Thieno[3,2-]thiophene-based bridged BODIPY dimers: synthesis, electrochemistry, and one- and two-photon photophysical properties.

Four BODIPY dyes (6a-6d) with electron-donating or electron-withdrawing groups at the -position were synthesized by the Sonogashira coupling reaction of 2,5-diethynylthieno[3,2-]thiophene with mono-iodo-BODIPY moieties. All compounds were fully characterized by H NMR and MALDI-TOF MS. Their photophysical and electrochemical properties were studied by UV-visible absorption spectroscopy, steady-state and time-resolved fluorescence spectroscopy, two-photon excitation spectroscopy and cyclic voltammetry.

Triplet-Triplet Annihilation Upconversion-Based Photolysis: Applications in Photopharmacology.

The emerging field of photopharmacology is a promising chemobiological methodology for optical control of drug activities that could ultimately solve the off-target toxicity outside the disease location of many drugs for the treatment of a given pathology. The use of photolytic reactions looks very attractive for a light-activated drug release but requires to develop photolytic reactions sensitive to red or near-infrared light excitation for better tissue penetration. This review will present the concepts of triplet-triplet annihilation upconversion-based photolysis and their recent in vivo applications for light-induced drug delivery using photoactivatable nanoparticles.

Ultrabright two-photon excitable red-emissive fluorogenic probes for fast and wash-free bioorthogonal labelling in live cells.

Fluorogenic bioorthogonal reactions are promising tools for tracking small molecules or biomolecules in living organisms. Two-photon excitation, by shifting absorption towards the red, significantly increases the signal-to-noise ratio and decreases photodamage, while allowing imaging about 10 times deeper than with a confocal microscope. However, efficient two-photon excitable fluorogenic probes are currently lacking.

Photoactivatable Liposomes for Blue to Deep Red Light-Activated Surface Drug Release: Application to Controlled Delivery of the Antitumoral Drug Melphalan.

Liposome-based nanoparticles able to release, via a photolytic reaction, a payload anchored at the surface of the phospholipid bilayer were prepared. The liposome formulation strategy uses an original drug-conjugated blue light-sensitive photoactivatable coumarinyl linker. This is based on an efficient blue light-sensitive photolabile protecting group modified by a lipid anchor, which enables its incorporation into liposomes, leading to blue to green light-sensitive nanoparticles.

Wavelength-Dependent, Orthogonal Photoregulation of DNA Liberation for Logic Operations.

In this study, we synthesized two phosphoramidites based on 2,7-bis-{4-nitro-8-[3-(2-propyl)-styryl]}-9,9-bis-[1-(3,6-dioxaheptyl)]-fluorene (BNSF) and 4,4'-bis-{8-[4-nitro-3-(2-propyl)-styryl]}-3,3'-di-methoxybiphenyl (BNSMB) structures as visible light-cleavable linkers for oligonucleotide conjugation. In addition to the commercial ultraviolet (UV) photocleavable (PC) linker, the BNSMB linker was further applied as a building component to construct photoregulated DNA devices as duplex structures, which are functionalized with fluorophores and quenchers. Selective cleavage of PC and BNSMB is achieved in response to ultraviolet (UV) and visible light irradiations as two inputs, respectively.

Red Light-Responsive Upconverting Nanoparticles for Quantitative and Controlled Release of a Coumarin-Based Prodrug.

Photolytic reactions allow the optical control of the liberation of biological effectors by photolabile protecting groups. The development of versatile technologies enabling the use of deep-red or NIR light excitation still represents a challenging issue, in particular for light-induced drug release (e.g.

On the Road Toward More Efficient Biocompatible Two-Photon Excitable Fluorophores.

Red-to-NIR absorption and emission wavelengths are key requirements for intravital bioimaging. One of the way to reach such excitation wavelengths is to use two-photon excitation. Unfortunately, there is still a lack of two-photon excitable fluorophores that are both efficient and biocompatible.

Two-Photon Sensitive Coumarinyl Photoremovable Protecting Groups with Rigid Electron-Rich Cycles Obtained by Domino Reactions Initiated by a 5--Dig Cyclocarbopalladation.

We herein report the design, synthesis, and photophysical characterization of extended and rigid coumarinyl derivatives showing large two-photon sensitivities ( ≤ 125 GM) at 740 and 800 nm. To efficiently synthesize these complex photoremovable protecting groups (PPGs), we used step-economic domino reactions. Moreover, those new coumarinyl PPGs display unique bathochromic shifts (≤100 nm) of the uncaging subproducts as a result of the formation of a more conjugated fulvene moiety.

Multimodal Theranostic Cyanine-Conjugated Gadolinium(III) Complex for Imaging of Amyloid-β in an Alzheimer's Disease Mouse Model.

