Imaging a photodynamic therapy photosensitizerin vivowith a time-gated fluorescence tomography system

Abstract

Abstract. We report the tomographic imaging of a photodynamic therapy (PDT) photosensitizer, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) in vivo with time-domain fluorescence diffuse optical tomography (TD-FDOT). Simultaneous reconstruction of fluorescence yield and lifetime of HPPH was performed before and after PDT. The methodology was validated in phantom experiments, and depth-resolved in vivo imaging was achieved through simultaneous three-dimensional (3-D) mappings of fluorescence yield and lifetime contrasts. The tomographic images of a human head-and-neck xenograft in a mouse confirmed the preferential uptake and retention of HPPH by the tumor 24-h post-injection. HPPH-mediated PDT induced significant changes in fluorescence yield and lifetime. This pilot study demonstrates that TD-FDOT may be a good imaging modality for assessing photosensitizer distributions in deep tissue during PDT monitoring.

Time-Resolved Fluorescence in Photodynamic Therapy

“…TRF studies relevant to different PDT photosensitizers have been reported by several research groups in the past decades [31,43,45,[70][71][72][73][74][75][76]. FDA-approved PDT photosensitizers include Photofrin ® , 5-aminolevulinic acid-induced protoporphyrin IX (ALA-PpIX), and verteporphyrin, Other photosensitizing agents in research stage, such as mTHPC (m-tetrahydroxyphenylchlorin, Foscan ® ), phthalocyanine (Pc) compounds, and chlorin-based compounds (i.e., HPPH), also showed promising results in terms of their singlet oxygen yield and more red-shifted absorption bands [77].…”

“…How these factors affect lifetime measurements of the photosensitizers will be further discussed. [43] 10 ns (Organic solution) [70] 5.5 ns (Mitochondria, MLL) [70] 13.3 ns (Monomer, mitochondria) [70] 13.6 ns (Monomer, mitochondria) [45] 8.5 ns (Aggregates, mitochondria) [45] 8.0 ns (Aggregates, mitochondria) [78] 4.8 ns (Cell membrane) [78] 1.0 ns (Aggregates, mouse model) [31] 13 ns (Monomers, mouse model) [31] 5 µg/mL 0.06-6 µg/mL 7.6 ns (liposome confined) [74] 6.4 ns (tissue phantom) [75] 4.3 ns (mouse tumor, before PDT) [75] 5.0 ns (mouse tumor, after PDT) [75] …”

“…Efforts have been made to direct this technique towards clinical applications including the investigation of the instrumentation and analysis in tissue phantom and in vivo, although photosensitizer studies were still quite limited. To achieve time-resolved mapping of photosensitizers in a thicker tissue volume, time-domain (TD) NIR fluorescence diffuse optical tomography (FDOT) has become an attractive option to account for light propagation in tissue by the use of multiple source-detector pairs across the targeted area [75,[97][98][99]. Imaging reconstruction was then performed based on the normalized Born approximation [100].…”

“…Imaging reconstruction was then performed based on the normalized Born approximation [100]. Mo et al in 2012 used a time-gated fluorescence tomography system to characterize the fluorescence lifetime of a PDT photosensitizer, 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH), in a tissue phantom as well as a human head-and-neck xenograft in a mouse model [75]. HPPH-based PDT has shown effective results in superficial cancers such as Barrett's esophagus [101], head, and neck tumors [102].…”

“…It is important to note that the change of physiological parameters, in particular oxygen level and blood perfusion, could all contribute to the changes in fluorescence lifetimes [103]. In addition, changes from the standard dose parameters-fluence distribution and photobleaching of the photosensitizers-should also be considered [75]. These influencing factors are discussed in the following sections.…”