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Review
. 2010 May 12;110(5):2795-838.
doi: 10.1021/cr900300p.

Imaging and photodynamic therapy: mechanisms, monitoring, and optimization

Jonathan P Celli  1 , Bryan Q Spring, Imran Rizvi, Conor L Evans, Kimberley S Samkoe, Sarika Verma, Brian W Pogue, Tayyaba Hasan
Affiliations
Review

Imaging and photodynamic therapy: mechanisms, monitoring, and optimization

Jonathan P Celli et al. Chem Rev. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
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.
Figure 2
Figure 2
A timeline of selected milestones in the historical development of PDT.
Figure 3
Figure 3
Imaging platforms for molecular structural and functional imaging across a broad range of size scales. For molecular concentration imaging, (the left side of the figure), optical spectroscopy and magnetic resonance spectroscopy (MRS) are primarily employed, but positron emission tomography (PET) can be used for imaging at these length scales. For structural and molecular imaging at length scales greater than 10’s of nanonmeters (the right side of the figure) a variety of imaging techniques can be employed including various types of microscopy, endoscopy, x-ray computed tomography (CT) and magnetic resonance imaging (MRI) depending on the size and composition of the structure being imaged.
Figure 4
Figure 4
Perrin-Jablonski energy diagram for a photosensitizer (PS) molecule. Various processes during the excited state lifetime of the PS and resulting from its relaxation back to its ground state are highlighted. While in its long lived triplet excited state the PS may undergo excited state reactions to generate cytotoxic species such as singlet molecular oxygen (via energy transfer from the PS to ground state, triplet oxygen). While both the excited singlet state and triplet state are involved in photosensitized cell killing, photodynamic killing comes primarily from the triplet manifold. PS fluorescence and phosphorescence may be used to image PS localization in tissue and time-resolved imaging techniques may be applied to monitor PS interactions with its microenvironment.
Figure 5
Figure 5
A schematic representation of the basic principles of photosensitizer fluorescence detection. The photosensitizer accumulates preferentially in neoplastic tissue (depicted as purple cells), which, upon excitation with light of the appropriate wavelength (blue arrows) emits red fluorescence emission (red arrows). The contrast generated by this fluorescence emission against backscattered illumination (blue arrows with dashed lines) can be used to demarcate the boundaries of neoplastic tissues for sensitive detection of a variety of human cancers and optimization of surgical resection. The backscattered illumination can be useful to observe surrounding non-fluorescent tissue, though in many applications an emission filter is placed before the observer or detector to exclude the backscattered light.
Figure 6
Figure 6
A schematic representation of the heme synthesis pathway which lead to synthesis and accumulation of protoporphyrin IX in vivo. Under normal physiological conditions, synthesis of PpIX is regulated by negative feedback control of free heme on ALA synthase. This feedback is bypassed by addition of exogenous ALA which, due to the relatively low rate of iron insertion by the enzyme ferrochelatase, leads to accumulation of excess PpIX that can be used either therapeutically, for PDT, or to generate fluorescence contrast, for PFD.
Figure 7
Figure 7
Structures of Aminolevulinic acid (ALA, Levulan) and its Methyl and Hexyl Esters (MAL or Metvix® and HAL or Hexvix® respectively).
Figure 8
Figure 8
Absorption (A) and fluorescence emission (B) spectrum obtained from PpIX in methanol. Positions of absorption maxima typically (although not exclusively) used for PFD and therapeutic PDT applications are marked with arrows.
Figure 9
Figure 9
Comparison of white light and PpIX fluorescence images of an intermediate grade malignant lesion in the bladder of a human patient, obtained via cystoscopy. In the white light image (A), the lesion is not evident, while in the PpIX fluorescence image obtained under blue illumination (B), the lesion is readily visible as a pink region just above the large air bubble in the lower middle part of the field. (Figure reproduced with permission from ref . Copyright 1999 BJU International.)
Figure 10
Figure 10
Progression free survival data by treatment group for the large multicenter trial reported by Stummer et al in 2006, which compared white light and fluorescence guided resection for treatment of malignant glioma. After 6 months there is a significant enhancement in progression free survival in the 5-ALA group as compared to white light, while the two curves collapse after 15 months. (Figure reproduced with permission from ref . Copyright 2006 Elsevier Ltd.)
