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Biophysical Determinants of Photodynamic Therapy and Approaches to Improve Outcome. Theresa M. Busch, Ph.D. Department of Radiation Oncology University of Pennsylvania, Philadelphia, PA. What is Photodynamic Therapy ?.

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Biophysical determinants of photodynamic therapy and approaches to improve outcome

Biophysical Determinants of Photodynamic Therapy and Approaches to Improve Outcome

Theresa M. Busch, Ph.D.

Department of Radiation Oncology

University of Pennsylvania, Philadelphia, PA


What is Photodynamic Therapy?

  • PDT is a directed, light-based method of damaging malignant or otherwise abnormal tissues.

Image from Wikipedia


hv

Oxidation of

Organic

Substrates

Photosensitizer

3O2

1O2

Photosensitizer3

Energy transfer

How Does it Work?

Type 2 Reaction


How does it work
How Does it Work?

  • Mechanisms of PDT action

    • Direct Cell Effects

      • Direct 1O2-mediated toxicity to tumor cells

    • Indirect Effects

      • Vascular damage

        • During light treatment

        • Delayed development within several hours after light treatment

      • Stimulation of host immune responses.

  • Cell death may occur by apoptosis, necrosis, and/or autophagy


Pdt variables
PDT Variables

  • Photosensitizer

    • Drug type

    • Dose

    • Drug-light interval

  • Light Delivery

    • Wavelength

    • Fluence

    • Fluence rate


What is it used for

FDA-Approved Indications (Oncology)

Obstructive esophageal cancer*

Obstructive endobronchial lung cancer*

Microinvasive endobronchial lung cancer

Actinic keratosis

Barrett’s esophagus/ high grade dysplasia

*for palliative intent

Clinical Trials

Pleural spread of nonsmall cell lung cancer

Mesothelioma

Intraperitoneal malignant tumors

Head and Neck- pre-malignant through advanced disease

Brain tumors

Skin cancer

Prostate cancer

What is it used for?


Heterogeneity in pdt
Heterogeneity in PDT

  • Photosensitizer distribution

  • Tissue optical properties (light distribution)

  • Microenvironment

    • Tumor oxygenation

    • Vascular network


Heterogeneity in photosensitizer uptake a lesson from the intraperitoneal pdt clinical trial
Heterogeneity in Photosensitizer Uptake: A Lesson From the Intraperitoneal PDT Clinical Trial

  • Hahn SM, et al. Clin Cancer Res 12:5464-70, 2006



Light absorption and scattering affects the fluence rate seen by the tissue
Light absorption and scattering affects the fluence rate seen by the tissue.

Tumor surface

75 mW/cm2

630 nm

Normalized fluence rate

3 mm depth

Distance (mm)


The tumor microenvironment is highly heterogeneous
The tumor microenvironment is highly heterogeneous…. seen by the tissue.

  • Busch TM, et al. Clin. Cancer Res.10: 4630–4638, 2004


And pdt exacerbates heterogeneity in hypoxia distribution
…. and PDT exacerbates heterogeneity in hypoxia distribution

Control RIF Tumor

During PDT

5 mg/kg Photofrin

135 J/cm2, 75 mW/cm2

  • Busch TM, et al. Cancer Res.62:, 7273-7279, 2002


Heterogeneity abounds so what to do
Heterogeneity Abounds distributionSo what to do?

Modify

Monitor


Approach 1 modify light delivery
Approach 1: Modify Light Delivery distribution

Rationale:

  • Lowering PDT fluence rate reduces the rate of photochemical oxygen consumption.

    • Better maintenance of tumor oxygenation during illumination.

    • Improves long-term tumor responses

      • Enhanced direct cell kill

      • Enhanced vascular shutdown in the treatment field


Hypoxia assay
Hypoxia Assay distribution

  • EF3 and EF5 are nitroimidazole-based drugs that binds to hypoxic cells as an inverse function of oxygen tension.

  • Detection is by a fluorochrome-conjugated monoclonal antibody.

  • Fluorescent micrographs are digitally analyzed for binding.

