💡Biophotonics Unit 6 – Photodynamic Therapy: Principles & Applications

Basic Principles of Photodynamic Therapy

• Involves the use of a photosensitizer, light, and molecular oxygen to induce localized cell death or tissue damage
• Photosensitizer accumulates selectively in target cells or tissues (tumors, abnormal blood vessels)
• Light of a specific wavelength activates the photosensitizer, generating reactive oxygen species (ROS)
  • ROS, primarily singlet oxygen, cause oxidative damage to cellular components leading to cell death
• Photodynamic effect is confined to the area where light is delivered, minimizing systemic toxicity
• Requires careful selection of photosensitizer, light source, and dosimetry for optimal therapeutic outcomes
• Can induce apoptosis, necrosis, or autophagy depending on the photosensitizer and treatment parameters
• Stimulates immune response and vascular damage, contributing to long-term tumor control

Light Sources and Delivery Systems

• Light sources for PDT include lasers, light-emitting diodes (LEDs), and broadband lamps
• Lasers provide monochromatic, coherent light with high power density (diode lasers, dye lasers)
• LEDs offer cost-effective, compact, and versatile light sources with narrow emission spectra
• Broadband lamps (halogen, xenon) have wide emission spectra and require filters for wavelength selection
• Light delivery systems ensure uniform illumination of the target area while minimizing exposure to surrounding tissues
  • Fiber optics, diffusers, and lens systems are used for endoscopic or interstitial light delivery
  • Planar or curved applicators are employed for superficial lesions (skin cancers, actinic keratosis)
• Light dosimetry considers factors such as wavelength, fluence rate, total fluence, and exposure time

Photosensitizers: Types and Mechanisms

• Photosensitizers are compounds that absorb light and transfer energy to molecular oxygen, generating ROS
• First-generation photosensitizers include hematoporphyrin derivatives (Photofrin) with absorption peaks around 630 nm
  • Drawbacks include prolonged skin photosensitivity and suboptimal tissue penetration
• Second-generation photosensitizers have improved selectivity, absorption, and pharmacokinetic properties
  • Examples include chlorins (Foscan), phthalocyanines (Pc 4), and protoporphyrin IX precursors (5-aminolevulinic acid, methyl aminolevulinate)
• Third-generation photosensitizers are conjugated with targeting moieties (antibodies, peptides) for enhanced specificity
• Photosensitizers can localize in various subcellular compartments (mitochondria, lysosomes, plasma membrane) influencing the mode of cell death
• Mechanisms of action involve Type I (electron transfer) and Type II (energy transfer) reactions generating ROS
  • Type II reactions, primarily producing singlet oxygen, are the dominant mechanism in PDT

Cellular and Molecular Responses

• PDT induces oxidative stress, leading to damage of proteins, lipids, and nucleic acids
• Mitochondrial damage and cytochrome c release can trigger intrinsic apoptotic pathway
• Plasma membrane damage can lead to necrosis or activation of extrinsic apoptotic pathway
• Autophagy may be induced as a cytoprotective mechanism or contribute to cell death
• PDT can cause vascular shutdown, leading to tumor hypoxia and nutrient deprivation
• Inflammatory response and immune activation contribute to tumor destruction and systemic antitumor immunity
  • Release of damage-associated molecular patterns (DAMPs) and tumor antigens stimulate innate and adaptive immune responses
• Transcriptional and translational changes occur in response to PDT-induced oxidative stress and cellular damage
  • Upregulation of stress response genes (heat shock proteins, antioxidant enzymes)
  • Modulation of apoptotic and survival pathways (p53, Bcl-2 family proteins)