Despite the wide use of magnetic resonance imaging (MRI) as a clinical diagnostic tool, there are still no clinically approved MRI contrast agents that can be applied for cerebral Alzheimer's disease (AD) biomarker imaging. We report here the design and development of the first amyloid-β (Aβ)-targeted, blood-brain barrier (BBB) penetrable theranostic Gd(DOTA)-cyanine dyad, which was synthesized by the conjugation of Gd(DOTA) complex and carbazole-based cyanine dye by the copper(I)-catalyzed azide-alkyne cycloaddition click reaction for imaging of Aβ and in AD mouse models. This dyad, as a multimodal probe, possesses desirable multifunctional properties, including good biocompatibility, low cytotoxicity, high Aβ selectivity, strong fluorescence enhancement upon binding with Aβ species, good paramagnetic properties, high stability, good BBB penetrability, and fast elimination from the mouse.

Synthesis and In Vitro Studies of a Gd(DOTA)-Porphyrin Conjugate for Combined MRI and Photodynamic Treatment.

With the aim of developing new molecular theranostic agents, a π-extended Zn(II) porphyrin as photosensitizer for photodynamic therapy (PDT) linked to two GdDOTA-type complexes for magnetic resonance imaging (MRI) detection was synthesized. The relaxivity studies revealed a much higher relaxivity value per Gd ion for this medium sized molecule (19.32 mM s at 20 MHz and 298 K) compared to clinical contrast agents-a value which strongly increases in the presence of bovine serum albumin, reaching 25.

Tuning the pK of two-photon bis-chromophoric probes for ratiometric fluorescence imaging of acidic pH in lysosomes.

Lysosomes are organelles containing many hydrolytic enzymes responsible for degrading macromolecules. Abnormal lysosomal pH changes are known to associate with dysfunction of cells linking to various diseases such as cancer and neurodegenerative disorders. Thus, it is of paramount importance to monitor lysosomal pH changes in order to investigate the pathological conditions.

Tumour-targeting photosensitisers for one- and two-photon activated photodynamic therapy.

Despite the advantages of photodynamic therapy (PDT) over chemotherapy or radiotherapy such as low side effects, lack of treatment resistance and spatial selectivity inherent to light activation of the drug, several limitations especially related to the photosensitiser (PS) prevent PDT from becoming widespread in oncology. Herein, new folic acid- and biotin-conjugated PSs for tumour-targeting PDT are reported, with promising properties related to PDT such as intense absorption following one-photon excitation in the red or two-photon excitation in the near-infrared, and also high singlet oxygen quantum yield (close to 70% in DMSO). Cellular studies demonstrated that both targeted PSs induced phototoxicity, the folate-targeted PS being the most effective one with 80% of cell death following 30 min of irradiation and a phototoxicity four times higher than that of the non-targeted PS.

A Porphyrin Dimer-GdDOTA Conjugate as a Theranostic Agent for One- and Two-Photon Photodynamic Therapy and MRI.

A molecular theranostic agent designed for photodynamic therapy (PDT) treatment in the near-infrared and for imaging tissue tumors with magnetic resonance imaging (MRI) is reported. It consists of a linear π-conjugated Zn(II) porphyrin dimer linked at each extremity to a GdDOTA-type complex. This agent has shown very promising potential for PDT applications with good singlet oxygen generation in DMSO and high linear absorption in the near-infrared (λ = 746 nm, ε ≈ 10 M cm).

Two-Photon Absorption Properties and Structures of BODIPY and Its Dyad, Triad and Tetrad.

A series consisting of a dyad, a triad and a tetrad containing either two, three and four BODIPY units, respectively, has been synthesized and fully characterized and compared to two mono-BODIPY analogs (used as references). The one- and two-photon photophysical properties have been measured and the X-ray structures of four of the BODIPY derivatives have been determined. In the 700-900 nm range, the two-photon absorption (TPA) cross sections range from 30 GM to 160 GM for these compounds.

Synthesis and Characterization of Photoactivatable Doxycycline Analogues Bearing Two-Photon-Sensitive Photoremovable Groups Suitable for Light-Induced Gene Expression.

We report the synthesis and photolytic properties of caged 9-aminodoxycycline derivatives modified with 2-{4'-bis-[2-(2methoxyethoxy)ethyl]-4-nitrobiphenyl-3-yl}prop-1-oxy (EANBP) and PEG7-ylated (7-diethylamino-2-oxo-2H-chromen-4-yl)methyl (PEG7-DEACM) groups. 9-Aminodoxycycline is a tetracycline analogue capable of activating transcription through the inducible TetOn transgene expression system and can be regioselectively coupled to two-photon-sensitive photo-removable protecting groups by carbamoylation. The EANBP-based caged 9-aminodoxycycline showed complex photochemical reactions but did release 10 % of 9-aminodoxycycline.

Four Gadolinium(III) Complexes Appended to a Porphyrin: A Water-Soluble Molecular Theranostic Agent with Remarkable Relaxivity Suited for MRI Tracking of the Photosensitizer.

