Correction: Cyclopeptidic photosensitizer prodrugs as proteolytically triggered drug delivery systems of pheophorbide A: part II - co-loading of pheophorbide A and black hole quencher.

Correction for 'Cyclopeptidic photosensitizer prodrugs as proteolytically triggered drug delivery systems of pheophorbide A: part II - co-loading of pheophorbide A and black hole quencher' by Jordan Bouilloux et al., Photochem. Photobiol. Sci., 2018, 17, 1739-1748.

Correction: Cyclopeptidic photosensitizer prodrugs as proteolytically triggered drug delivery systems of pheophorbide A: part I - self-quenched prodrugs.

Correction for 'Cyclopeptidic photosensitizer prodrugs as proteolytically triggered drug delivery systems of pheophorbide A: part I - self-quenched prodrugs' by Jordan Bouilloux et al., Photochem. Photobiol. Sci., 2018, 17, 1728-1738.

Secure Quantum Key Distribution over 421 km of Optical Fiber.

We present a quantum key distribution system with a 2.5 GHz repetition rate using a three-state time-bin protocol combined with a one-decoy approach. Taking advantage of superconducting single-photon detectors optimized for quantum key distribution and ultralow-loss fiber, we can distribute secret keys at a maximum distance of 421 km and obtain secret key rates of 6.5 bps over 405 km.

Cyclopeptidic photosensitizer prodrugs as proteolytically triggered drug delivery systems of pheophorbide A: part I - self-quenched prodrugs.

Herein, we report the synthesis of a new prodrug system consisting of regioselectively addressable functionalized templates bearing multiple pheophorbide A moieties for use in photodynamic therapy. These coupling reactions were achieved using copper-free "click" chemistry, namely a strain-promoted azide-alkyne cycloaddition. This new design was used to obtain well-defined quenched photosensitizer prodrugs with perfect knowledge of the number and position of loaded photosensitizers, providing structures bearing up to six photosentitizers and two PEG chains. These conjugates are ideally quenched in their native state regarding their fluorescence emission (up to 155 ± 28 times less fluorescent for an hexasubstituted conjugate than a monosubstituted non-quenched reference compound) or singlet oxygen production (decreased 8.7-fold in the best case) when excited. After 2 h of proteolytic activation, the fluorescence emission of a tetrasubstituted conjugate was increased 17-fold compared with the initial fluorescence emission.

Cyclopeptidic photosensitizer prodrugs as proteolytically triggered drug delivery systems of pheophorbide A: part II - co-loading of pheophorbide A and black hole quencher.

Previously, we have shown that the use of a cyclopeptidic carrier could be of great interest for the design of fully characterized prodrugs for further use in photodynamic therapy. In order to further optimize the design, we decided to modify the highly quenched conjugate uPA-cPPP4/5 by co-loading a long-distance fluorescence quencher. For this purpose we tethered two black hole quenchers (BHQ3) together with two pheophorbide A moities onto the same PEGylated backbone and assessed the modified photophysical properties. In addition, to prove the reliability of our concept, we designed two analogues, uPA-cPPQ2+2/5 and CathB-cPPQ2+2/5, by using two different peptidic linkers as substrates for uPA and cathepsin B, respectively. These two conjugates proved to be much more water-soluble than their analogues bearing only Phas. These conjugates are not only highly quenched in their native state with regard to their fluorescence emission (up to 850 ± 287 times less fluorescent for CathB-cPPQ2+2/5 as compared to the unquenched monosubstituted reference uPA-cPPP1/5), but also prevent singlet oxygen production (with a total quenching of the emission when the quenchers are co-loaded with photosensitizers) when the photosentistizers are excited. After proteolytic activation, these conjugates recover their photophysical properties in the same way as occurred for uPA-cPPP4/5, with up to a 120-fold increase in fluorescence emission for uPA-cPPQ2+2/5 after two hours of incubation with uPA.

Temporal jitter in free-running InGaAs/InP single-photon avalanche detectors.

Negative-feedback avalanche diodes (NFADs) provide a practical solution for different single-photon counting applications requiring free-running mode operation with low afterpulsing probability. Unfortunately, the timing jitter has never been as good as for gated InGaAs/InP single-photon avalanche diodes. Here we report on the timing jitter characterization of InGaAs/InP based NFADs with particular focus on the temperature dependence and the effect of carrier transport between the absorption and multiplication regions. Values as low as 52 ps full-width at half-maximum were obtained at an excess bias voltage of 3.5 V and an operating temperature of around -100°C.

24-Hour Relativistic Bit Commitment.

Bit commitment is a fundamental cryptographic primitive in which a party wishes to commit a secret bit to another party. Perfect security between mistrustful parties is unfortunately impossible to achieve through the asynchronous exchange of classical and quantum messages. Perfect security can nonetheless be achieved if each party splits into two agents exchanging classical information at times and locations satisfying strict relativistic constraints. A relativistic multiround protocol to achieve this was previously proposed and used to implement a 2-millisecond commitment time. Much longer durations were initially thought to be insecure, but recent theoretical progress showed that this is not so. In this Letter, we report on the implementation of a 24-hour bit commitment solely based on timed high-speed optical communication and fast data processing, with all agents located within the city of Geneva. This duration is more than 6 orders of magnitude longer than before, and we argue that it could be extended to one year and allow much more flexibility on the locations of the agents. Our implementation offers a practical and viable solution for use in applications such as digital signatures, secure voting and honesty-preserving auctions.

