Article

Noninvasive monitoring of murine tumor blood flow during and after photodynamic therapy provides early assessment of therapeutic efficacy.

Department of Physics and Astronomy, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Clinical Cancer Research (Impact Factor: 8.19). 05/2005; 11(9):3543-52. DOI: 10.1158/1078-0432.CCR-04-2582
Source: PubMed

ABSTRACT To monitor tumor blood flow noninvasively during photodynamic therapy (PDT) and to correlate flow responses with therapeutic efficacy.
Diffuse correlation spectroscopy (DCS) was used to measure blood flow continuously in radiation-induced fibrosarcoma murine tumors during Photofrin (5 mg/kg)/PDT (75 mW/cm2, 135 J/cm2). Relative blood flow (rBF; i.e., normalized to preillumination values) was compared with tumor perfusion as determined by power Doppler ultrasound and was correlated with treatment durability, defined as the time of tumor growth to a volume of 400 mm3. Broadband diffuse reflectance spectroscopy concurrently quantified tumor hemoglobin oxygen saturation (SO2).
DCS and power Doppler ultrasound measured similar flow decreases in animals treated with identical protocols. DCS measurement of rBF during PDT revealed a series of PDT-induced peaks and declines dominated by an initial steep increase (average +/- SE: 168.1 +/- 39.5%) and subsequent decrease (59.2 +/- 29.1%). The duration (interval time; range, 2.2-15.6 minutes) and slope (flow reduction rate; range, 4.4 -45.8% minute(-1)) of the decrease correlated significantly (P = 0.0001 and 0.0002, r2= 0.79 and 0.67, respectively) with treatment durability. A positive, significant (P = 0.016, r2= 0.50) association between interval time and time-to-400 mm3 was also detected in animals with depressed pre-PDT blood flow due to hydralazine administration. At 3 hours after PDT, rBF and SO2 were predictive (P < or = 0.015) of treatment durability.
These data suggest a role for DCS in real-time monitoring of PDT vascular response as an indicator of treatment efficacy.

0 Followers
 · 
88 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dosimetry of singlet oxygen ((1)O2) is of particular interest because it is the major cytotoxic agent causing biological effects for type-II photosensitizers during photodynamic therapy (PDT). An in-vivo model to determine the singlet oxygen threshold dose, [(1)O2]rx,sh, for PDT was developed. An in-vivo radiation-induced fibrosarcoma (RIF) tumor mouse model was used to correlate the radius of necrosis to the calculation based on explicit PDT dosimetry of light fluence distribution, tissue optical properties, and photosensitizer concentrations. Inputs to the model include five photosensitizer-specific photochemical parameters along with [(1)O2]rx,sh. Photosensitizer-specific model parameters were determined for benzoporphyrin derivative monoacid ring A (BPD) and compared with two other type-II photosensitizers, Photofrin(®) and m-tetrahydroxyphenylchlorin (mTHPC) from the literature. The mean values (standard deviation) of the in-vivo [(1)O2]rx,sh are approximately 0.56 (0.26) and 0.72 (0.21) mM (or 3.6×10(7) and 4.6×10(7) singlet oxygen per cell to reduce the cell survival to 1/e) for Photofrin(®) and BPD, respectively, assuming that the fraction of generated singlet oxygen that interacts with the cell is 1. While the values for the photochemical parameters (ξ, σ, g, β) used for BPD were preliminary and may need further refinement, there is reasonable confidence for the values of the singlet oxygen threshold doses. In comparison, the [(1)O2]rx,sh value derived from in-vivo mouse study was reported to be 0.4 mM for mTHPC-PDT. However, the singlet oxygen required per cell is reported to be 9×10(8) per cell per 1/e fractional kill in an in-vitro mTHPC-PDT study on a rat prostate cancer cell line (MLL cells) and is reported to be 7.9 mM for a multicell in-vitro EMT6/Ro spheroid model for mTHPC-PDT. A theoretical analysis is provided to relate the number of in-vitro singlet oxygen required per cell to reach cell killing of 1/e to in-vivo singlet oxygen threshold dose (in mM). The sensitivity of threshold singlet oxygen dose for our experiment is examined. The possible influence of vascular vs. apoptotic cell killing mechanisms on the singlet oxygen threshold dose is discussed by comparing [(1)O2]rx,sh for BPD with 3 hr and 15 min drug-light-intervals, with the later being known to have a dominantly vascular effect. The experimental results of threshold singlet oxygen concentration in an in-vivo RIF tumor model for Photofrin(®), BPD, and mTHPC are about 20 times smaller than those observed in vitro. These results are consistent with knowledge that factors other than singlet oxygen-mediated tumor cell killing can contribute to PDT damage in-vivo.
    02/2015; 4(1). DOI:10.1515/plm-2014-0037
  • [Show abstract] [Hide abstract]
    ABSTRACT: Photodynamic therapy (PDT) has recently emerged as a potential treatment alternative for head and neck cancer. There is strong evidence that imprecise PDT dosimetry results in variations in clinical responses. Quantitative tools are likely to play an essential role in bringing PDT to a full realization of its potential benefits. They can provide standardization of site-specific individualized protocols that are used to monitor both light and photosensitizer (HPPH) dose, as well as the tissue response for individual patients. To accomplish this, we used a custom instrument and a hand-held probe that allowed quantification of blood flow, blood volume, blood oxygen saturation and drug concentration.
    Conference on Optical Methods for Tumor Treatment and Detection -; 03/2013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Selection and design of individualized treatments remains a key goal in cancer therapeutics; prediction of response and tumor recurrence following a given therapy provides a basis for subsequent personalized treatment design. We demonstrate an approach towards this goal with the example of photodynamic therapy (PDT) as the treatment modality and photoacoustic imaging (PAI) as a non-invasive, response and disease recurrence monitor in a murine model of glioblastoma (GBM). PDT is a photochemistry-based, clinically-used technique that consumes oxygen to generate cytotoxic species, thus causing changes in blood oxygen saturation (StO2). We hypothesize that this change in StO2 can be a surrogate marker for predicting treatment efficacy and tumor recurrence. PAI is a technique that can provide a 3D atlas of tumor StO2 by measuring oxygenated and deoxygenated hemoglobin. We demonstrate that tumors responding to PDT undergo approximately 85% change in StO2 by 24-hrs post-therapy while there is no significant change in StO2 values in the non-responding group. Furthermore, the 3D tumor StO2 maps predicted whether a tumor was likely to regrow at a later time point post-therapy. Information on the likelihood of tumor regrowth that normally would have been available only upon actual regrowth (10-30 days post treatment) in a xenograft tumor model, was available within 24-hrs of treatment using PAI, thus making early intervention a possibility. Given the advances and push towards availability of PAI in the clinical settings, the results of this study encourage applicability of PAI as an important step to guide and monitor therapies (e.g. PDT, radiation, anti-angiogenic) involving a change in StO2.
    Theranostics 01/2015; 5(3):289-301. DOI:10.7150/thno.10155 · 7.83 Impact Factor

Preview

Download
1 Download
Available from