6.1 Fundamentals of photodynamic therapy (PDT)

Photodynamic therapy combines light, photosensitizers, and oxygen to kill targeted cells. It's a powerful tool in medicine, using light-activated compounds to create toxic substances that destroy unwanted tissue. This process is precise and minimally invasive.

The therapy relies on careful timing and placement. Photosensitizers accumulate in target areas, then light exposure triggers a chain reaction. This creates reactive oxygen species, damaging cellular components and ultimately leading to cell death.

Photodynamic Therapy Fundamentals

Core Components of PDT

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• Photodynamic therapy combines light, a photosensitizer, and oxygen to induce targeted cell death
• Photosensitizers absorb light energy and transfer it to surrounding oxygen molecules
• Light activation occurs when the photosensitizer is exposed to a specific wavelength of light
• Photodynamic effect results from the interaction of light-activated photosensitizer with oxygen, producing cytotoxic species

Photosensitizer Characteristics

• Photosensitizers are light-sensitive compounds that accumulate preferentially in target tissues
• Ideal photosensitizers have high absorption in the therapeutic window (600-800 nm)
• Common photosensitizers include porphyrins, chlorins, and phthalocyanines
• Photosensitizer localization determines the specificity and efficacy of PDT

Light Delivery and Activation

• Light sources for PDT include lasers, LEDs, and filtered broad-spectrum lamps
• Light dose measured in J/cm² determines the extent of photodynamic effect
• Light penetration depth varies with wavelength, affecting treatment efficacy
• Fractionated light delivery can enhance PDT efficacy by reoxygenating tissues

Photochemical Reactions

Fundamentals of Photochemical Processes

• Photochemical reactions initiate when the photosensitizer absorbs light energy
• Excited photosensitizer transfers energy to surrounding oxygen molecules
• Reactive oxygen species generated include singlet oxygen, superoxide, and hydroxyl radicals
• Tissue oxygenation plays a crucial role in the efficiency of photochemical reactions

Singlet Oxygen Generation

• Singlet oxygen serves as the primary cytotoxic agent in most PDT applications
• Energy transfer from excited photosensitizer to ground state oxygen produces singlet oxygen
• Singlet oxygen has a short lifetime (~40 ns) and limited diffusion distance (~20 nm)
• Quantum yield of singlet oxygen production varies among different photosensitizers

Oxygen-Dependent Mechanisms

• Type I reactions involve electron transfer, producing radical species
• Type II reactions generate singlet oxygen through energy transfer
• Oxygen depletion during PDT can limit treatment efficacy
• Strategies to maintain tissue oxygenation include fractionated light delivery and hyperbaric oxygen therapy

Cellular Effects

Mechanisms of Cell Death

• Cytotoxicity in PDT results from oxidative damage to cellular components
• Apoptosis involves programmed cell death triggered by PDT-induced damage
• Necrosis occurs when severe oxidative stress leads to rapid cell lysis
• Oxidative stress damages proteins, lipids, and nucleic acids within cells

Subcellular Targets and Responses

• Mitochondria serve as primary targets for many photosensitizers
• Endoplasmic reticulum damage can trigger the unfolded protein response
• Lysosomes, when targeted, release hydrolytic enzymes contributing to cell death
• Nuclear damage may lead to cell cycle arrest or genetic instability

Cellular Signaling and Immune Response

• PDT induces release of damage-associated molecular patterns (DAMPs)
• Cytokine production stimulates inflammatory and immune responses
• Vascular effects of PDT can lead to tumor hypoxia and nutrient deprivation
• Immunogenic cell death promotes long-term anti-tumor immunity