The synthesis of a new star‐shaped hydrophobic porphyrin photosensitizer (PS), decorated with four strong two‐photon absorbing antennae is reported. This compound, acting as a powerful fluorescent two‐photon PS in organic solvents, is encapsulated at various loadings into biocompatible poly(benzyl malate)‐based polymeric nanoparticles (NPs). The resulting formulations are characterized in terms of NPs size and dispersity. Herein, it is shown that stable monodisperse formulations can be obtained up to 25 wt% loadings (relative to polymer mass). Given that the highest loading are desirable in therapy, the influence of porphyrin loading on the one‐ and two‐photon photophysical properties of the NPs in water is subsequently investigated. While fluorescence is not significantly affected by increasing loadings, the singlet oxygen quantum yield decreases at higher loadings together with the two‐photon absorption (2 PA) cross‐section (σ2) values. However, the 2 PA capacity of PS at 25 wt% loading remained competitive, keeping the same order of magnitude than at lower loadings. Finally, to evaluate how loading affects two‐photon phototherapy and fluorescence imaging, the performances of the NPs are evaluated through in vitro studies on MCF‐7 breast cancer cells. Despite the strong confinement experienced in situ by the PS, the better results were obtained with the most highly loaded NPs (25 wt%) validating a posteriori the potential of these nanoobjects for theranostic applications.

We report the use of σ-alkynyl d6 electron-rich transition metal complexes as electron-releasing end-groups in octupolar molecules designed for nonlinear optical (NLO) applications, specifically, N,N′,N″-triarylisocyanurates (5,7,8,10,12) and 1,3,5-triarylbenzenes (6,9,11) functionalized by Fe(II) and Ru(II) organometallic moieties, and their NLO properties, as assessed by hyper-Rayleigh scattering (HRS) and Z-scan. The redox properties are briefly investigated through isolation of the corresponding Fe(III) trications 5[PF6]3 and 6[PF6]3. The second-harmonic generation (SHG) or two-photon absorption (2PA) performance of the Fe(II) and Ru(II) parents is compared with the help of TD-DFT calculations performed on models. Comparison with tris-ferrocenyl isocyanurate 4 reveals that the σ-connection of the metallic centers to the π-manifold is superior to the η5-connection for enhancing NLO properties. The positive effect of organometallic end-groups on NLO properties relative to purely organic electron-releasing substituents is established. The mechanism by which NLO enhancement occurs is complex and possibly connected to the polarizable π-electrons in the ligands surrounding the metal alkynyl units, but in most cases, the observed NLO enhancement must arise from the transition metal centers interacting with the central π-manifold.

In this work, we explore the use of porphyrin/fluorene assemblies as luminescent photosensitizers (PSs) for two-photon photodynamic therapy in biological media. In this context, we systematically investigated a series of star-shaped hydrophobic porphyrins bearing four arms composed of either a single fluorenyl unit or two fluorenyls linked by triple or double bonds. These fluorenyl-porphyrins, previously identified as efficient fluorescent two-photon PSs in organic solvents, were encapsulated at various loadings in poly(benzyl malate)-based polymeric nanoparticles (NPs). Notably, promising PDT activity was observed in aqueous media for formulations with high PS loading (25 wt %), confirming this encapsulation strategy as an accessible and cost-effective approach for porphyrin biocompatibilization. Despite their strong confinement within the nanoparticles, the encapsulated porphyrins retained significant luminescent properties suitable for bioimaging, supporting the theranostic potential of these nanosystems.

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While pursuing the exploration of porphyrin/fluorene combinations at the molecular level and their application as luminescent photosensitizers for two-photon photodynamic therapy (2P-PDT), we wondered about the impact of adding electron-releasing endgroups to these molecular structures. Furthermore, we also wondered about the influence of spacers within the arms of these star-shaped architectures and about the impact of the metalation of these free-base porphyrins by zinc. To address these questions, we synthesized a series of ten novel star-shaped meso-tetraarylporphyrins, featuring various aromatic rings with 1,2-ethenyl fluorenyl and/or 1,2-ethynyl spacers, capped by diphenylamine endgroups. The linear and nonlinear optical properties of these compounds were characterized through absorption, emission, and two-photon excited fluorescence studies, thereby screening the impact of endgroups, metalation and arm composition on the optical parameters of interest. Subsequently, their singlet oxygen-photosensitizing properties were also evaluated. The enhanced properties observed for compounds presenting diphenylamino (DPA) endgroups in comparison to analogs with none, along with the impact of metalation by Zn(II) and that of 1,2-ethenyl versus 1,2-ethynyl linkers on these, were eventually analyzed using classical figures of merit. This contribution highlights the strong potential of DPA-capped star-shaped free-base porphyrins as fluorescent photosensitizers for combined 2P-PDT and imaging applications.

