The improved killing of both androgen-dependent and independent prostate cancer cells by etoposide loaded SPIONs coupled with NIR irradiation.

Etoposide (Eto) is a toxic drug that shows promise in treating prostate cancer (PCa) but confers significant side effects, and has poor solubility and bioavailability. Nanoparticles are quite successful in overcoming such problems. Multifunctional nanoparticles that provide an opportunity to perform combination therapy have attracted great interest in recent years. Superparamagnetic iron oxide nanoparticles (SPIONs) are popular in various biomedical applications, including magnetic resonance imaging, drug delivery, magnetic hyperthermia and recently in photothermal therapy, combining imaging with therapy. Here, for the enhanced killing of PCa cells that are either androgen-dependent or not, the combination of SPION based Eto delivery and mild hyperthermia triggered by laser irradiation is proposed for the first time in the literature. For the encapsulation of Eto, highly stable, small, polyacrylic acid coated SPIONs were conjugated with bovine serum albumin (BSA) (Eto-BSA@PAA@SPION). Eto-BSA@PAA@SPION with 9% drug content produced better chemotherapeutic outcomes than free Eto on both androgen-dependent/castration sensitive LNCaP and androgen-independent/castration-resistant PC3 and DU145 PCa cells by enhancing drug internalization. Single and short irradiation of Eto-BSA@PAA@SPION treated cells at 808 nm improved the drug release and sensitized cells for Eto, hence, increasing the toxicity dramatically in all studied PCa cell lines. Caspase-mediated apoptosis, DNA damage, and ROS generation were detected in the treated cells, increasing with the Eto dose and laser treatment. The IC50 for Eto is reduced to 0.08 µg mL-1, 0.13 µg mL-1 and 2.8 µg mL-1 with laser/Eto-BSA@PAA@SPION for LNCaP, DU145 and PC3 cells, respectively. These are the lowest IC50 values seen in the literature for Eto on these cell lines so far, suggesting that the demonstrated nanoparticles and treatment approaches have great potential to treat various PCa cells at low doses of the drug under mild laser treatment conditions.

Broad spectrum antibacterial photodynamic and photothermal therapy achieved with indocyanine green loaded SPIONs under near infrared irradiation.

Antimicrobial photodynamic therapy (aPDT) and antimicrobial photothermal therapy (aPTT) are promising local and effective alternative therapies for antibiotic resistant bacterial infections and biofilms. A combination of nanoparticles and organic photosensitizers offers a great opportunity to combine PDT and PTT for effective eradication of both planktonic bacteria and their biofilms. In this work, photo-induced antibacterial activity of indocyanine green (ICG), 3-aminopropylsilane coated superparamagnetic iron oxide nanoparticles (APTMS@SPIONs) and ICG loaded APTMS@SPIONs was evaluated on planktonic cells and biofilms of Gram-negative (E. coli, K. pneumoniae, P. aeruginosa) and Gram-positive (S. epidermis) bacteria. A relatively low dose of ICG (25 µg mL-1) and SPIONs (0.425 µg mL-1 nanoparticle) in combination with single, short (10 min) laser irradiation at 808 nm with a power of 1150 mW was used in this study. No dark toxicity of the agents or antibacterial effect of the laser irradiation was observed. The charge of the particles did not provide a significant difference in their penetration to Gram-negative versus Gram-positive bacterial strains or their biofilms. APTMS@SPION/laser treatment completely eliminated P. aeruginosa and provided 7-log reduction in the colony forming unit (CFU) of E. Coli, but was not effective on the other two bacteria. This is the first example for antibacterial phototoxicity of this nanoparticle. ICG/laser and ICG-APTMS@SPION/laser treatments provided complete killing of all planktonic cells. Successful eradication of all biofilms was achieved with ICG/laser (3.2-3.7 log reduction in CFUs) or ICG-APTMS@SPION/laser treatment (3.3-4.4 log reduction in CFUs). However, an exceptionally high, 6.5-log reduction as well as a dramatic difference between ICG versus ICG/APTMS@SPION treatment was observed in K. pneumoniae biofilms with ICG-APTMS@SPION/laser treatment. Investigation of the ROS production and increase in the local temperature of the biofilms that were subjected to phototherapy suggested a combination of aPTT and aPDT mechanisms for phototoxicity, exhibiting a synergistic effect when ICG-APTMS@SPION/laser was used. This approach opens an exciting and novel avenue in the fight against drug resistant infections by successfully utilizing the antimicrobial and antibiofilm activity of low dose FDA approved optically traceable ICG and relatively low cost clinically acceptable iron oxide nanoparticles to enable effective aPDT/aPTT combination, induced via short-duration laser irradiation at a near-infrared wavelength.

