with neurophysiology since several years (Fig. 6a and b) [34]. During the last decade many caged-GABA and Glutamate were developed and have been recently reviewed in literature [15]. In this section, we will first describe the recently reported compounds applied in neurophysiology (Fig. 7). Concerning caged glutamate, Abe and associates developed a π-extended coumarin chromophore [35] combined with a naphthalenyl core 18a-b Fig. 7 providing a promising uncaging quantum yield. The same group in collaboration with Kobayashi’s team used a similar strategy on the nitrobenzyl series leading to the synthesis of a π-extended 1,2-dihydronaphtalene containing chromophore 19a-b Fig. 7. They were able to apply this new photoremovable group to the two-photon release of glutamate [36]. Almutairi and associates [37] have developed a self-immolative dendritic scaffold based on the well-known bromohydroxycoumarin (Bhc). The idea was to increase the number of glutamates that can be released by one molecular species. This strategy led to a release of 1.63 and 2.80-fold higher glutamate concentration for G1 and G2 respectively compared to the monomeric N-(6-bromo-7-hydroxycoumarin-4-ylmethoxycarbonyl)-l-glutamate (Bhc-glu), Fig. 6(c).
Fig. 6 (a) Uncaging of CANBP-GABA activates GABA receptors in brain slices. L2/3 pyramidal cell were filled with an Alexa 488 fluorophore in order to visualize neurons. Two-photon photoactivation is located within the white box. The puffer pipette containing CANBP-GABA is visible as a shadow (arrow). (b) Outward current evoked obtained by patch clamp technique by λ = 800 nm uncaging flash (blue line) in the presence of CANBP-GABA (black), which is blocked by picrotoxin (red). Scale bar = 2 pA/200 ms (Reproduced from [38]. with permission from John Wiley and Sons). (c) Self-immolative principle for Generation 0, 1 and 2 glutamate release (Reproduced from [37]. with permission from The Royal Society of Chemistry). (d) molecular formula of the second generation (G2) of [37] dendrimer for glutamate uncaging.
Concerning GABA uncaging, p-methoxynitrobiphenyl based molecules (6a-b Fig. 4) used for glutamate two-photon induced photorelease were improved with the replacement of the alkoxy moiety by an amino group which is a better electron donating substituent, leading to higher two-photon sensitivity (6c-d Fig. 4). They were successfully used in neuron activation using two-photon excitation at 800 nm, Fig. 6(a)-6(b).
A fluorenyl dye linked to a pyridinium salt 17 [32] was developed by Anderson’s group to release two GABA molecules upon PeT. One of the highest two-photon uncaging action cross-sections was obtained GM) due to a tremendous TPA of the already optimized two-photon sensitive PeT antenna based on a fluorenyl central core. An enhancement of the uncaging quantum yield in this series will for sure give compounds with unprecedented uncaging action cross-sections.
As stated earlier throughout the last decade, a large number of photosensitive protecting group has been reported in order to develop efficient one photon and two-photon red shifted photoremovable groups. In 2013, Ellis-Davies and collaborators developed a 7-diethylamino coumarin derivative 20 effective to release GABA at 900 nm and combined it with the previously developed 4-Carboxymethoxy-5,7-Dinitroindolinyl glutamate 21 (or CDNI-Glu), efficient at 720 nm [39]. They revealed that it was possible to choose which neurotransmitter can be released by tuning the irradiation wavelength. A recent review emphasises the possibility to independently control different activities using specific excitations at given wavelengths (multiplexing); a domain called “multicrohomic uncaging” [40].