Improving the efficiency of photothermal (PT) therapies and photoacoustic (PA) imaging at the microscopic scale hinges on developing multiphoton-absorbing photothermal molecules or contrast agents that operate in the near-infrared (NIR) range. These advanced agents or molecules will enable excitation with NIR lasers, in an improved transparency range for biological tissues, while enabling minute, highly localized spatial control of the excitation volume. However, progress in this field requires innovative experimental techniques to characterize photothermal and photoacoustic effects under multiphoton excitation. In this article, we showcase a study of a model organometallic molecular compound excited via two-photon absorption (2 PA) using femtosecond laser pulses. Based on a time-domain Brillouin scattering technique, well adapted for investigating ultrafast nonlinear optical absorption processes in ultrathin films on substrates, we determine the effective nonlinear absorption coefficients of the compound directly linked to PT/PA. Our findings provide a practical approach for exploring and optimizing nonlinear PT/PA absorbers and contrast agents.

We report the synthesis of multifunctional periodic mesoporous organosilica nanoparticles (PMO NPs) with substantial two-photon absorption properties and targeting capability for two-photon excitation fluorescence (TPEF) and photodynamic therapy (TPE-PDT). Prepared using an adapted sol-gel synthesis, the nanoplatforms integrated two silylated chromophores in their three-dimensional matrix to maximize non-radiative Förster resonance energy transfer from a high two-photon absorption fluorophore donor to a porphyrin derivative acceptor, leading to an enhanced generation of reactive oxygen species. Combinations of biodegradable and non-biodegradable bis(triethoxysilyl)alkoxysilanes were employed for the synthesis of the NPs, and the corresponding photophysical studies revealed high efficiency levels of FRET. Next, the cellular uptake and toxicities of pristine and functionalized NPs were evaluated on breast cancer cell lines upon TPEF and TPE-PDT. Notably, the use of TPE-PDT treatment led to high levels of phototoxicity on MCF-7 and MDA-MB-231 cancer cells with substantial effects when compared to one-photon excitation (OPE)-PDT treatment. Preliminary in vivo data on selective and biodegradable NPs showed a significant phototoxicity towards MDA-MB-231 on zebrafish xenograft embryos, making these advanced nanoplatforms promising candidates for future TPE-PDT-based cancer treatments.

In the continuation of previous studies on carbon-rich meso-tetraarylporphyrins featuring 2,7-fluorene units at their periphery, the effect of changing the peripheral dendritic arms for linear arms on their oxygen-photosensitizing ability, their fluorescence and their two-photon absorption (2PA) properties is now analyzed. Thus, starburst porphyrins possessing up to twenty conjugated fluorenyl units were isolated and studied. More precisely, a series of five new free-base porphyrins featuring fully conjugated arms incorporating an increasing number of fluorenyl groups connected via 1,2-alkenyl spacers were synthesized, along with their Zn(II) complexes. Upon excitation in the arm-centred π-π* absorption band, an efficient energy transfer takes place from the peripheral fluorenyl units to the central porphyrin core, leading to intense red-light emission and oxygen photosensitization by the latter. More interestingly, while the linear optical properties of these porphyrins were only slightly improved compared to those of their dendrimer analogues for photodynamic therapy (PDT) or fluorescence imaging, their 2PA cross-sections were much more significantly boosted, evidencing the key role played by different structures on nonlinear optical properties. Finally, by comparison with other porphyrin-based two-photon photosensitizers reported in the literature, we show that these new "semi-disconnected" starburst systems exhibit a remarkable trade-off between intrinsic 2PA, fluorescence and oxygen photosensitization.

The study of nonlinear optics in the 1960s attracted considerable attention from a theoretical standpoint, engendering many proposals for practical use of these new photonic effects. Among these suggestions, the development of efficient two-photon absorption (2PA) has attracted sustained interest due to its demonstrated (or potential) use in a broad range of applications that include optical data storage, optical limiting and nanofabrication. The use of 2PA in biological applications is particularly appealing. This is because 2PA offers several advantages for biooriented applications, such as intrinsic three-dimensional resolution, increased penetration depth in biological materials such as tissue and highly focused excitation at half-energy, leading to a decrease of auto-fluorescence and photodamage. In this Primer Review, we introduce the essential background theory needed for an understanding of the field, we describe the key experiments deployed to quantify material performance, we discuss the evolution of 2PA molecular design, and we summarise the state-of-the-art and the existing challenges in the use of 2PA in imaging, therapy and theranostics.