Investigation of the factors affecting the photothermal therapy potential of small iron oxide nanoparticles over the 730-840 nm spectral region.

The use of superparamagnetic iron oxide nanoparticles (SPIONs) as a sensitizer in photothermal therapy (PTT) is relatively new and the origin of such a phenomenon is not known. Usually, large crystals and aggregated particles are preferred in the literature, suggesting that these increase the absorbance of particles at the irradiation wavelength, and hence, provide a larger temperature increase. This study has two major goals: identification of the key factors that affect the photo-induced temperature increase in well-controlled experiments and the influence of laser irradiation on nanoparticle properties. Small, biocompatible poly(acrylic acid) coated SPIONs (PAA/SPIONs) were used since they are more practical for future medical use than large aggregates. We studied the impact of three major laser-dependent variables, namely the wavelength (between 728 and 838 nm), intensity (1.85-9.76 W cm-2) and power (105-800 mW) as well as attenuation at the irradiation wavelength, on photothermal heating achieved with PAA/SPIONs. Within the studied range of these variables, only the laser power plays a critical role on the magnitude of photothermal heating in solutions. There is no strong correlation between the attenuation at the excitation wavelength and the temperature increase. In addition, extensive characterization of SPIONs before and after irradiation revealed no significant difference, which supports the re-usability of SPIONs. Lastly, the PTT potential of these small PAA/SPIONs was demonstrated in vitro on HeLa cells. At these low laser powers no temperature increase in SPION-free water or cell death in SPION-free cells was detected. Hence, this study provides a new insight into the photothermal effect of SPIONs, provides a clear and repeatable experimental procedure and demonstrates great potential for small SPIONs to be exploited in PTT.

Femtosecond pulse generation with voltage-controlled graphene saturable absorber.

We report, for the first time to our knowledge, the demonstration of a graphene supercapacitor as a voltage-controlled saturable absorber for femtosecond pulse generation from a solid-state laser. By applying only a few volts of bias, the Fermi level of the device could be shifted to vary the insertion loss, while maintaining a sufficient level of saturable absorption to initiate mode-locked operation. The graphene supercapacitor was operated at bias voltages of 0.5-1V to generate sub-100 fs pulses at a pulse repetition rate of 4.51 MHz from a multipass-cavity Cr(4+):forsterite laser operating at 1255 nm. The nonlinear optical response of the graphene supercapacitor was further investigated by using pump-probe spectroscopy.

Graphene mode-locked femtosecond Cr:ZnSe laser at 2500 nm.

We report, for the first time to our knowledge, femtosecond pulse generation from a graphene mode-locked Cr:ZnSe laser at 2500 nm. To minimize the insertion losses at the lasing wavelength, high-quality monolayer graphene transferred on a CaF(2) substrate was used in the experiments. Once mode-locking was initiated, the laser generated a stable train of 226 fs pulses with a time-bandwidth product of 0.39. The mode-locked laser operated at a pulse repetition rate of 77 MHz and produced 80 mW output power with an incident pump power of 1.6 W. To our knowledge, this is the longest laser wavelength at which graphene-based passive mode-locking has been demonstrated to date.

Energy scaling of a carbon nanotube saturable absorber mode-locked femtosecond bulk laser.

We report successful energy scaling of a room-temperature femtosecond Cr4+: forsterite laser by using a single-walled carbon nanotube saturable absorber (SWCNT-SA). By incorporating a q-preserving multipass cavity, a repetition rate of 4.51 MHz was realized, and the oscillator produced 121 fs, 10 nJ pulses at 1247 nm, with an average output power of 46 mW. To the best of our knowledge, the peak power of 84 kW is the highest generated to date from a SWCNT-SA mode-locked oscillator. Furthermore, energy scaling of a femtosecond multipass-cavity laser, mode-locked using a SWCNT-SA, is demonstrated for the first time.

Prolonged Raman lasing in size-stabilized salt-water microdroplets on a superhydrophobic surface.

We demonstrate prolonged Raman lasing from individual salt-water microdroplets with 10-20 microm diameters located on a superhydrophobic surface. The mechanism is based on the absorption heating of a 1064 nm cw IR laser and the resonant heating of a 532 nm pulsed, pump laser. A clear hysteresis is observed in the lasing intensity as the droplet size is photothermally tuned by the IR laser, indicating a self-stabilization mechanism due to the resonant absorption of the pump laser. Using this mechanism, Raman lasing near 650 nm is sustained for up to 25 min, approximately 1000 times longer than lasing durations reported in previous studies.

Raman lasing near 630 nm from stationary glycerol-water microdroplets on a superhydrophobic surface.

