As photodynamic therapy (PDT) continues to develop and find new clinical indications, robust individualized dosimetry is warranted to achieve effective treatments. We posit that the most direct PDT dosimetry is achieved by monitoring singlet oxygen (1O2), the major cytotoxic species generated photochemically during PDT. Its detection and quantification during PDT have been long-term goals for PDT dosimetry and the development of techniques for this, based on detection of its near-infrared luminescence emission (1270 nm), is at a noteworthy stage of development. We begin by discussing the theory behind singlet-oxygen luminescence dosimetry (SOLD) and the seminal contributions that have brought SOLD to its current status. Subsequently, technology developments that could potentially improve SOLD are discussed, together with future areas of research, as well as the potential limitations of this method. We conclude by examining the major thrusts for future SOLD applications: as a tool for quantitative photobiological studies, a point of reference to evaluate other PDT dosimetry techniques, the optimal means to evaluate new photosensitizers and delivery methods and, potentially, a direct and robust clinical dosimetry system.
"The 1O2 molecules are highly sensitive to the environment and have an intracellular lifetime on the order of 3 μs.28, 29 At the therapeutic dosage, their reaction with biomolecules leads to apoptosis and necrosis of cells.30 Because of its transient nature, effective generation of 1O2 at the target site is important for the success of PDT. "
[Show abstract][Hide abstract] ABSTRACT: We have demonstrated that gold nanocage-photosensitizer conjugates can enable dual image-guided delivery of photosensitizer and significantly improve the efficacy of photodynamic therapy in a murine model. The photosensitizer, 3-devinyl-3-(1'-hexyloxyethyl)pyropheophorbide (HPPH), was noncovalently entrapped in the poly(ethylene glycol) monolayer coated on the surface of gold nanocages. The conjugate is stable in saline solutions, while incubation in protein rich solutions leads to gradual unloading of the HPPH, which can be monitored optically by fluorescence and photoacoustic imaging. The slow nature of the release in turn results in an increase in accumulation of the drug within implanted tumors due to the passive delivery of gold nanocages. Furthermore, the conjugate is found to generate more therapeutic singlet oxygen and have a lower IC50 value than the free drug alone. Thus the conjugate shows significant suppression of tumor growth as compared to the free drug in vivo. Short-term study showed neither toxicity nor phenotypical changes in mice at therapeutic dose of the conjugates or even at 100-fold higher than therapeutic dose of gold nanocages.
"Organic NIR dyes that are fluorescent or capable of generating cytotoxic singlet oxygen (1O2), have been used for the visualization of deep tissues via fluorescence imaging 32, and for the noninvasive treatment of tumors by photodynamic therapy (PDT) 33,34, respectively. The photo-thermal properties of NIR dyes have also been exploited for their potential application to hyperthermal treatment of cancer 35,36. "
[Show abstract][Hide abstract] ABSTRACT: Nanotechnology approaches offer the potential for creating new optical imaging agents with unique properties that enable uses such as combined molecular imaging and photo-thermal therapy. Ideal preparations should fluoresce in the near-infrared (NIR) region to ensure maximal tissue penetration depth along with minimal scattering and light absorption. Due to their unique photophysical properties, upconverting ceramics such as NaYF4:Er(3+),Yb(3+) nanoparticles have become promising optical materials for biological imaging. In this work, the design and synthesis of NaYF4:Er(3+),Yb(3+)@SiO2 core-shell nano-composites, which contain highly absorbing NIR carbocyanine dyes in their outer silica shell, are described. These materials combine optical emission (from the upconverting core nanoparticle) with strong NIR absorption (from the carbocyanine dyes incorporated into the shell) to enable both optical imaging and photo-thermal treatment, respectively. Ultimately, this hybrid composite nanomaterial approach imparts the ability to both visualize, via upconversion imaging, and treat, via photo-thermal heating, using two distinct optical channels. Proof-of-principle in vitro experiments are presented to demonstrate the combined imaging and photo-thermal properties of this new functional nano-composite.
"Explicit dosimetry necessitates measurement of multiple photodynamic parameters that are related to PDT outcome, such as local PS concentration, fluence rate at the target site, and reactive oxygen species.   However, obtaining real-time measurements of a combination of these parameters can be cumbersome and requires specialized instrumentation. Implicit dosimetry involves measurement of a photodynamic parameter that is not directly responsible for, but may indicate, the treatment effect. "
[Show abstract][Hide abstract] ABSTRACT: Photodynamic therapy (PDT) dosimetry is an active area of study that is motivated by the need to reliably predict treatment outcomes. Implicit dosimetric parameters, such as photosensitizer (PS) photobleaching, may indicate PDT efficacy and could establish a framework to provide patient-customized PDT. Here, tumor destruction and benzoporphryin-derivative (BPD) photobleaching are characterized by systematically varying BPD-light combinations to achieve fixed PDT doses (M * J * cm-2) in a three-dimensional (3D) model of micrometastatic ovarian cancer (OvCa). It is observed that the BPD-light parameters used to construct a given PDT dose significantly impact nodule viability and BPD photobleaching. As a result, PDT dose, when measured by the product of BPD concentration and fluence, does not reliably predict overall efficacy. A PDT dose metric that incorporates a term for BPD photobleaching more robustly predicts PDT efficacy at low concentrations of BPD. These results suggest that PDT dose metrics that are informed by implicit approaches to dosimetry could improve the reliability of PDT-based regimens and provide opportunities for patient-specific treatment planning.
Proceedings of SPIE - The International Society for Optical Engineering 03/2013; 8568:0S. DOI:10.1117/12.2010840 · 0.20 Impact Factor
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