We report the synthesis of new graftable three-branched octupolar fluorophores (F and F2), based on a triphenylamine core connected to electron-withdrawing sulfone-based peripheral groups through one or two & pi;-conjugated phenylene-vinylene linkers. Their two-photon absorption (TPA), solvatochromism and photoluminescence properties were investigated to derive structure-property relationships. Notably, the chromophores presented TPA bands in the biological window (700-900 nm) and high TPA cross-sections at peak of 810 GM for F and F2. Then, after silylation, fluorophore F was further covalently integrated within the sol-gel synthesis of different periodic mesoporous organosilica nanoparticles (PMO NPs). Transmission electronic microscopy imaging revealed the formation of spherical NPs with good monodispersity in size, as confirmed by dynamic light scattering measurements. The obtained fluorophore-based nanoplatforms were shown to be biocompatible in vitro and demonstrated a good potential for two-photon imaging in cancer cells using twophoton excited fluorescence microscopy.

In the continuation of our sustained interest in porphyrin-based dendrimers and their use as luminescent photosensitizers for two-photon photodynamic therapy (2P-PDT), we wondered about the effect of changing the connectors in our macromolecular structures. We also wanted to initiate preliminary studies on meso-tetraarylporphyrins decorated with more electron-releasing arms. Thus, various meso-tetrafluorenylporphyrin-cored star-shaped and dendrimeric derivatives have been synthesized and characterized, as well as their zinc(II) complexes. In the new dendrimeric derivatives, the peripheral fluorenyl units of the dendrons are linked to the inner core either by N-phenylcarbazole (CCbz) or triphenylamine (CTpa) connectors instead of the more classic 1,3,5-phenylene (CPh) linkers previously used by us. Selected linear and non-linear optical (LO and NLO) properties were then determined for these compounds via absorption or emission studies and by two-photon excited fluorescence (TPEF) measurements. It was found that the CCbz-containing dendrimer, which has the most rigid structure, exhibits a significantly lower two-photon absorption (2PA) cross-section than its CTpa analog, presenting a more flexible structure while rather similar luminescence and singlet oxygen activation quantum yields are found for both. The origin of this unexpected discrepancy is briefly discussed based on our photophysical data. It is then demonstrated that the latter dendrimer also outperforms several closely related dendrimers in terms of 2PA action cross-section and 2PA-oxygen sensitization, making its molecular architecture quite appealing for developing new 2PA photosensitizers suited to theranostic uses.

The linear and nonlinear optical properties of two quadrupolar bithiophenes and two quadrupolar cyclopentadithiophenes have been investigated. At the 5,5′ positions of the central bi/dithiophene units, the molecules possess 1,4-phenylalkynyl groups that bear either electron-donating (NPh2) or electron-withdrawing (SO2CF3) groups. The optical properties were experimentally studied and modelled via quantum chemistry computations of key configurations and conformations. All the compounds show good light harvesting efficiency due to their strong absorption in the visible range. These fluorescent compounds are also good two-photon absorbers in the NIR range that can photosensitize oxygen in toluene. DFT calculations reveal that the mixtures of conformers in a solution show similar linear optical properties. TD-DFT calculations reproduce the experimental spectroscopic data fairly well, including vibronic couplings in the fluorescence spectra. The lowest excited state for two-photon absorption corresponds to the S2 state. The roles of the SO2CF3 and NPh2 terminal groups on the nonlinear response were analyzed for possible bio-oriented applications, with the cyclopentadithiophenes showing the most promising figures of merit.

The synthesis and the optical properties of a family of new fluorenyl phthalocyanines substituted with water-solubilizing triethyleneglycol chains is described. These biocompatible molecules exhibit strong one- and two-photon absorptions, together with fluorescence and photosensitization properties similar to those of their lipophilic analogues, thus outperforming unsubstituted zinc phthalocyanine in terms of brightness and singlet oxygen production. They were subsequently probed in vitro on cancer cells under one and two-photon excitation in both fluorescence imaging and photodynamic therapy experiments. The metal-free compound was shown to be more biocompatible and thus more promising than the zinc complex for theranostic applications.