We demonstrate, for the first time to our knowledge, Raman lasing from stationary microdroplets on a superhydrophobic surface. In the experiments, glycerol-water microdroplets with radii in the 11-15 microm range were pumped at 532 nm with a pulsed, frequency-doubled Nd:YAG laser. Two distinct operation regimes of the microdroplets were observed: cavity-enhanced Raman scattering and Raman lasing. In the latter case, the Raman lasing signal was higher than the background by more than 30 dB. Investigation of the Raman spectra of various glycerol-water mixtures indicates that lasing occurs within the glycerol Raman band. Raman lasing was not sustained; rather, oscillation would occur in temporally separated bursts. Increasing the rate of convective cooling by nitrogen purging improved the lasing performance and reduced the average interburst separation from 2.3 to 0.4 s.

Determination of the stimulated-emission cross section in an end-pumped solid-state laser from laser-induced pump saturation data.

A novel method for the determination of the stimulated-emission cross section in an end-pumped solid-state laser is presented. The technique is based on the fact that increasing intracavity laser intensity stimulates faster decay of excited atoms and reduces the saturation of pump absorption. The use of this laser-induced pump saturation method is demonstrated with experimental data collected from a Cr(4+): YAG laser and analyzed by use of a numerical model that calculates the change in the pump transmission as a function of the intracavity laser intensity. The predicted cross-section value of 1.1x10(-19)cm(2) agrees well with previously reported results.

Mode-locked Cr(2+):ZnSe laser.

We describe active mode locking of a Cr(2+):ZnSe laser operating near 2.5 mum. The laser produces 4.4-ps transform-limited Gaussian-shaped pulses and produces 82 mW of average power.

Experimental determination of fractional thermal loading in an operating diode-pumped Nd:YVO4 minilaser at 1064 nm.

A practical in situ method is described and used for determination of the fractional thermal-loading parameter eta(h) in an operating diode-pumped Nd:YVO(4) minilaser at 1064 nm. Readily applicable to the thermal characterization of other solid-state media, the method is based on the fact that thermally induced lensing will cause the laser oscillation to be quenched at a critical pump power whose magnitude depends on the cavity configuration, thermo-optical properties of the gain medium, and, in particular, on the value of eta(h). In the experiments described here, a 0.5-mm-long coated Nd:YVO(4) crystal with 3-at. % Nd concentration was used to construct the diode-pumped laser with a flat highly reflecting end mirror and an intracavity lens. For the method to be effective, the resonator was set up close to the edge of the stability range. Above the oscillation threshold, the pump power at which lasing was quenched because of the onset of the thermally induced resonator instability was measured as a function of the intracavity lens position. A numerical model that accounted for absorption saturation and pump-induced thermal lensing was then used to analyze the experimentally measured data with eta(h) as an adjustable parameter. The average best-fit value of eta(h) was determined to be 0.40 with an estimated statistical variation of 8%.

Continuous-wave power transmission and thermal lensing of a saturable absorber subject to excited-state absorption.

Rate-equation analysis has been used in an investigation of the role of saturation and excited-state absorption in the power transmission characteristics and thermal lensing of an absorber. Use of an iterative approach gives explicit analytical results for power transmission and thermal focal length in the presence of excited-state absorption. Sample calculations indicate that pump absorption can increase or decrease with increasing incident pump power, depending on the relative strength of the excited-state absorption cross section with respect to the ground-state absorption cross section. In the case of thermal lensing, results further indicate that saturation and excited-state absorption act as two competing effects, the former reducing the strength of the thermal lens and the latter causing the opposite effect. The analytical formulas derived in this analysis should prove useful to experimentalists in determination of ground-state and excited-state absorption cross sections from experimental power transmission and lensing data.

Determination of the optimum absorption coefficient in Cr(4+):forsterite lasers under thermal loading.

We present the results of a novel experimental and numerical investigation aimed at minimizing thermal loading effects in room-temperature Cr(4+): forsterite lasers. In the model we numerically calculated the incident pump power required for oscillation threshold to be attained by taking into account pump absorption saturation, pump-induced thermal gradients inside the crystal, and the temperature dependence of the upper-state fluorescence lifetime. Excellent agreement was obtained between model predictions and experimental threshold data. We then used the model to calculate the optimum absorption coefficient that minimizes the incident threshold pump power. At a crystal boundary temperature of 15 degrees C the optimum value of the absorption coefficient was numerically determined to be 0.64 cm(-1) . Such optimization studies, which are readily applicable to other laser systems, should make a significant contribution to the improvement of the power performance of Cr(4+): forsterite lasers at room temperature.

Efficient continuous-wave radiatively cooled cr(4+):forsterite lasers at room temperature.