Figure 11
Figure 11
Intraoperative images of a partially resected brain tumor (A and B) and the surface of the brain (C and D), comparing images obtained by white light (A and C) and mTHPC fluorescence imaging under blue light (B and D). In A, a partially resected tumor is difficult to discern while it is readily apparent in the blue-light mTHPC fluorescence image of the same tissue. Similarly, in C (a white light image of the surface of the brain), there is no apparent tumor, while the mTHPC fluorescence image, which is complemented by spectroscopy (inset) of the same field reveals the presence of malignancy. (Figure reproduced with permission from ref . Copyright 2001 American Society for Photobiology.)
Figure 12
Figure 12
Laparoscopic images of peritoneal metastases in a rat model of ovarian cancer obtained by white light imaging (right) and HAL-induced PpIX fluorescence imaging under blue light illumination (left). Image (A) shows a lesion that is only visible in the blue light mode, but not by white light (position marked by a circle) (8mM HAL after 2 h). Image (B) shows three lesions visible by both blue and white light (big circle) and one only detectable by fluorescence (small circle) (8mM HAL after 2 h). (Figure reproduced with permission from ref . Copyright 2003 Cancer Research UK.)
Figure 13
Figure 13
Laparoscopic images comparing metastatic ovarian carcinoma lesions in human patients under white and blue light illumination following intraperitoneal instillation of ALA in human patients. As observed in preclinical studies for detection of micrometastatic ovarian cancer using PFD, lesions are visible Tumor was detected on tissue specimens by strong red fluorescence, in lesions measuring <0.5 mm. (Figure reproduced with permission from ref . Copyright 2004 American Cancer Society.)
Figure 14
Figure 14
(A) Schematic of the prototype fiber-optic fluorescence microendoscope imaging system. Fluorescence excitation is provided by a light emitting diode (LED) which is directed through the objective via a dicrhoic mirror. Excitation light is directed into the mouse through a flexible sub-millimeter imaging fiber which also collects fluorescence emission. The longer wavelength emission passes the dichroic mirror and is registered on a CCD camera with on chip multiplication gain. (B) Fluorescence image of microscopic tumor nodules (tens of microns in size) detected on the peritoneal wall of an ovarian cancer mouse by the fluorescence microendoscope using BPD as the contrast agent. Scale bar is 100 μm. (C) H & E stain of a 5 μm section from the same region. Arrows indicate tumor nodules. (Reproduced with permission from ref . Copyright 2009 Nature Publishing Group.)
Figure 15
Figure 15
Multispectral images (A-D) taken pre-PDT of a superficial BCC on the ankle and the corresponding white-light image (E) taken before ALA application. Real-time image processing displays the difference between the 630 and 600 nm images displayed with a false color scale (F) showing clearly the extent of the lesion and the differential accumulation of PpIX in the SBCC compared with the application site and surrounding healthy tissue. Scale bars for these images were not available. (Figure reproduced with permission from ref . Copyright 2001 Wiley.)
Figure 16
Figure 16
MAL induced PpIX fluorescence images of two patients (A-C, and D-F) who received Mohs micrographic surgery (MMS). Images were obtained 3 hours following administration of MAL. Clinical pictures showing the outlines of the first MMS excision (white lines) were conducted without respect to the fluorescence images. The “real margins” of the tumors confirmed by histopathologic analysis are also included (red areas) and were already delineated by the fluorescence seen in panels B and E. The agreement between the fluorescence and histopathology margins suggests that the use of PFD may speed up Mohs surgery by reducing the number of step-wise excisions necessary. (Figure reproduced with permission from ref . Copyright 2008 American Medical Association.)
Figure 17
Figure 17
Comparison of white light and ALA induced PpIX fluorescence imaging (excitation wavelengths = 375–440 nm) for identification of oral cancer. (A) White light image of a tumor in the right floor of the mouth. (B) Autofluorescence imaging under excitation with blue-violet light of the same region. (C) The same region imaged again under ordinary white light, 1.5 hours after application of ALA. D. PpIX fluorescence image of the same region. (Figure reproduced with permission from ref . Copyright 2000 Wiley.)
