Applications of Photosensitisers to Cancer, Viral, Bacterial Disease and Immunology

Terry Wright

http://www.cytoluminator.com

Non-toxic Sensitizer

Cell

Photosensitising agent

•Dye molecule•Not cytotoxic•Taken up by cell (i.e. staining)

Cell Survives

Tuned Laser Light

Cell

Light exposure

•Red or near IR•Cell is transparent•Not cytotoxic•No heating

Cell Survives

Light (Red)

ROS Flood = Death

Cell

PS + Light

•Cell not transparent•Energy is absorbed•Reactive oxygen species•Oxidative stress

Cell Dies!!

Light (Red)

Chemical Targeting

Nanomolecular Delivery

• 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– 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)

Absorption

Emission

Fluorescencedetection

Laser: 685nm

Detection of Fluorescence

• Laser excitation• Near-IR fluorescence• Camera with IR filter

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

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

Before treatment After treatment

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

• 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?

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