Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment. CA Cancer J Clin 2011;61:250-281. V C

/pdf/photodynamic-therapy-of-cancer-an-update-4fcrlehb17.pdf

Photodynamic therapy of cancer: An update†‡

In recent years, organic solar cells utilizing π-conjugated polymers have attracted widespread interest in both the academic and, increasingly, the commercial communities. These polymers are promising in terms of their electronic properties, low cost, versatility of functionalization, thin film flexibility, and ease of processing. These factors indicate that organic solar cells, although currently producing relatively low power conversion efficiencies (∼5-7%),1–3 compared to inorganic solar cells, have the potential to compete effectively with alternative solar cell technologies. However, in order for this to be feasible, the efficiencies of organic solar cells need further improvement. This is the focus of extensive studies worldwide. The backbone of a π-conjugated polymer is comprised of a linear series of overlapping pz orbitals that have formed via sp2 hybridization, thereby creating a conjugated chain of delocalized electron density. It is the interaction of these π electrons that dictates the electronic characteristics of the polymer. The energy levels become closely spaced as the delocalization length increases, resulting in a ‘band’ structure somewhat similar to that observed in inorganic solid-state semiconductors. In contrast to the latter, however, the primary photoexcitations in conjugated polymers are bound electron-hole pairs (excitons) rather than free charge carriers; this is largely due to their low dielectric constant and the presence of significant electron-lattice interactions and electron correlation effects.4 In the absence of a mechanism to dissociate the excitons into free charge carriers, the exciton will undergo radiative and nonradiative decay, with a typical exciton lifetime in the range from 100 ps to 1 ns. Achieving efficient charge photogeneration has long been recognized as a vital challenge for molecular-based solar cells. For example, the first organic solar cells were simple single-layer devices based on the pristine polymer and two electrodes of different work function. These devices, based on a Schottky diode structure, resulted in poor photocurrent efficiency.5–7 Relatively efficient photocurrent generation in an organic device was first reported by Tang in 1986,8 employing a vacuum-deposited CuPc/ perylene derivative donor/acceptor bilayer device. The differing electron affinities (and/or ionization potentials) between these two materials created an energy offset at their interface, thereby driving exciton dissociation. However, the efficiency of such bilayer devices is limited by the requirement of exciton diffusion to the donor/acceptor interface, typically requiring film thicknesses less than the optical absorption depth. Organic materials usually exhibit exciton diffusion lengths of ∼10 nm and optical absorption depths of 100 nm, although we note significant progress is now being made with organic materials with exciton diffusion lengths comparable to or exceeding their optical absorption depth.9–12 The observation of ultrafast photoinduced electron transfer13,14 from a conjugated polymer to C60 and the * To whom correspondence should be addressed. E-mail: j.durrant@ imperial.ac.uk. Chem. Rev. 2010, 110, 6736–6767 6736

Charge Photogeneration in Organic Solar Cells

1.1 Photodynamic Therapy and Imaging
The purpose of this review is to present the current state of the role of imaging in photodynamic therapy (PDT). In order for the reader to fully appreciate the context of the discussions embodied in this article we begin with an overview of the PDT process, starting with a brief historical perspective followed by detailed discussions of specific applications of imaging in PDT. Each section starts with an overview of the specific topic and, where appropriate, ends with summary and future directions. The review closes with the authors’ perspective of the areas of future emphasis and promise. The basic premise of this review is that a combination of imaging and PDT will provide improved research and therapeutic strategies.