Results of a detailed experimental investigation aimed at reducing the thermal loading problem in a cw Cr(4+):forsterite laser at elevated temperatures are presented. From a Cr(4+):forsterite crystal with a differential absorption coefficient of 0.57 cm(-1), as much as 900 mW of cw output power has been obtained at 1.26 mum and at a crystal boundary temperature of 15 degrees C with an absorbed pump power of only 4.5 W at 1.06 mum. No chopping of the pump beam was necessary. An efficient radiative cooling technique was further employed to cool the laser and no subsequent power fading was observed. To the author's knowledge, the measured absorbed power slope efficiency of 29.5% represents the highest cw power performance reported to date from a Cr(4+):forsterite laser pumped by a Nd:YAG laser around room temperature. The role of the low differential absorption coefficient in the reduction of thermal loading is further elucidated by presenting comparative cw power performance data with a second Cr(4+):forsterite crystal having a differential absorption coefficient of 1.78 cm(-1) in the temperature range between 12 and 35 degrees C. Finally, some interesting multipulse effects of the laser observed in the millisecond regime during quasi-cw operation at 50% duty cycle are described.

Comparative experimental investigation of thermal loading in continuous-wave cr(4 +):forsterite lasers.

Results of a detailed experimental study aimed at reducing the thermal loading effects in room-temperature continuous-wave Cr(4+):forsterite lasers are presented. By using a Nd:YAG pump laser operated at 1.06 mum, the effect of the absorption coefficient and crystal cross-sectional area on the power performance of three crystals was compared between 12 and 36 degrees C. Experiments indicated that a low differential absorption coefficient significantly reduces the pump-induced thermal effects and cavity losses that would otherwise give rise to inefficient operation and increased temperature sensitivity. In particular, a Cr(4+):forsterite crystal with an absorption coefficient of 0.57 cm(-1) yielded as much as 900 mW of output power at 1.26 mum and a crystal temperature of 15 degrees C with an incident pump power of only 7.6 W. To the author's knowledge, the demonstrated slope efficiency of 30% represents the highest continuous-wave power performance reported to date from this laser system at elevated temperatures.

Continuous wave thermal loading in saturable absorbers: theory and experiment.

Theoretical and experimental results of a study that investigates cw thermal loading in solid-state saturable absorbers with low heat conductivities are presented. In addition to the temperature dependence of the refractive index, the proposed model considers the temperature dependence of the fluorescence lifetime to account for the local variations in the saturation intensity resulting from thermal gradients. In the calculations an iterative scheme is employed to calculate first the temperature distribution produced by the pump beam subject to saturable absorption with a constant saturation intensity and then the resulting modifications in the propagation parameters that are due to the presence of the calculated temperature distribution. Excellent agreement is obtained between the numerically calculated results and experimentally measured cw transmission data obtained with use of a Cr:YAG saturable absorber. Because the absorption cross section of the medium is used as one of the fitting parameters to yield the best fit between theory and experiment, the model further offers an accurate method whereby the cw power transmission data can be used to determine the absorption cross section of a saturable absorber subject to thermal loading.

Continuous-wave self-mode-locked operation of a femtosecond Cr(4+):YAG laser.

Continuous-wave self-mode-locked operation of a chromium-doped YAG laser pumped by a continuous-wave Nd:YAG laser at 20 degrees C is described. We used both regenerative initiation and continuous-wave self-mode-locking techniques to generate nearly transform-limited pulses of 120-fs (FWHM) duration at 1.52 microm. The TEM(00) output power was as high as 360 mW. The output of this femtosecond source was tunable from 1.51 to 1.53 microm.

Generation of 48-fs pulses and measurement of crystal dispersion by using a regeneratively initiated self-mode-locked chromium-doped forsterite laser.

A regeneratively initiated self-mode-locked chromium-doped forsterite laser operated at 3.5 degrees C is described. By employing intracavity negative-group-velocity dispersion compensation, nearly transform-limited femtosecond pulses of 48-fs (FWHM) duration were generated with average TEM(00) output powers of 380 mW at 1.23 microm. Regenerative initiation provides improvement in the output stability and ease of operation compared with fixed-frequency acousto-optic modulators. By tuning the mode-locked laser in the range 1.21-1.26 microm, estimated values for forsterite dispersion constants have also been obtained for the first time to our knowledge. The demonstrated power and stability open the door to applications such as efficient second-harmonic generation.

Femtosecond pulse generation by using an additive-pulse mode-locked chromium-doped forsterite laser operated at 77 K.

Using an acousto-optically mode-locked chromium-doped forsterite laser, operated at 77 K and coupled to a nonlinear resonator containing a single-mode fiber, we have produced femtosecond pulses of 150-fs duration at 1.23 microm with useful output powers of approximately 60 mW This represents what is to our knowledge the first demonstration of femtosecond pulse generation from this laser system using the coupled-cavity mode-locking scheme.