Figure 18
Figure 18
Disease-targeted constructs for PFD and PDT, showing the targeting moeity, imaging agent, and biological application. (A) Ovarian cancer cells incubated for 15h with 140nM equivalent BPD-C225 construct. A confocal laser scanning fluorescence microscope is used to monitor the subcellular localization of the PS with high spatial resolution, fluorescence from the mitochondrial markers is shown in false color as green and BPD is shown in false color as red; (B) confocal microscopy shows that TPC conjugated to a membrane-penetrating arginine oligopeptide (R7) enters MDA-MB-468 (human breast carcinoma) cells efficiently where red represents fluorescence signal from TPC; (C) monitoring fluorescence signal distribution after intravenous injection of 100 nmol of Pyro-GDEVDGSGK-Folate conjugate to double tumor-bearing mice (with a FR positive tumor on the right side and negative one on the left side), indicates preferential accumulation of construct in the receptor positive tumor, establishing NIR imaging ability of the targeted PS construct; (D) fluorescence from aortic segments 24 hr post injection of Ce6-maleylated albumin conjugate indicates the constructs ability to detect and/or photodynamically treat inflamed plaques. Red represents Ce6 and yellow is tissue autofluorescence from the elastic fibers; (E) post-PDT changes in VEGF expression are monitored with the molecular imaging strategy, where an Avastin-Alexa Fluor construct was imaged in PDT-treated subcutaneous PC-3 (prostate cancer) tumors, 6 h following laser irradiation and fluorescence image of tumor labeling is pseudocolored in gold; and (F) T2-weighted magnetic resonance images at day 8 after PDT treatment from F3-targeted Photofrin-containing nanoparticles in a 9L brain tumor showing imaging and monitoring of therapeutic efficacy post treatment. (Figures reproduced with permission from: (A) ref . Copyright 2006, The International Society for Optical Engineering (SPIE); (B) ref . Copyright 2006, Wiley; (C) ref . Copyright 2007, American Chemical Society; (D) ref . Copyright 2008, The Royal Society of Chemistry and Owner Societies; (E) ref . Copyright 2008, American Association for Cancer Research; and (F) ref . Copyright 2006, American Association for Cancer Research.)
Figure 19
Figure 19
Concept design and application of PS fluorescence in site-activated constructs. (A) Release of Ce6 for PFD and PDT following cleavage of a cathepsin-B-specific construct in a subcutaneous murine model for human fibrosarcoma. Three-dimensional fluorescence-mediated tomography was used to image the HT1080 fibrosarcomas following 24 h incubation with a poly-L-lysine-Ce6 construct (0.125 mg Ce6 eq./kg). (B) Proof-of-concept study demonstrating the cleavage of a peptide linker by MMP-7 for PFD and PDT in a subcutaneous murine model for human epidermoid cancer. The PPMMP7B construct (drug) was injected intravenously (80nmol) in a single mouse bearing two KB tumors on each hind leg. Only one tumor, left leg, was treated and this mouse was monitored by white light and fluorescence imaging before treatment (left image, 3 h after drug injection) and 1 h after PDT (right image, 5 h after drug injection) on one hind flank. Right Image: Treated tumor on the left leg became edematous one hour post PDT while no fluorescence change is observed in untreated right tumor. (C) Mechanism for the cleavage of an enzyme activated prodrug where the blue balls represent the inactive PSs in the uncleaved construct, and the red balls represent the photoactive PSs. The image shows PS fluorescence in cellular co-cultures of S. aureus with human foreskin fibroblasts (HFF) where significantly greater fluorescence intensity is observed in bacterial cells, than in the neighboring fibroblasts indicating cleavage of construct only at the site of infection. (Figures reproduced with permission from: (A) ref ; Copyright 2006, American Association for Cancer Research. (B) ref ; Copyright 2007, The National Academy of Sciences of the USA. (C) ref ; Copyright 2009, Wiley.)
Figure 20
Figure 20
A schematic diagram depicting the intersecting roles of imaging in key steps of pre-treatment planning, therapy monitoring, and outcome assessment.