PDT is a photochemistry-based approach that uses a light-activatable chemical, termed a photosensitizer (PS), and light of an appropriate wavelength, to impart cytotoxicity via the generation of reactive molecular species (Figure 1a). In clinical settings, the PS is typically administered intravenously or topically, followed by illumination using a light delivery system suitable for the anatomical site being treated (Figure 1b). The time delay, often referred to as drug-light interval, between PS administration and the start of illumination with currently used PSs varies from 5 minutes to 24 hours or more depending on the specific PS and the target disease. Strictly speaking, this should be referred to as the PS-light interval, as at the concentrations typically used the PS is not a drug, but the drug-light interval terminology seems to be used fairly frequently. Typically, the useful range of wavelengths for therapeutic activation of the PS is 600 to 800 nm, to avoid interference by endogenous chromophores within the body, and yet maintain the energetics necessary for the generation of cytotoxic species (as discussed below) such as singlet oxygen (1O2). However, it is important to note that photosensitizers can also serve as fluorescence imaging agents for which activation with light in the 400nm range is often used and has been extremely useful in diagnostic imaging applications as described extensively in Section 2 of this review. The obvious limitation of short wavelength excitation is the lack of tissue penetration so that the volumes that are probed under these conditions are relatively shallow.






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Figure 1


(A) A schematic representation of PDT where PS is a photoactivatable multifunctional agent, which, upon light activation can serve as both an imaging agent and a therapeutic agent. (B) A schematic representation of the sequence of administration, localization and light activation of the PS for PDT or fluorescence imaging. Typically the PS is delivered systemically and allowed to circulate for an appropriate time interval (the “drug-light interval”), during which the PS accumulates preferentially in the target lesion(s) prior to light activation. In the idealized depiction here the PS is accumulation is shown to be entirely in the target tissue, however, even if this is not the case, light delivery confers a second layer of selectivity so that the cytotoxic effect will be generated only in regions where both drug and light are present. Upon localization of the PS, light activation will result in fluorescence emission which can be implemented for imaging applications, as well as generation cytotoxic species for therapy. In the former case light activation is achieved with a low fluence rate to generate fluorescence emission with little or no cytotoxic effect, while in the latter case a high fluence rate is used to generate a sufficient concentration of cytotoxic species to achieve biological effects.

/pdf/imaging-and-photodynamic-therapy-mechanisms-monitoring-and-76rc7acuq5.pdf

Imaging and photodynamic therapy: mechanisms, monitoring, and optimization.

4. Survey of Novel Multiphoton Active Materials 1257 4.1. Multiphoton Absorbing Systems 1257 4.2. Organic Molecules 1257 4.3. Organic Liquids and Liquid Crystals 1259 4.4. Conjugated Polymers 1259 4.4.1. Polydiacetylenes 1261 4.4.2. Polyphenylenevinylenes (PPVs) 1261 4.4.3. Polythiophenes 1263 4.4.4. Other Conjugated Polymers 1265 4.4.5. Dendrimers 1265 4.4.6. Hyperbranched Polymers 1267 4.5. Fullerenes 1267 4.6. Coordination and Organometallic Compounds 1271 4.6.1. Metal Dithiolenes 1271 4.6.2. Pyridine-Based Multidentate Ligands 1272 4.6.3. Other Transition-Metal Complexes 1273 4.6.4. Lanthanide Complexes 1275 4.6.5. Ferrocene Derivatives 1275 4.6.6. Alkynylruthenium Complexes 1279 4.6.7. Platinum Acetylides 1279 4.7. Porphyrins and Metallophophyrins 1279 4.8. Nanoparticles 1281 4.9. Biomolecules and Derivatives 1282 5. Nonlinear Optical Characterizations of Multiphoton Active Materials 1282

Multiphoton Absorbing Materials : Molecular Designs, Characterizations, and Applications

Two-photon excitation provides a means of activating chemical or physical processes with high spatial resolution in three dimensions and has made possible the development of three-dimensional fluorescence imaging, optical data storage, and lithographic microfabrication. These applications take advantage of the fact that the two-photon absorption probability depends quadratically on intensity, so under tight-focusing conditions, the absorption is confined at the focus to a volume of order λ3 (where λ is the laser wavelength). Any subsequent process, such as fluorescence or a photoinduced chemical reaction, is also localized in this small volume. Although three-dimensional data storage and microfabrication have been illustrated using two-photon-initiated polymerization of resins incorporating conventional ultraviolet-absorbing initiators, such photopolymer systems exhibit low photosensitivity as the initiators have small two-photon absorption cross-sections (δ). Consequently, this approach requires high laser power, and its widespread use remains impractical. Here we report on a class of π;-conjugated compounds that exhibit large δ (as high as 1, 250 × 10−50 cm4 s per photon) and enhanced two-photon sensitivity relative to ultraviolet initiators. Two-photon excitable resins based on these new initiators have been developed and used to demonstrate a scheme for three-dimensional data storage which permits fluorescent and refractive read-out, and the fabrication of three-dimensional micro-optical and micromechanical structures, including photonic-bandgap-type structures.