Gated-sted microscopy with subnanosecond pulsed fiber laser for reducing photobleaching.

The spatial resolution of a stimulated emission depletion (STED) microscope is theoretically unlimited and practically determined by the signal-to-noise ratio. Typically, an increase of the STED beam's power leads to an improvement of the effective resolution. However, this improvement may vanish because an increased STED beam's power is often accompanied by an increased photobleaching, which worsen the effective resolution by reducing the signal strength. A way to lower the photobleaching in pulsed STED (P-STED) implementations is to reduce the peak intensity lengthening the pulses duration (for a given average STED beam's power). This also leads to a reduction of the fluorophores quenching, thus a reduction of the effective resolution, but the time-gated detection was proved to be successful in recovering these reductions. Here we demonstrated that a subnanosecond fiber laser beam (pulse width ∼600 ps) reduces the photobleaching with respect to a traditional stretched hundreds picosecond (∼200 ps) beam provided by a Ti:Sapphire laser, without any effective spatial resolution lost.

Characterization of a time-resolved non-contact scanning diffuse optical imaging system exploiting fast-gated single-photon avalanche diode detection.

We present a system for non-contact time-resolved diffuse reflectance imaging, based on small source-detector distance and high dynamic range measurements utilizing a fast-gated single-photon avalanche diode. The system is suitable for imaging of diffusive media without any contact with the sample and with a spatial resolution of about 1 cm at 1 cm depth. In order to objectively assess its performances, we adopted two standardized protocols developed for time-domain brain imagers. The related tests included the recording of the instrument response function of the setup and the responsivity of its detection system. Moreover, by using liquid turbid phantoms with absorbing inclusions, depth-dependent contrast and contrast-to-noise ratio as well as lateral spatial resolution were measured. To illustrate the potentialities of the novel approach, the characteristics of the non-contact system are discussed and compared to those of a fiber-based brain imager.

Time-resolved singlet-oxygen luminescence detection with an efficient and practical semiconductor single-photon detector.

In clinical applications, such as PhotoDynamic Therapy, direct singlet-oxygen detection through its luminescence in the near-infrared range (1270 nm) has been a challenging task due to its low emission probability and the lack of suitable single-photon detectors. Here, we propose a practical setup based on a negative-feedback avalanche diode detector that is a viable alternative to the current state-of-the art for different clinical scenarios, especially where geometric collection efficiency is limited (e.g. fiber-based systems, confocal microscopy, scanning systems etc.). The proposed setup is characterized with Rose Bengal as a standard photosensitizer and it is used to measure the singlet-oxygen quantum yield of a new set of photosensitizers for site-selective photodynamic therapy.

Towards next-generation time-domain diffuse optics for extreme depth penetration and sensitivity.

Light is a powerful tool to non-invasively probe highly scattering media for clinical applications ranging from oncology to neurology, but also for molecular imaging, and quality assessment of food, wood and pharmaceuticals. Here we show that, for a paradigmatic case of diffuse optical imaging, ideal yet realistic time-domain systems yield more than 2-fold higher depth penetration and many decades higher contrast as compared to ideal continuous-wave systems, by adopting a dense source-detector distribution with picosecond time-gating. Towards this aim, we demonstrate the first building block made of a source-detector pair directly embedded into the probe based on a pulsed Vertical-Cavity Surface-Emitting Laser (VCSEL) to allow parallelization for dense coverage, a Silicon Photomultiplier (SiPM) to maximize light harvesting, and a Single-Photon Avalanche Diode (SPAD) to demonstrate the time-gating capability on the basic SiPM element. This paves the way to a dramatic advancement in terms of increased performances, new high impact applications, and availability of devices with orders of magnitude reduction in size and cost for widespread use, including quantitative wearable imaging.

Gated STED microscopy with time-gated single-photon avalanche diode.

Stimulated emission depletion (STED) microscopy provides fluorescence imaging with sub-diffraction resolution. Experimentally demonstrated at the end of the 90s, STED microscopy has gained substantial momentum and impact only in the last few years. Indeed, advances in many fields improved its compatibility with everyday biological research. Among them, a fundamental step was represented by the introduction in a STED architecture of the time-gated detection, which greatly reduced the complexity of the implementation and the illumination intensity needed. However, the benefits of the time-gated detection came along with a reduction of the fluorescence signal forming the STED microscopy images. The maximization of the useful (within the time gate) photon flux is then an important aspect to obtain super-resolved images. Here we show that by using a fast-gated single-photon avalanche diode (SPAD), i.e. a detector able to rapidly (hundreds picoseconds) switch-on and -off can improve significantly the signal-to-noise ratio (SNR) of the gated STED image. In addition to an enhancement of the image SNR, the use of the fast-gated SPAD reduces also the system complexity. We demonstrate these abilities both on calibration and biological sample. The experiments were carried on a gated STED microscope based on a STED beam operating in continuous-wave (CW), although the fast-gated SPAD is fully compatible with gated STED implementations based on pulsed STED beams.