Section,

Stain for EF3/5

Fluorescence microscopy


Hoechst distribution

EF3

Labeling of Hypoxia during PDT

PDT

  • RIF murine tumor

  • EF3 at 52 mg/kg

  • Treated animals receive Photofrin-PDT at 75 or 38 mW/cm2, 135 J/cm2

  • Hoechst 33342 at 1.5 min before tumor excision

  • Cryosectioning, immunohistochemistry, fluorescence microscopy

Hoechst (perfusion)

Anti-EF3

Anti-CD31

Hoechst (tissue label)


Fluence rate effects on pdt created hypoxia

38 mW/cm distribution2

75 mW/cm2

Fluence rate effects on PDT-created hypoxia

EF3 Binding

EF3 Binding



Causes of depth dependent hypoxia during pdt
Causes of depth-dependent PDT-created hypoxiahypoxia during PDT

  • Light distribution?

Tumor surface

Normalized fluence rate

3 mm depth

Distance (mm)


Causes of depth dependent hypoxia during pdt1
Causes of depth-dependent PDT-created hypoxiahypoxia during PDT

  • Photosensitizer distribution?

Photofrin Uptake (ng/mg)

S D


Causes of depth dependent hypoxia during pdt2
Causes of depth-dependent PDT-created hypoxiahypoxia during PDT

  • Does not appear to be a result of photochemical oxygen consumption.

  • How about PDT-induced vascular effects?


Getting at heterogeneity in vascular response during pdt
Getting at heterogeneity in vascular response during PDT PDT-created hypoxia

sources

  • Diffuse Correlation Spectroscopy

    • Measures the temporal correlation of fluctuations in the intensity of transmitted light (785 nm) to provide information on the motion of tissue scatters, e.g. red blood cells

    • Data used to calculate relative blood flow, i.e. flow normalized to a pre-treatment baseline

    • Monitoring throughout PDT is facilitated by a non-contact camera probe equipped with optical filters to block the 630 nm treatment light

    • Separation distance between unique source-detector pairs determines the depth of tissue probed.

detectors

Distance (mm)


Substantial intratumor heterogeneity exists in pdt created vascular effects
Substantial intratumor heterogeneity exists in PDT-created vascular effects

  • PDT induces an initial increase in blood flow.

  • PDT leads to significant depth-dependent intratumor heterogeneity in blood flow response during illumination.


Intratumor heterogeneity in vascular effects controls
Intratumor heterogeneity in vascular effects vascular effects (controls)




Low fluence rate improves long term tumor response
Low fluence rate improves long-term tumor response cytotoxic response.

% of animals with tumors <400 mm3


Lowering pdt fluence rate improves therapeutic outcome summary
Lowering PDT fluence rate improves therapeutic outcome (summary)

  • Delivering a light dose more slowly provides

    • Less intra-tumor heterogeneity in PDT-created hypoxia during illumination

    • Less intra-tumor heterogeneity in vascular responses during illumination

    • Greater direct cell kill of tumor cells

    • Better long-term treatment response


Heterogeneity abounds so what to do1
Heterogeneity Abounds (summary)So what to do?

Modify

Monitor


Monitoring rationale
Monitoring: Rationale (summary)

  • PDT can create significant hypoxia in even vascular-adjacent tumor cells.

  • Vascular monitoring, including oxygenation and/or blood flow, may be indicative of tumor response.


Monitoring methods
Monitoring: Methods (summary)

Diffuse optical spectroscopy

  • Broadband reflectance spectroscopy with a noninvasive probe

  • Measures tissue optical properties in the range of 600-800 nm

  • Data used to calculate concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb)

  • Tissue hemoglobin oxygen saturation (SO2 or StO2) = [HbO2]/[HbO2 + Hb]

  • In mouse tissues SO2 of 50% at pO2 of 40 mmHg

  • Diffuse correlation spectroscopy with a non-contact probe

  • Measures temporal fluctuations in transmitted light (785 nm) to provide information on the motion of tissue scatters, e.g. red blood cells

  • Data used to calculate relative blood flow, i.e. flow normalized to a pre-treatment baseline