Two-photon polymerization initiators for three-dimensional optical data storage and microfabrication

Experimental investigations of organic molecular nonlinear optical polarizabilities. 2. A study of conjugation dependences

During the past five years there has been considerable progress in the design of organic materials for optical power limiting. Among the more promising of the new material approaches are new reverse saturable absorbers (RSA) which derive their limiting capability on the photogeneration of highly absorbing charge states. Equally intriguing are the new approaches to designing chromophores with large two-photon cross-sections which give access to highly absorbing transient excited states. It now seems possible to combine these two new optical limiting paradigms in single structures which may therefore be considered as bimechanistic optical power limiters.

Recent development in the design of organic materials for optical power limiting

We present, for the first time, unambiguous spectroscopic evidence of strong cooperative enhancement of two-photon absorption (TPA) in a series of dendritic macromolecules. The maximum TPA cross section increases in proportion to N2, where N = 2, 4, 6 is the number of constituent identical chromophore units. We show that the enhancement is facilitated by the quasi-planar structure, which allows direct interbranch conjugation throughout the molecule.

/pdf/strong-cooperative-enhancement-of-two-photon-absorption-in-5fsfqyoz13.pdf

Strong cooperative enhancement of two-photon absorption in dendrimers

Thermal [1,j] sigmatropic rearrangements

Purpose: The aim of this study was to show that novel photodynamic therapy (PDT) sensitizers can be activated by two-photon absorption in the near-IR region of the spectrum and to show, for the first time, that such activation can lead to tumor regressions at significant tissue depth. These experiments also evaluated effects of high-energy femtosecond pulsed laser irradiation on normal tissues and characterized the response of xenograft tumors to our PDT protocols. Experimental Design: Human small cell lung cancer (NCI-H69), non-small cell lung cancer (A549), and breast cancer (MDA-MB-231) xenografts were induced in SCID mice. Irradiation of sensitized tumors was undertaken through the bodies of tumor-bearing mice to give a treatment depth of 2 cm. Posttreatment tumor regressions and histopathology were carried out to determine the nature of the response to these new PDT agents. Microarray expression profiles were conducted to assess the similarity of responses to single and two-photon activated PDT. Results: Regressions of all tumor types tested were seen. Histopathology was consistent with known PDT effects, and no, or minimal, changes were noted in irradiated normal tissues. Cluster analysis of microarray expression profiling showed reproducible changes in transcripts associated with apoptosis, stress, oxygen transport, and gene regulation. Conclusions: These new PDT sensitizers can be used at a depth of 2 cm to produce excellent xenograft regressions. The tumor response was consistent with known responses to single-photon activated PDT. Experiments in larger animals are warranted to determine the maximal achievable depth of treatment.

https://clincancerres.aacrjournals.org/content/clincanres/14/20/6564.full.pdf

New two-photon activated photodynamic therapy sensitizers induce xenograft tumor regressions after near-IR laser treatment through the body of the host mouse.

Charles W. Spangler

Papers

Experimental investigations of organic molecular nonlinear optical polarizabilities. 2. A study of conjugation dependences

Recent development in the design of organic materials for optical power limiting

Strong cooperative enhancement of two-photon absorption in dendrimers

Thermal [1,j] sigmatropic rearrangements

New two-photon activated photodynamic therapy sensitizers induce xenograft tumor regressions after near-IR laser treatment through the body of the host mouse.