Figure 21
Figure 21
An example of structural imaging for PDT outcome assessment. PDT of the prostate was monitored with MRI before (top panel) and 7 days after PDT (bottom panel). The results of Tookad-PDT in the prostate are evident. A) The pathological necrosis is circled with the bold black line, while the transition region showing signs of inflammation and edema is indicated with the dotted line. Post-gadolinium contrast-enhanced T1-weighted MRI (B) shows that the necrotic region does not enhance, while the transition region strongly enhances. The opposite is seen in the T2-weighted image (C). D) The apparent diffusion coefficient map indicates that the necrotic region (arrows) has a different diffusion rate (1000 × 10−6 mm2/s) than the remaining prostate (arrow heads, 2500 × 10−6 mm2/s). (Reproduced with permission from ref . Copyright 2006, Wiley.)
Figure 22
Figure 22
Cross-section OCT B-scans of a patient with subfoveal choroidal neovascularization (CNV) treated with PDT, pseudocolored for reflectance intensity. (A) One day before PDT, the presence of intraretinal and subretinal fluid AMD can clearly be seen with OCT. (B) One day after PDT, increased intraretinal and subretinal fluid can be seen. (C) After one week following treatment, the OCT reveals substantial decrease in both intraretinal and subretinal fluid. (Reproduced with permission from ref . Copyright 2006, Elsevier.)
Figure 23
Figure 23
Comparison of Doppler OCT images of a Dunning prostate tumor before (top panels), during (middle panels), and after (bottom panels) exposure to light. The cross-sectional area of the blood vessels was reduced during the treatment, with some vasodilation observed after treatment. The leftmost blood vessel was seen to constrict first, and did not recover after the treatment was completed. (Reproduced with permission from ref . Copyright 2006, Wiley-Liss.)
Figure 24
Figure 24
An application of TLOCT for studying the basic tumor biology of PDT response, demonstrating a series of OCT cross-sectional images of ovarian cancer acini taken from a full 3D data set at time points following BPD-PDT. (A) Ovarian cancer acini appeared as small, solid and spherical structures immediately following treatment (B). Twelve hours post-PDT, signs of structural breakdown were seen (C). One day after PDT, the acini showed large-scale structural deformation with the appearance of apoptotic cell clusters at the nodules’ periphery. Few structural differences can be seen between 24 and 48 hours (D) following treatment. Reproduced with permission from ref . Copyright 2010, SPIE.
Figure 25
Figure 25
Fluorescence contrast agents relevant for molecular imaging of biological responses to PDT. Fluorescently labeled antibodies, target-activated probes and genetically encoded fluorescent proteins are examples of fluorescence contrast agents that have been applied for molecular imaging of biological responses to PDT. This figure highlights the use of these contrast agents for detecting molecular factors in both the intracellular and extracellular spaces. The natural clearance of unbound antibody-fluorophore conjugates from the extracellular space enables their use for labeling cell surface proteins and extracellular secreted factors. Target-activated probes based on FRET (as shown here) or ground state quenching, are applicable for imaging both intracellular and extracellular factors. Fluorescent proteins (an endogenous labeling scheme) are useful for monitoring protein expression levels and protein-protein interactions, and for visualizing protein trafficking. Fluorescent protein FRET sensors also exist and can be used to detect protein-protein interactions. Examples of the application of these contrast agents for studying PDT-induced molecular mechanisms are shown in Figure 28 and are discussed in the text.
Figure 26
Figure 26
Imaging of molecular mechanisms induced by PDT using the fluorescence contrast agents introduced in Figure 27. The ability to image critical molecular responses in tumors and proximal tissue following PDT is crucial for the development of effective therapeutic strategies designed to abrogate tumor survival and to enhance proapoptotic and immune-based responses. Examples of specific molecular targets and fluorescence contrast agents for imaging each of these mechanisms are shown in circles. The specific mechanisms shown here are: executioner caspase activation, increased expression of HSPs, immune cell migration, and secretion of VEGF and MMPs. These biological responses include both cellular death and pro-survival signaling pathways. Cellular death signaling includes the induction of the apoptotic cascade (see Section 5.3), and, separately, the activation of an immune response to tumor-specific antigens and inflammation. Pro-survival signaling includes increased production of certain proteins as part of the cellular stress response for repairing damage resulting from the generation of ROS during PDT (see Section 5.4), and the secretion of cytokines and enzymes to manipulate the tumor microenvironment. The secreted factors VEGF and MMP are important for tumor growth and metastasis (and are discussed in Section 5.5).