Fast silicon photomultiplier improves signal harvesting and reduces complexity in time-domain diffuse optics.

We present a proof of concept prototype of a time-domain diffuse optics probe exploiting a fast Silicon PhotoMultiplier (SiPM), featuring a timing resolution better than 80 ps, a fast tail with just 90 ps decay time-constant and a wide active area of 1 mm2. The detector is hosted into the probe and used in direct contact with the sample under investigation, thus providing high harvesting efficiency by exploiting the whole SiPM numerical aperture and also reducing complexity by avoiding the use of cumbersome fiber bundles. Our tests also demonstrate high accuracy and linearity in retrieving the optical properties and suitable contrast and depth sensitivity for detecting localized inhomogeneities. In addition to a strong improvement in both instrumentation cost and size with respect to legacy solutions, the setup performances are comparable to those of state-of-the-art time-domain instrumentation, thus opening a new way to compact, low-cost and high-performance time-resolved devices for diffuse optical imaging and spectroscopy.

Spatial resolution in depth for time-resolved diffuse optical tomography using short source-detector separations.

Diffuse optical tomography for medical applications can require probes with small dimensions involving short source-detector separations. Even though this configuration is seen at first as a constraint due to the challenge of depth sensitivity, we show here that it can potentially be an asset for spatial resolution in depth. By comparing two fiber optic probes on a test object, we first show with simulations that short source-detector separations improve the spatial resolution down to a limit depth. We then confirm these results in an experimental study with a state-of-the-art setup involving a fast-gated single-photon avalanche diode allowing maximum depth sensitivity. We conclude that short source-detector separations are an option to consider for the design of probes so as to improve image quality for diffuse optical tomography in reflectance.

Diffuse optics using a dual window fast-gated counter.

In this paper we demonstrate the advantages of a fast-gated counter in achieving high count-rate and reducing costs of timing equipment in a time-resolved diffuse optical spectroscopy setup. We experimentally prove the equivalence between the fast-gated counter we developed and a traditional time-correlated single-photon counting setup in terms of depth sensitivity and signal-to-noise ratio. Additionally, we show the suitability of this device for bilayer analysis and to estimate the absorption coefficient of homogeneous diffusing media. Finally, we present a proof-of-principle arterial occlusion measurement on a healthy volunteer to validate the proposed approach in a real application. Fast-gated counters can dramatically reduce both costs and complexity in time-resolved multichannel systems, while achieving high count-rate, thus offering a great advantage in applications like brain and muscle functional imaging.

Time-gated single-photon detection module with 110 ps transition time and up to 80 MHz repetition rate.

We present the design and characterization of a complete single-photon counting module capable of time-gating a silicon single-photon avalanche diode with ON and OFF transition times down to 110 ps, at repetition rates up to 80 MHz. Thanks to this sharp temporal filtering of incoming photons, it is possible to reject undesired strong light pulses preceding (or following) the signal of interest, allowing to increase the dynamic range of optical acquisitions up to 7 decades. A complete experimental characterization of the module highlights its very flat temporal response, with a time resolution of the order of 30 ps. The instrument is fully user-configurable via a PC interface and can be easily integrated in any optical setup, thanks to its small and compact form factor.

High-throughput gated photon counter with two detection windows programmable down to 70 ps width.

We present the design and characterization of a high-throughput gated photon counter able to count electrical pulses occurring within two well-defined and programmable detection windows. We extensively characterized and validated this instrument up to 100 Mcounts/s and with detection window width down to 70 ps. This instrument is suitable for many applications and proves to be a cost-effective and compact alternative to time-correlated single-photon counting equipment, thanks to its easy configurability, user-friendly interface, and fully adjustable settings via a Universal Serial Bus (USB) link to a remote computer.

Time-resolved diffuse optical tomography using fast-gated single-photon avalanche diodes.

We present the first experimental results of reflectance Diffuse Optical Tomography (DOT) performed with a fast-gated single-photon avalanche diode (SPAD) coupled to a time-correlated single-photon counting system. The Mellin-Laplace transform was employed to process time-resolved data. We compare the performances of the SPAD operated in the gated mode vs. the non-gated mode for the detection and localization of an absorbing inclusion deeply embedded in a turbid medium for 5 and 15 mm interfiber distances. We demonstrate that, for a given acquisition time, the gated mode enables the detection and better localization of deeper absorbing inclusions than the non-gated mode. These results obtained on phantoms demonstrate the efficacy of time-resolved DOT at small interfiber distances. By achieving depth sensitivity with limited acquisition times, the gated mode increases the relevance of reflectance DOT at small interfiber distance for clinical applications.