  • Monitoring throughout PDT is facilitated by a non-contact camera probe equipped with optical filters to block the 630 nm treatment light


Pdt induces variable changes in tumor hemoglobin oxygen saturation

50 (summary)

40

30

SO2 (%)

20

10

0

0 h 3 h

Before PDT After PDT

PDT induces variable changes in tumor hemoglobin oxygen saturation


Pre or post pdt so 2 is not associated with tumor response

Time-to-400 mm (summary)3 (days)

Time-to-400 mm3 (days)

SO2 after PDT (%)

SO2 before PDT(%)

Pre- or post-PDT SO2 is not associated with tumor response


The pdt induced change in so 2 in individual tumors is highly predictive of response
The PDT-induced change in SO (summary)2 in individual tumors is highly predictive of response

Relative SO2=

SO2 after PDT

SO2 before PDT

Time-to-400 mm3 (days)

Wang H-W, et al. Cancer Res.

64(20):7553-7561, 2004

Relative-SO2


The pdt induced change in blood flow is highly predictive of response
The PDT-induced change in blood flow is highly predictive of response

Time to a tumor volume

of 400 mm3 (days)

Slope of decrease in blood flow

  • Yu G, et al. Clin Cancer Res.11:3543-52, 2005


Monitoring summary
Monitoring (Summary) response

  • Pre-existing tumor SO2 of similarly-sized tumors of the same line can be highly heterogeneous.

  • PDT-induced changes in SO2 and blood flow can vary from tumor-to-tumor, even for the same PDT treatment conditions.

  • Individualized measurement of PDT effect on blood flow or blood oxygenation in a given tumor is predictive of long term response in that animal.

    • Changes associated with better maintenance of tumor oxygen (smaller PDT-induced decreases in SO2 or blood flow) lead to better tumor response.

  • Diffuse optical spectroscopy, can be readily applied in the clinic and thereby may provide a means for the rapid, individualized assessment of PDT outcome.


Conclusions
Conclusions response

  • Both and clinical and preclinical studies indicate that tumors can be characterized by substantial heterogeneity in the essential components of PDT.

  • MODIFICATION (e.g. light delivery or tumor microenvironment) can be used reduce physiologic, hemodynamic, and cytotoxic heterogeneity.

  • MONITORING offers potential to optimize treatment through individualized, real-time dosimetry based on hemodynamic responses.


Pdt at penn
PDT at Penn response

Physicists

Timothy Zhu

Jarod Finlay

Andreea DiMofte

Pre-clinical Researchers

Theresa Busch

Sydney Evans

Cameron Koch

Stephen Tuttle

Keith Cengel

Arjun Yodh

Xioaman Xing

Dermatology

Steve Fakharzadeh

Surgery

Douglas Fraker

Joseph Friedberg

Scott Cowan

Bert O’Malley

S. Bruce Malkowicz

Ara Chalian

Nursing Coordinators

Debbie Smith

Susan Prendergast

Melissa Culligan

Medicine

Dan Sterman

Colin Gilespie

Andrew Haas

Gregory Ginsberg

Laser Specialist/Manager

Carmen Rodriguez

Biostatistics

Rosie Mick

Mary Putt

Radiation Oncology

Eli Glatstein

Stephen Hahn

Robert Lustig

James Metz

Harry Quon

Neha Vapiwala

Keith Cengel

Veterinary Medicine

Lilly Duda

Jolaine Wilson


Acknowledgements

Radiation Oncology response

Steve Hahn

Eli Glatstein

Keith Cengel

Cameron Koch

Sydney Evans

Statistics/Image Analysis

E. Paul Wileyto

Mary Putt

Kevin Jenkins

Physics and Astronomy

Arjun Yodh

Xiaoman Xing

Guoqiang Yu

Hsing-Wen Wang

Medical Physics

Timothy Zhu

Jarod Finlay

Ken Wang

Carmen Rodriguez

Andreea Dimofte

Busch lab

Elizabeth Rickter

Shirron Carter

Min Yuan

Amanda Maas

Grant Support (NIH)

R01 CA 85831

P01 CA 87971

Acknowledgements


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