Transcript document

Applications of Photosensitisers
to Cancer, Viral, Bacterial
Disease and Immunology
Terry Wright
http://www.cytoluminator.com
Non-toxic Sensitizer
Photosensitising agent
•Dye molecule
•Not cytotoxic
•Taken up by cell
(i.e. staining)
Cell Survives
Cell
Tuned Laser Light
Light exposure
Light (Red)
•Red or near IR
•Cell is transparent
•Not cytotoxic
•No heating
Cell Survives
Cell
ROS Flood = Death
PS + Light
Light (Red)
•Cell not transparent
•Energy is absorbed
•Reactive oxygen species
•Oxidative stress
Cell Dies!!
Cell
Chemical Targeting
Nanomolecular Delivery
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Proprietary sensitiser formulation
20 nm nanoparticles containing sensitiser
Cationic surface charge targets cancer
Reduced sensitisation of healthy tissue
– Eyes
– Skin
• Rapid clearance
– 1wk vs 6
Nanomolecular Delivery
Accumulation of sensitizer in skin
of Bufo Marinus with
nanomolecule
Same sensitizer and same dose
without nanomolecule formula
Gentle Death
• High dose: necrosis
• Minimum dose: apoptosis
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Sensitiser bound to mitochondrial membrane
Cleave Bcl-2 / Bcl-XL
Loss of mitochondrial membrane potential
Programmed cell death follows
PDT of Cancer
• Barret’s Oesophagus
• Adjunct therapy for solid tumours
– Systemic administration
– Non-surgical debulking
– Killing microscopic remnants
• Topical application for non-melanoma SC
• Glioblastoma Multiforme at RMH
– 50% survival at 10 yr, vs ~5% at 2 yr chemo
S. S. Stylli and A. H. Kaye, J. Clin. Neurosci. 13, 709-717 (2006)
PDT Causes in-situ Vaccination
• Adaptive immunity frequently observed
• Remote metastases controlled / eliminated
– Tc / NK cells, macrophages
• Animal models resistant to rechallenge
• Adoptively transferable
• Inflammation due to necrosis, immune
response due to apoptosis?
F.H. van Duijnhoven et al., Immunobiol. 207, 105-113 (2003).
Activating the Immune System
• Because PDT creates a perfect vaccination
against the cancer in the patients body, the
immune system immediately begins to
attack the cancer.
• With antibody therapy the suppressor t-cells
are activated.
• When killing a large tumor up to 95% of the
bodies white cells rush to attack the cancer
Disabling the Defense
• Cancer mounts a defense against the
immune system.
• T-cells are converted to suppressor cells
which suppress new TIL.
• Immature myeloid cells are converted to
suppressors via ROS.
• Antibodies disable the defense systems
mounted by cancer to enable immune attack
Risk Factors with PDT
• High level necrotic kills can cause swelling
and inflammation- severe risk for brain
tumors.
• Even with apoptotic kills the amount of
cancer killed can be huge.
• Toxin load can be challenging for hepatic
and renal elimination, so maintainance of
organ health is vital.
Absorption/Fluorescence Spectra
λ = 685 nm
(excitation)
Fluorescence
detection
Absorption
Emission
Detection of Fluorescence
• Laser excitation
• Near-IR fluorescence
• Camera with IR filter
Laser: 685nm
IR: 695-780nm
Image on PC Screen
Lymphatic Involvement
When cancer is not present in lymph nodes, no fluorescence
is seen, as in the left picture above.
When cancer is present, photodynamic fluorescence is very
obvious. A few minutes of laser will resolve this condition.
Metastatic Bone Cancer
• Patient 2: metastasis in the manubrium
Before Treatment
After Treatment
Metastatic Bone Cancer
• Skull mets
• Ankle mets
Post-Salvage Breast Cancer
Following surgery, chemotherapy and radiotherapy
Post-Salvage Breast Cancer
Following Photodynamic Therapy
Post-Salvage Breast Cancer
Psoriasis
• Active leukocytes accumulate sensitiser
• Topical PDT of skin autoimmune disorders
Psoriasis treated with our sensitiser
Two weeks later
Scleroderma
• Scleroderma Treated over two years ago
• No indication of return to date
Scleroderma treated with our sensitiser
Multiple Sclerosis
Before treatment
After treatment
Multiple Sclerosis treatment is remarkably easy. A one hour
infusion with laser illumination at the same time resets the
immune system resulting in long lasting remission of symptoms
Diabetes
Diabetes Mellitus type I has been treated in animal
models.
Mice genetically programmed to develop DM I treated
with PDT have a 60% lower chance of developing DM I.
Both types of Diabetes are now being considered as
autoimmune diseases.
In one diabetic patient treated for cancer, blood sugar
levels dropped from 10+ to six range within days after
treatment.
Diabetic Wound Healing
Wounds which normally don’t heal for days or weeks can be
treated with a topical application of sensitizer and a few minutes
of laser. Wound healing proceeds normally after treatment
Bacteria
Golden Staph has been tested to 20 generations of LD 50 kills
It has never shown indication of developing resistance to PDT.
PDT for golden staph can be delivered fast and cost effectively.
In Staph from recent injuries or surgeries, the sensitizer can be
administered topically and will absorb through the wound.
Bloodborne golden staph can be treated with IV infusions.
Conclusion
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PDT: a clinical reality in most developed countries
But Australia is trailing ~15 years behind
No sensitiser approved for systemic use
Locally developed and manufactured:
– Portable laser, >5W at present and >10W planned
– Photosensitisers: systemic, intratumoural, topical
– IR camera and uniform illumination
Questions?
http://www.cytoluminator.com