A molecular theranostic agent for magnetic resonance imaging (MRI) and photodynamic therapy (PDT) consisting of four [GdDTTA](-) complexes (DTTA(4-) = diethylenetriamine-N,N,N″,N″-tetraacetate) linked to a meso-tetraphenylporphyrin core, as well as its yttrium(III) analogue, was synthesized. A variety of physicochemical methods were used to characterize the gadolinium(III) conjugate 1 both as an MRI contrast agent and as a photosensitizer. The proton relaxivity measured in H2O at 20 MHz and 25 °C, r1 = 43.

Fluorescent Tobacco mosaic virus-Derived Bio-Nanoparticles for Intravital Two-Photon Imaging.

Multi-photon intravital imaging has become a powerful tool to investigate the healthy and diseased brain vasculature in living animals. Although agents for multi-photon fluorescence microscopy of the microvasculature are available, issues related to stability, bioavailability, toxicity, cost or chemical adaptability remain to be solved. In particular, there is a need for highly fluorescent dyes linked to particles that do not cross the blood brain barrier (BBB) in brain diseases like tumor or stroke to estimate the functional blood supply.

A Theranostic Agent Combining a Two-Photon-Absorbing Photosensitizer for Photodynamic Therapy and a Gadolinium(III) Complex for MRI Detection.

The convergent synthesis and characterization of a potential theranostic agent, [DPP-ZnP-GdDOTA](-), which combines a diketopyrrolopyrrole-porphyrin component DPP-ZnP as a two-photon photosensitizer for photodynamic therapy (PDT) with a gadolinium(III) DOTA complex as a magnetic resonance imaging probe, is presented. [DPP-ZnP-GdDOTA](-) has a remarkably high longitudinal water proton relaxivity (19.94 mm(-1)  s(-1) at 20 MHz and 25 °C) for a monohydrated molecular system of this size.

A Reversible DNA Logic Gate Platform Operated by One- and Two-Photon Excitations.

We demonstrate the use of two different wavelength ranges of excitation light as inputs to remotely trigger the responses of the self-assembled DNA devices (D-OR). As an important feature of this device, the dependence of the readout fluorescent signals on the two external inputs, UV excitation for 1 min and/or near infrared irradiation (NIR) at 800 nm fs laser pulses, can mimic function of signal communication in OR logic gates. Their operations could be reset easily to its initial state.

Synthesis and Characterization of Carbazole-Linked Porphyrin Tweezers.

Herein the synthesis, spectroscopic characterization, two-photon absorption and electrochemical properties of 3,6-disubstituted carbazole tweezers is reported. A dimer resulting from a Glaser homocoupling was isolated during a Sonogashira coupling reaction between a diethynyl-carbazole spacer and a 5-bromo-triarylporphyrin and the properties of this original compound were compared with the 3,6-disubstituted carbazole bisporphyrin tweezers. The dyads reported herein present a two-photon absorption maximum at 920 nm with two-photon absorption cross-section in the 1200 GM range.

Conformational Change of Self-Assembled DNA Nanotubes Induced by Two-Photon Excitation.

Two-photon-regulated, shape-changing DNA nanostructures are demonstrated by integrating a DNA nanotube with a two-photon photocleavable module that enables the opening of the cavities of tube, and becomes partially single-stranded in response to two-photon excitation under 800 nm fs laser pulses.

Indole-based cyanine as a nuclear RNA-selective two-photon fluorescent probe for live cell imaging.

We have demonstrated that the subcellular targeting properties of the indole-based cyanines can be tuned by the functional substituent attached onto the indole moiety in which the first example of a highly RNA-selective and two-photon active fluorescent light-up probe for high contrast and brightness TPEF images of rRNA in the nucleolus of live cells has been developed. It is important to find that this cyanine binds much stronger toward RNA than DNA in a buffer solution as well as selectively stains and targets to rRNA in the nucleolus. Remarkably, the TPEF brightness (Φσmax) is dramatically increased with 11-fold enhancement in the presence of rRNA, leading to the record high Φσmax of 228 GM for RNA.

Diketopyrrolopyrrole-porphyrin conjugates with high two-photon absorption and singlet oxygen generation for two-photon photodynamic therapy.

Two-photon photodynamic therapy is a promising therapeutic method which requires the development of sensitizers with efficient two-photon absorption and singlet-oxygen generation. Reported here are two new diketopyrrolopyrrole-porphyrin conjugates as robust two-photon absorbing dyes with high two-photon absorption cross-sections within the therapeutic window. Furthermore, for the first time the singlet-oxygen generation efficiency of diketopyrrolopyrrole-containing systems is investigated.

Functionalized two-photon absorbing diketopyrrolopyrrole-based fluorophores for living cells fluorescent microscopy.

Two-photon excited microscopy has evolved as a routine technique for long-term cellular and in vivo imaging and is now available in most optical microscopy facilities. Classical dyes and fluorescent proteins, developed for epifluorescence or confocal microscopy, are used but unfortunately present a low efficiency upon two-photon excitation inducing the need of high excitation power (over 20 mW). To reduce this excitation power, new dyes need to be developed, allowing really low two-photon excitation power in the milliwatt or sub-milliwatt range.