Figure 27
Figure 27
Imaging the activation dynamics of a proapoptotic factor and its cellular trafficking during PDT-induced apoptosis. A genetically encoded FRET sensor reports the dynamics of Bid (a key proapoptotic protein) activation and trafficking of its activated/truncated form (tBid) to the mitochondria during NPe6-PDT-induced apoptosis. (A & B) The temporal dynamics of Bid activation are visualized as a loss of FRET quenching of CFP fluorescence emission (i.e., increased CFP fluorescence - labeled as the “CFP” channel) and as a concomitant loss of YFP fluorescence due to FRET (labeled as the “FRET” channel) using the FRET-Bid fluorescent protein sensor described in the text. (C & D) Time-lapse images and quantification of tBid-CFP (activated Bid) trafficking from the cytosol into the mitochondria are shown, following cleavage of the FRET-Bid sensor. The bars represent the percentage of cells showing Bid translocation to mitochondria at the indicated time points. Scale bar: 10 μm. (Adapted with permission from ref . Copyright 2008 Wiley).
Figure 28
Figure 28
In vivo molecular imaging of a cellular stress response to PDT. The figure shows images of increased heat shock protein expression in an EMT6 (mouse mammary carcinoma) tumor, a molecular response to acute cellular stress during PDT. In this experiment, GFP-transfected EMT6 cells were implanted into mice subcutaneously, where GFP expression is driven by the activation of the heat shock protein 70 (HSP70) promoter and GFP fluorescence is used to visualize the HSP70 expression level. (A) Before and (B) 6 hours after PDT. The GFP fluorescence increases substantially following PDT, indicating an up-regulation in HSP70 expression. (Reproduced with permission from ref . Copyright 2003 Wiley).
Figure 29
Figure 29
A preliminary demonstration of in vivo molecular imaging of a secreted, proteolytic enzyme important for metastasis. The fluorescence images are of an MMP7-activated dual probe and PS agent. (A) A brightfield image of a mouse bearing two KB (human nasopharyngeal epidermoid carcinoma, an MMP7+ cancer cell line) tumors, one in each flank as indicated by the arrows. (B-E) Whole-body fluorescence images of the mouse before and after administration of the MMP7-activated probe/PS. (B, Prescan before i.v. injection of the target-activated fluorescent probe; C, 10 minutes post-injection of the probe; D, 3 hours post-injection; and E, 1 hour following PDT). Note that the circle in (D) demarks the tumor in the left flank, which received light irradiation while the right flank served as a “No Light” control. (F) Photograph of the same mouse 30 days following PDT. Note that the left flank tumor exhibits reduced tumor burden in comparison to the right flank. This represents a promising outcome; although, only a single mouse was tested. (Adapted with permission from ref . Copyright 2007 National Academy of Sciences).
Figure 30
Figure 30
In vivo molecular imaging of cytokine secretion dynamics in response to PDT. Here, fluorescence hyperspectral imaging has been applied to acquire a secreted VEGF level time-course in subcutaneous prostate cancer tumors (PC-3 human prostate cancer cells) following PDT. (A) Overlay of Avastin-AF488 conjugate (contrast agent for secreted VEGF, CAVEGF) fluorescence images (after spectral unmixing and calibration to a dye standard) and monochromatic reflectance images for a PDT-treated and a nontreated tumor. The CAVEGF fluorescence amplitude is false colored gold. (B) Average calibrated fluorescence intensity of PDT-treated and nontreated tumors at 1, 3, 6, 9, and 24 hrs following PDT. The CAVEGF fluorescence stabilizes after 24 hrs. Full time courses reveal a peak in VEGF secretion 24 hrs post-PDT, which returns to its pre-PDT baseline value after 3–7 days. The peak in secreted VEGF levels represents an opportune/critical time period for inhibiting VEGF activity. (Reproduced with permission from ref . Copyright 2008 American Association for Cancer Research).