Since then, many biomolecules involved in the control of a given physiological process can be covalently linked to a photoremovable group. In this second section we will focus on the recent applications of two-photon sensitive uncaging to control physiological processes. The EANBP photoremovable group (see 6c), first designed for neuroscience, was adapted by Specht et al. [41] for the study of inorganic phosphate (Pi) signal transduction cascade in living plant cells. Indeed, system 22 acts as a caged inorganic phosphate able to release Pi upon two-photon excitation. Recently, Wombacher’s group made an improvement to the ortho-nitrophenethyl scaffold by using a π-extended diphenylacetylene core such leading to compound 23 [42]. The two-photon uncaging efficiency of the new photoremovable group (pcGA3-3) showed a 1.8-fold higher two-photon uncaging efficacy compared to the biphenyl chromophore 6c. Gibberellic acid, a phytohormone involved in the control of protein translocation (dimerization) was used to control protein translocation in-vivo with high spatiotemporal precision by using two-photon photoactivation as an external trigger.
4. Biomaterial sciences
4.1 Micelles & polymers for drug releases
Various other applications can be imagined for photoremovable groups, and we will now focus on their recent applications in biomaterial sciences [43]. BlockCoPolymer (BCP) micelles became powerful tools for carrying dyes and drugs to specific target Fig. 8(a). The historical way to disrupt micelles for release compound was to use redox-active surfactant, or pH-dependent moiety. In 1999, light was used for the first time as orthogonal trigger to control dynamic surface tension with a photoswitchable azobenzene derivative 24 Fig. 9 [44]. Rapidly, photolabile protecting groups became very attractive tools for drug delivery systems. A very recent review provided an extended history of biomaterials using light as trigger [45].
Fig. 8 (a) Light sensitive Block CoPolymer with co-encapsulated hydrophobic drug and upconverting nanoparticle (Reprinted with permission from [47]. Copyright (2011) American Chemical Society.” (b) Mesoporous silica nanoparticle coated by light sensitive BCP and hydrophobic drug loading (Reproduced from [50]. with permission from The Royal Society of Chemistry).
Fig. 9 Caging systems used in micelles, nanoparticles, polymers for drug release and micropatterning.
In 2009, a two-photon sensitive BCP nanocarrier 25 Fig. 9 [46] was designed, by Zhao and collaborators, with a coumarin chromophore. The Nile red dye was encapsulated as a hydrophobic compound and released after one- and two-photon excitation, revealing the high potential of such carrier. Two years later, the same group used a nitrobenzyl platform 26 Fig. 9 as light sensitive moiety and co-encapsulated upconverting nanoparticules (UCNP) and nile red [47] Fig. 8(a). This system showed relatively fast control of the drug release (4 h for complete disrupting) upon one-photon excitation at 980 nm. The UCNP absorbed NIR light and reemitted UV light employed by nitrobenzyl moieties to reach the excited state. Following the same principle, another BCP also based on a nitrobenzyl photremovable group 27 Fig. 9 [48] gave faster delivery (1 h).
Light-controlled drug release also take advantage of the high biocompatibility of mesoporous silica nanoparticle (MSN) by grafting light sensitive group to this material. For example, Zhu and associates were able to attach a coumarin derivative 28 Fig. 9 on a MSN in order to release the anticancer drug chlorambucil [49] by light. This nanovehicle was efficient in one- and two-photon excitation and showed good biocompatibility. In 2013, an association of the two previous presented techniques, BCP and MSN Fig. 8(b), allowed to design an NIR-triggered nanocomposite for anticancer drug delivery, again using a coumarin moiety [50]. BCPs formed a hydrophobic core that allowed hydrophobic drug (doxorubicin) to be carried. In addition, conjugation with folic acid yielded to target tumor cells with over-expressing folic acid receptors.
Interestingly, UCNP have also been recently co-encapsulated with drugs into MSN coated by a light sensitive amphiphilic polymer based on spiropyran photoswitch [51]. In this case, drugs were released upon one-photon excitation at 980 nm and showed promising in vitro and in vivo results for future applications in the biomedical field.