Star-shaped hydrophobic porphyrins, acting as powerful fluorescent two-photon photosensitizers for oxygen in organic solvents, can easily be loaded into PMLABe polymeric nanoparticles at various concentrations. In this contribution, the performance of these porphyrin-containing nanoparticles in terms of photodynamic therapy (PDT) is compared to those of the corresponding water-soluble porphyrin analogues when irradiated in MCF-7 cancer cells. While quite promising results are obtained for performing PDT with these nanoparticles, validating this approach as a mean for using more easily accessible and less expensive photosensitizers, from a synthetic perspective, we also show that their luminescence can still be used for bioimaging purposes in spite of their confinement in the nanoparticles, validating also the use of these nano-objects for theranostic purposes.

A series of 1,1,4,4-tetracyanobutadienes (TCBD) bearing a large diversity of fluorophores was prepared following a multi-step synthesis. In a crucial last step, all compounds were obtained from the corresponding ynamides which were particularly suitable for the formation of the TCBDs in the presence of tetracyanoethylene via a [2+2] cycloaddition/retroelectrocyclization step (CA-RE). Fluorenyl derivatives including several variations on position 7 and 9, in addition to phenanthrenyl and terphenyl derivatives provided ynamide-based TCBD affording remarkable emission properties covering a large range of wavelengths. Those compounds emit both in solid state and in solution from the visible region to the NIR range, depending on the molecular structures. Quantum yields in cyclohexane reached unforeseen values for such derivatives, up to 7.8%. A huge sensitivity to the environment of the TCBDs has also been unraveled for most of the compounds since we observed a dramatic fall of the quantum yields when changing the solvent from cyclohexane to toluene, while they are almost non-emissive in dichloromethane.

We report herein the linear optical properties of some extended 2,4,6-triphenyl-s-triazines of formula 2,4,6-[(1,4-C6H4)C≡C(4-C6H4X)]3-1,3,5-(C3H3N3) (3-X; X = NO2, CN, OMe, NMe2, NPh2) and related analogues 4 and 7-X (X = H, NPh2), before briefly discussing their two-photon absorption (2PA) cross-sections. Their 2PA performance is discussed in relation to 2PA values previously measured for closely related octupoles such as N,N′,N″-triphenylisocyanurates (1-X, 5, and 6-X) or 1,3,5-triphenylbenzenes (2-X). While s-triazines are usually much better two-photon absorbers in the near-IR range than these molecules, especially when functionalised by electron-releasing substituents at their periphery, they present a decreased transparency window in the visible range due to their red-shifted first 1PA peak, in particular when compared with corresponding isocyanurates analogues. In contrast, due to their significantly larger two-photon brilliancy, 2,4,6-triphenyl-s-triazines appear more promising than the latter for two-photon fluorescence bio-imaging purposes. Rationalisation of these unexpected outcomes is proposed based on DFT calculations.

Electron density difference between the S2 state reached by the 2PA and the ground state S0 (Δ μ S2–S0 = 1.70 D) for 2TM-NMe3+.

The synthesis of a series of four porphyrin derivatives based on a meso-tetrafluorenylporphyrin core functionalized with one to four trans-chlorobis(dppe)ruthenium alkynyl units (dppe = 1,2-bis(diphenylphosphino) ethane) at the periphery, together with cyclic voltammetry (CV) and UV?Vis absorption and emission spectroscopy studies, are reported. In these multipolar assemblies, the organoruthenium endgroups are potential electron-donors and the central porphyrin core is a potential electron-acceptor. The third-order nonlinear optical (NLO) responses have been assessed by Z-scan, revealing that these extended ?-networks incorporating polarizable organometallic units behave as nonlinear absorbers in the near-IR range. The role of the peripheral transition metal centers on the third-order NLO properties is discussed.

The synthesis and characterization of four new tetracyanobutadiene (TCBD) derivatives (1, 3c and 4b-c) incorporating tosylamido and 4-triphenylamino moieties are reported. Along with those of five closely related or differently branched TCBDs derivatives (2, 3a-b, 4c and 5), their linear and (third-order) nonlinear optical properties were investigated by electronic absorption spectroscopy and Z-scan measurements. Among these compounds, the tri-branched compounds 3c and 5 are the most active two-photon absorbers, with effective cross-sections of 275 and 350 GM at 900 nm, respectively. These properties are briefly discussed with the help of DFT calculations, focussing on structural and electronic factors, and contextualized with results obtained previously for related compounds.

Star shaped porphyrins decorated with external fluorenonyl arms have been isolated. Their luminescence and selected photophysical properties are discussed in the frame of two-photon-induced theranostics.