Clinical Applications and Protocols

• PDT is approved for various oncological and non-oncological indications
  • Oncological: esophageal, lung, bladder, head and neck, and skin cancers
  • Non-oncological: age-related macular degeneration (AMD), actinic keratosis, Barrett's esophagus, psoriasis
• Treatment protocols vary depending on the indication, photosensitizer, and light source
• Photosensitizer administration route (intravenous, oral, topical) and dose are determined based on pharmacokinetics and target tissue
• Drug-light interval allows for optimal photosensitizer accumulation in target tissues while minimizing skin photosensitivity
• Light delivery parameters (wavelength, fluence rate, total fluence) are adjusted for tissue penetration and photosensitizer activation
• Fractionated or repeated treatments may be employed for enhanced efficacy and management of side effects
• Combination with other therapies (chemotherapy, radiotherapy, immunotherapy) can improve treatment outcomes

Treatment Planning and Dosimetry

• Accurate treatment planning is crucial for effective and safe PDT
• Factors to consider include photosensitizer properties, tissue optical properties, and target geometry
• Imaging techniques (fluorescence, MRI, PET) aid in photosensitizer localization and treatment planning
  • Fluorescence imaging allows real-time monitoring of photosensitizer accumulation and photobleaching
• Light dosimetry aims to deliver a sufficient photodynamic dose (PD) to the target tissue while minimizing damage to surrounding structures
  • PD is a function of photosensitizer concentration and light fluence
• Computational models and dosimetry software assist in predicting light distribution and optimizing treatment parameters
• Real-time dosimetry techniques (spectroscopy, fluorescence) enable monitoring and adjustment of light delivery during treatment
• Standardization of dosimetry protocols is essential for reproducibility and comparison of treatment outcomes across different studies and centers

Side Effects and Safety Considerations

• PDT is generally well-tolerated with fewer systemic side effects compared to conventional therapies
• Skin photosensitivity is a common side effect, requiring patients to avoid direct sunlight and bright indoor light for a period after photosensitizer administration
  • Duration of photosensitivity varies depending on the photosensitizer (days to weeks)
• Local side effects at the treatment site include pain, erythema, edema, and scarring
  • Pain management strategies include topical anesthetics, cooling, and systemic analgesics
• Transient flu-like symptoms (fever, chills, fatigue) may occur due to immune activation
• Rare but serious side effects include severe phototoxicity, anaphylaxis, and cardiovascular events
• Safety precautions during PDT include eye protection for patients and healthcare providers, as well as shielding of non-target tissues
• Contraindications for PDT include porphyria, known allergies to photosensitizers, and severe liver or kidney dysfunction
• Long-term safety and potential late effects of PDT require further investigation, particularly for repeated treatments

Emerging Trends and Future Directions

• Development of targeted photosensitizers for improved selectivity and reduced side effects
  • Conjugation with antibodies, peptides, or nanoparticles for active targeting
  • Activatable photosensitizers that respond to specific tumor microenvironment conditions (pH, enzymes)
• Exploration of novel light sources and delivery systems for enhanced depth penetration and treatment of deep-seated tumors
  • Upconverting nanoparticles for near-infrared activation of photosensitizers
  • Fiber optic diffusers and light-emitting fabrics for uniform light delivery
• Combination therapies to exploit synergistic effects and overcome limitations of PDT
  • PDT with chemotherapy, radiotherapy, or immunotherapy for improved tumor control and systemic antitumor immunity
  • PDT with antiangiogenic agents to enhance vascular damage and tumor hypoxia
• Nanotechnology-based approaches for photosensitizer delivery and multifunctional platforms
  • Nanoparticle formulations for improved photosensitizer solubility, stability, and pharmacokinetics
  • Theranostic nanoplatforms combining PDT with imaging and other therapeutic modalities
• Personalized PDT based on patient and tumor characteristics
  • Predictive biomarkers for PDT response and resistance
  • Tailored treatment planning and dosimetry based on individual patient data
• Expansion of PDT applications beyond oncology
  • Antimicrobial PDT for treatment of localized infections and biofilms
  • PDT for tissue regeneration and wound healing
  • Ophthalmological applications (polypoidal choroidal vasculopathy, central serous chorioretinopathy)