Almutairi’s laboratory designed another style of drug delivery system based on light sensitive polymers. In 2013, this group developed a platform based on copolymerization of adipoyl chloride and 1,6-hexanediol, and using a fluorenyl backbone linked to a nitrophenethyl derivative 29 Fig. 9 to provide a high two-photon photorelease efficiency [52]. Nile red was successfully released upon NIR two-photon excitation. Freshly, they designed a new polymeric system using a ANBP derivative in order to formulate particles encapsulating various payloads [53]. Interestingly, we can notice that a tertiary amine function was added in close proximity to the ANBP chromophore in order to assist the deprotonation of the aci-nitro intermediate, a crucial step for an efficient photocleavage in a hydrophobic microenvironment. An implant depot was tested in vivo in order to release hydrophobic drugs upon one-photon UV light. Recently, TP photocleavage was successfully used to modulate the shape of polymeric DNA nanostructures too 30 Fig. 9 with low cytotoxicity and high biocompatibility [54].
4.2 Micropatterning
Photoremovable protecting groups were also useful in organic surface functionalization [55], thin layer polymer films and hydrogels provided spatio-temporal control during and after crosslinking, polymerization [56] or depolymerization [57] processes. In particular, 3D light mediated surface modification was recently reported by del Campo’s laboratory using photocleavable ruthenium(II) « caged » aminosilane [58]. A recent review from the latter group [59] describes these new biomaterials and their applications to light mediated micropatterning; we will only review here the most recent advances in this field.
In 2014, our group in collaboration with A. del Campo group [60, 61] was able to apply the two-photon sensitive 6a and 6c photoremovable groups on photocleavable monomers in order to sequentially photoactivate the crosslinking and the depolymerization steps in a dual polyurethane mixture. Using single photon exposure at 520 nm and 365 nm or two-photon exposure at 820 and 780 nm, 2D and 3D control of the reaction steps was achieved. Hamburger and associates have also developed fluorene based polymers linked to a nitrophenethyl analog of 23 able to turn-on a fluorescent emission by turning-off the polymer solubility upon one- or two-photon excitation [62]. This compound has been reported to be attractive for post-polymerisation modification linked to macroscopic properties. Some micropatterning tools have been developed by Zhu’s laboratory such as new series of photosensitive polymethacrylate copolymers with π-conjugated o-nitrobenzyl ester as photolabile chains [63]. High-resolution microfabrication was performed due to NIR two-photon sensitivity of the compound. More recently, an upgrade has been done to this research field with a macrocyclic coumarin-caged thiol 31 Fig. 9, being copolymerized with polyethyleneglycol metacrylate and a macromolecule bearing multi-maleimide side groups [64]. After one or two-photon irradiation, a thiol-Michael addition provided a highly cytocompatible gel with a precise control in size, shape and stiffness. A great potential can be imagined for such type of material in different scientific fields like cell biology, 3D bioprinting and regenerative medicine.
Finally, another step was crossed by Tampé and associates which provided the first protein network that can be assembled by two-photon activation and followed (using a green fluorescent protein) in real time without any intermediate [65]. They used the interaction between glutathione (caged by a nitrodibenzofuran 32 photoremovable group NDBF) and glutathione S-transferase (GST) to control the formation of GST complexes; 3D protein networks were generated after two-photon irradiation with an unseen resolution in time and space.
Conclusion
In summary, we have highlighted here recent innovations for two-photon uncaging using IR light. In neuroscience, great effort has been done to obtain more sensitive compounds for underlining neuron behavior; these will for sure be able to provide fine understanding of the brain functions from a mechanistic point of view. Photolabile protecting group can also be easily adapted for the study of other physiological phenomena, like cell signaling pathways [66] or protein expression. More recently, photolabile protecting groups were adapted for biomaterial sciences uses. In particular, when these photochemical tools are incorporated in block copolymer or mesoporous silica nanoparticles, an astonishing potential for light induced drug delivery has recently been reported. Micropatterning enters a new era with 3D two-photon bioprinting improvements during the last years, and will certainly play a key role in regenerative medicine in the future.
Acknowledgments
Agence Nationale de la Recherche (ANR-13-JSV5-0009-01) and Human Frontier Science Program Organization (HFSPO RGP0041-2012) are greatly acknowledged for financial support.
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