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Excited-state singlet oxygen (1O2), generated during photodynamic therapy (PDT), is believed to be the primary cytotoxic agent with a number of clinically approved photosensitizers. Its relative concentration in cells or tissues can be measured directly through its near-infrared (NIR) luminescence emission, which has correlated well with in vitro cell and in vivo normal skin treatment responses. Here, its correlation with the response of tumor tissue in vivo is examined, using the photosensitizer meso-tetrahydroxyphenylchlorin (mTHPC) in an animal model comprising luciferase- and green fluorescent protein (GFP)-transduced gliosarcoma grown in a dorsal window chamber. The change in the bioluminescence signal, imaged pretreatment and at 2, 5 and 9 d post treatment, was used as a quantitative measure of the tumor response, which was classified in individual tumors as "non", "moderate" and "strong" in order to reduce the variance in the data. Plotting the bioluminescence-based response vs the 1O2 counts demonstrated clear correlation, indicating that 1O2 luminescence provides a valid dosimetric technique for PDT in tumor tissue. [ABSTRACT FROM AUTHOR]

To date, singlet oxygen (O) luminescence (SOL) detection was predictive of photodynamic therapy (PDT) treatment responses both in vitro and in vivo, but accurate quantification is challenging. In particular, the early and strongest part of the time-resolved signal (500-2000 ns) is difficult to separate from confounding sources of luminescence and system noise, and so is normally gated out. However, the signal dynamics change with oxygen depletion during PDT, so that this time gating biases the O measurements. Here, the impact of gating was investigated in detail, determining the rate constants from SOL and direct pO measurements during meso-tetra(hydroxyphenyl)chlorin (mTHPC)-mediated PDT of cells in vitro under well-controlled conditions. With these data as input, numerical simulations were used to examine PDT and SOL dynamics, and the influence of various time gates on cumulative SOL signals. It is shown that gating can underestimate the SOL at early treatment time points by ∼40% and underestimate the cumulative SOL signal by 20-25%, representing significant errors. In vitro studies with both mTHPC and aminolevulinic acid-photosensitizer protoporphyrin IX demonstrate that rigorous analysis of SOL signal kinetics is then crucial in order to use SOL as an accurate and quantitative PDT dose metric. [ABSTRACT FROM AUTHOR]

Polymeric micelles are emerging as an effective drug delivery system for hydrophobic photosensitizers in photodynamic therapy (PDT). The objective of this study was to investigate the formulation of hydrophobic protoporphyrin IX (PpIX) with MePEG5000-b-PCL4100 [methoxy poly (ethylene glycol)-b-poly (caprolactone)] diblock copolymers and to compare their PDT response to that of free PpIX. The photophysical and photochemical properties of the polymeric PpIX micelles were studied by measuring absorbance and fluorescence spectra, PpIX-loading efficiency and stability, the micelle particle size and morphology, as well as singlet oxygen luminescence and lifetime. The spherical micelles have a high PpIX-loading efficiency of 82.4% and a narrow size distribution with a mean diameter of 52.2 ± 6.4 nm. The cellular uptake of PpIX in RIF-1 cells using PpIX micelles was approximately two-fold higher than that for free PpIX. Free PpIX and PpIX formulated in micelles exhibited similar subcellular localization in or around the cellular plasma membrane, as demonstrated using fluorescence microscopy. In vitro PDT results showed that the PpIX micelles have markedly increased photocytotoxicity over that with free PpIX, by nearly an order of magnitude at the highest light dose used. The micelles alone had no evident phototoxicity or dark toxicity. These findings suggest that MePEG5000-b-PCL4100 diblock copolymer micelles have great potential as a drug delivery system for hydrophobic photodynamic sensitizers. [ABSTRACT FROM AUTHOR]

Molecular beacons are FRET-based target-activatable probes. They offer control of fluorescence emission in response to specific cancer targets, thus are useful tools for in vivo cancer imaging. Photodynamic therapy (PDT) is a cell-killing process by light activation of a photosensitizer (PS) in the presence of oxygen. The key cytotoxic agent is singlet oxygen (¹O2). By combining these two principles (FRET and PDT), we have introduced a concept of photodynamic molecular beacons (PMB) for controlling the PS's ability to generate ¹O2 and, ultimately, for controlling its PDT activity. The PMB comprises a disease-specific linker, a PS, and a ¹O2 quencher, so that the PS's photoactivity is silenced until the linker interacts with a target molecule, such as a tumor-associated protease. Here, we report the full implementation of this concept by synthesizing a matrix metalloproteinase-7 (MMP7)-triggered PMB and achieving not only MMP7-triggered production of ¹O2 in solution but also MMP7-mediated photodynamic cytotoxicity in cancer cells. Preliminary in vivo studies also reveal the MMP7-activated PDT efficacy of this PMB. This study validates the core principle of the PMB concept that selective PDT-induced cell death can be achieved by exerting precise control of the PS's ability to produce ¹O2 by responding to specific cancer-associated biomarkers. Thus, PDT selectivity will no longer depend solely on how selectively the PS can be delivered to cancer cells. Rather, it will depend on how selective a biomarker is to cancer cells, and how selective the interaction of PMB is to this biomarker. [ABSTRACT FROM AUTHOR]

This study aims to simulate a therapeutic plan for a normal human blood model under various patho-physiological conditions, such as the development of leukemia/blood diseases, by means of Monte Carlo multilayered simulation. The photosensitizing compound selectively accumulates in the target cells. A superficial treatment of a blood sample was performed at different ratios of oxygen saturation ( f oxy = 50 % , 53 % , 55 % , 60 % , 65 % , and 70 % ) under the concentration ( C MC 540 = 30 µM) effect of merocyanine 540 (MC540) in the blood irradiation. This was done under the application of visible light of wavelength ~ 580 nm at an exposure time ~ 60 s. The dose of photodynamic therapy (PDT) was evaluated for the biological damage, leading to necrosis and blood damage during the treatment. In addition, the effect of PDT treatment response in the blood is related to hemoglobin oxygen saturation, resulting in an excellent relationship between the changes caused by the treatment in the blood at a peculiar oxygen saturation rate (for the highest response: f oxy = 50%) and a light dose (LD) of 3.83 Jcm - 2 above the minimal toxicity of normal tissues. The photodynamic dose is related to the depth of necrosis and the time of treatment for the achievement of the LD delivery at the PDT of blood. [ABSTRACT FROM AUTHOR]

Neeme Jarvi is one of the most prolific living conductors in the world with more than 350 recordings. During his 15 years as Music Director of the Detroit Symphony Orchestra (DSO), he gained international reputation as an orchestra builder. When Jarvi took over the DSO, the demoralized and debt-ridden orchestra was floundering. Under Jarvi's inspiring and creative team-oriented leadership, the DSO was touring, recording, and out of debt within 2 years. Jarvi immigrated with his family to the United States in 1980 from then communist-controlled Estonia. He accepted a contract with Columbia Artists and has now given more than 1,200 concerts in 125 cities, conducting 72 orchestras. A graduate of the Leningrad Conservatory, he has held or currently holds posts with major orchestras in Estonia, Japan, Sweden, Scotland, and now New Jersey. His debuts were with the New York Philharmonic, Philadelphia Orchestra, San Francisco Symphony, and Cincinnati Symphony Orchestra. He has conducted nearly all of the major orchestras of the United States and Europe. [ABSTRACT FROM AUTHOR]