Figure 31
Figure 31
Examples of multimodal molecular imaging for PDT. MRI-guided fluorescence molecular tomography with EGF labeled IRDye 800CW (LI-COR Biosciences). (A-C) provides both structural and functional information about the target tissue, in this case a pancreatic tumor. Singlet oxygen phosphorescence and PS fluorescence monitoring (D & E) can be used for dosimetry, treatment monitoring and assessment. (A) An axial T1-weighted gadolinium contrast enhanced MR image of a mouse. The yellow arrows indicate fiducials that mark the placement of the optical fibers for fluorescence detection and the red arrow indicates the tumor. (B) Segmentation of the abdomen in relevant tissues based on significant fluorophore localization, absorption and scattering properties; the tumor is in purple, the intestine in pink, the right kidney in blue and the remaining abdomen is in yellow. (C) The EGF-IRDye 800CW fluorescence reconstruction of the mouse abdomen based on the segmentation in B and the assumption that there are heterogeneous distributions of the optical properties within each of the segements, i.e. soft priors. The EGF-IRDye 800CW was injected intravenously 48 hours prior to imaging. (D) The combined singlet oxygen phosphorescence and photosensitizer fluorescence imager developed by PSI is shown. (E) Simultaneous phosphorescence and fluorescence images can be produced. In this case solutions of the PS Ce6 were used. (Reproduced with permission from refs. ,. Copyright 2009 SPIE).
Figure 32
Figure 32
In vivo imaging of fluorescently labeled, circulating tumor cells for the detection of metastatic disease. Combined image of three still frames, spanning 200 ms, acquired at video rate showing fluorescently labeled rat prostate cancer cells (MLL cells) traveling through an artery vein pair. Two cells are highlighted along the vein (top vessel) and one cell along the artery (bottom vessel) using blue, green, and red for the same cells as they are imaged in the first, second, and third frames, respectively. The vascular endothelium is labeled with anti-platelet/endothelial cell adhesion molecule-1 (CD31) conjugated to Cy5. As discussed in the text, the in vivo detection of circulating cancer cells is a powerful approach for the early assessment of response to therapy (e.g., detection of metastasis and/or its mitigation using combination therapies). (Reproduced with permission from ref . Copyright 2004 American Association for Cancer Research).
Figure 33
Figure 33
Imaging of immune cell populations in living specimens, which may potentially be applied for online monitoring of immune responses to PDT. In vivo confocal fluorescence images of immune cells are shown using an antibody-fluorescent dye conjugate injected into a tumor, after allowing 2 hours for unbound conjugate to clear. Here, an antibody-dye conjugate targeted to MHC-II (major histocompatibility complex Class II) labels dendritic MHC-II+ cells in an EMT6 (mouse mammary carcinoma) tumor grown intradermally in a mouse ear. (A) Positively stained dendritic MHC-II+ cells are labeled with a fluorescent antibody conjugate (red) at a depth of 80 μm in the tumor in the presence of a highly vascularized tumor microenvironment (green color indicates the CD31-fluorophore conjugate, which labels the vasculature). (B) Expanded views of the region of interest indicated by the white box superimposed on (A). In vivo imaging of immune cell trafficking is an exciting prospect for therapeutic monitoring (e.g., to optimize protocols for PDT-induced anti-tumor immune response). (Reproduced with permission from ref . Copyright 2008 SPIE).
Figure 34
Figure 34
In vivo monitoring of oxygen tension by time-resolved PS phosphorescence imaging, which has potential implications for PDT dosimetry. The images are of arteries 120 and 100 μm below the surface experiencing both normoxia (A,D) and hyperoxia (B,E), respectively. The phosphorescence decay data and best fit curves (C,F) are given for the points in A,B,D, and E. Regions under hypoxia have shorter lifetimes due to increased oxygen concentration. The monitoring of oxygen tension may be applied to record the consumption of molecular oxygen during PDT, to help determine the deposited PDT dose, and to identify hypoxic regions that may be resistant to PDT. pO2 values are given in units of mmHg. (Reproduced with permission from . Copyright 2008, The Optical Society of America.)
Figure 35
Figure 35
Examples of imaging workflow paradigms in PDT based on structural, dynamic and molecular imaging. The left panel shows a simplified scenario in which structural imaging is used to design the treatment plan, including the PDT regimen, which is followed by post-procedural imaging to assess treatment efficacy. The middle panel depicts implementations of dynamic imaging for online monitoring of blood flow and generation of singlet oxygen during PDT treatment. The right hand panel incorporates the additional level of sophistication that can be achieved if the treatment planning, monitoring and assessment workflow includes techniques for measurement of dynamic biological responses, such as levels of activation of receptors and/or secretion of key cytokines before and after treatment.
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