Description: <b>Photodynamic therapy</b> is a form of phototherapy involving light and a photosensitizing chemical substance used in conjunction with molecular oxygen to elicit cell death. <br>
Photodynamic therapy (PDT) is a 3-component cytotoxic platform: photosensitizer + light (matched wavelength) + oxygen. Light excites the photosensitizer, which then generates reactive oxygen species (ROS)—often dominated by singlet oxygen (¹O₂)—causing localized oxidative damage to tumor cells, tumor vasculature, and sometimes triggering immunogenic cell death (ICD). <br>
Key constraints are light penetration depth and tumor hypoxia (and PDT itself can transiently consume oxygen). <br>
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<b>Photodynamic Therapy (PDT) — Cancer-Oriented Time-Scale Flagged Pathway Table</b>
<!-- Photodynamic Therapy (PDT) — Cancer-Oriented Time-Scale Flagged Pathway Table -->
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer / Tumor Context</th>
<th>Normal Tissue Context</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>Type II photochemistry: singlet oxygen (¹O₂) generation</td>
<td>¹O₂ ↑↑ locally; oxidative damage ↑</td>
<td>Localized injury only where PS+light overlap</td>
<td>P</td>
<td>Core cytotoxic mechanism</td>
<td>PDT typically relies heavily on Type II energy transfer producing singlet oxygen as a primary cytotoxic agent (oxygen-dependent).</td>
</tr>
<tr>
<td>2</td>
<td>Type I photochemistry: radical ROS (O2•−, •OH, etc.)</td>
<td>Radical ROS ↑ (context; PS-dependent)</td>
<td>Localized oxidative injury (exposure-limited)</td>
<td>P</td>
<td>ROS amplification</td>
<td>Type I electron-transfer pathways can contribute, especially for some PS designs and oxygen-limited niches.</td>
</tr>
<tr>
<td>3</td>
<td>Direct tumor cell kill (membrane/protein/DNA oxidation)</td>
<td>Apoptosis/necrosis/other death programs ↑ (context)</td>
<td>Collateral damage limited by targeting + light field</td>
<td>R, G</td>
<td>Local tumor cytotoxicity</td>
<td>Oxidative injury can trigger multiple death modes; outcome depends on dose, PS localization (membrane/mitochondria/lysosome), and oxygen.</td>
</tr>
<tr>
<td>4</td>
<td>Vascular shutdown (tumor vasculature damage)</td>
<td>Perfusion ↓; secondary hypoxia/ischemia ↑</td>
<td>Local vascular injury possible</td>
<td>R</td>
<td>Indirect tumor starvation</td>
<td>PDT can damage tumor-associated vessels, restricting nutrient/oxygen supply and contributing to delayed tumor kill.</td>
</tr>
<tr>
<td>5</td>
<td>Oxygen dependence / hypoxia limitation</td>
<td>Efficacy ↓ in hypoxic tumors; PDT consumes O2 during reaction</td>
<td>—</td>
<td>P, R</td>
<td>Core constraint</td>
<td>Tumor hypoxia is a major barrier; PDT can transiently reduce local oxygen levels during illumination.</td>
</tr>
<tr>
<td>6</td>
<td>Immune activation / immunogenic cell death (ICD)</td>
<td>DAMP release ↑; anti-tumor immunity ↑ (protocol/PS-dependent)</td>
<td>Inflammatory signaling ↑ locally</td>
<td>G</td>
<td>Systemic immune leverage</td>
<td>PDT can trigger ICD and stimulate adaptive immune responses, but this is highly dependent on photosensitizer and protocol.</td>
</tr>
<tr>
<td>7</td>
<td>Inflammation & cytokine wave (acute)</td>
<td>Local cytokines ↑; immune cell recruitment ↑</td>
<td>Local inflammation ↑</td>
<td>R, G</td>
<td>Microenvironment remodeling</td>
<td>Post-PDT inflammation can support tumor clearance or, if suboptimal, contribute to repair/regrowth; protocol matters.</td>
</tr>
<tr>
<td>8</td>
<td>Combination leverage (radiation/chemo/immunotherapy)</td>
<td>Sensitization ↑ (context-dependent)</td>
<td>—</td>
<td>G</td>
<td>Adjunct synergy</td>
<td>PDT is often paired with other modalities; strongest logic is local tumor kill + immune priming + improved control of residual disease.</td>
</tr>
<tr>
<td>9</td>
<td>Light penetration depth constraint</td>
<td>Deep tumors harder to treat (limited light reach)</td>
<td>—</td>
<td>—</td>
<td>Translation constraint</td>
<td>Most activation light has limited tissue penetration; strategies include fiber optics, endoscopic delivery, or NIR-shifted PS designs.</td>
</tr>
<tr>
<td>10</td>
<td>Photosensitizer PK & phototoxicity risk</td>
<td>PS accumulation affects selectivity</td>
<td>Skin/eye photosensitivity risk (agent-dependent)</td>
<td>R, G</td>
<td>Clinical constraint</td>
<td>Systemic photosensitizers can cause prolonged photosensitivity; topical/ALA-based approaches reduce systemic exposure in some uses.</td>
</tr>
</table>
<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (photoactivation + ROS burst)</li>
<li><b>R</b>: 30 min–3 hr (vascular effects, acute stress signaling)</li>
<li><b>G</b>: >3 hr (cell-death completion, immune recruitment, ICD outcomes)</li>
</ul>
<br>
<br>
<b>Common Clinical Photosensitizers for Cancer PDT</b>
<!-- Common Clinical Photosensitizers for Cancer PDT -->
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Photosensitizer</th>
<th>Class</th>
<th>Activation Wavelength (nm)</th>
<th>Penetration Depth*</th>
<th>Photosensitivity Duration</th>
<th>Typical Clinical Use</th>
<th>Notes</th>
</tr>
<tr>
<td>5-ALA (→ Protoporphyrin IX)</td>
<td>Endogenous porphyrin precursor</td>
<td>~630–635 nm</td>
<td>Shallow–Moderate (~2–5 mm)</td>
<td>Short (24–48 hrs; topical shorter)</td>
<td>Skin cancers, actinic keratosis, bladder, glioma visualization</td>
<td>Prodrug converted intracellularly to PpIX; good tumor selectivity; minimal prolonged systemic photosensitivity.</td>
</tr>
<tr>
<td>Porfimer sodium (Photofrin®)</td>
<td>First-generation porphyrin</td>
<td>~630 nm</td>
<td>Moderate (~5–10 mm)</td>
<td>Long (4–6 weeks)</td>
<td>Esophageal, lung, bladder cancers</td>
<td>Prolonged skin photosensitivity is a major limitation.</td>
</tr>
<tr>
<td>Temoporfin (Foscan®)</td>
<td>Chlorin</td>
<td>~652 nm</td>
<td>Moderate (~5–10 mm)</td>
<td>2–3 weeks</td>
<td>Head & neck cancers</td>
<td>Higher potency than Photofrin; improved absorption spectrum.</td>
</tr>
<tr>
<td>Verteporfin (Visudyne®)</td>
<td>Benzoporphyrin derivative</td>
<td>~689 nm</td>
<td>Moderate–Deeper (~5–10+ mm)</td>
<td>Short (few days)</td>
<td>Primarily ophthalmology; investigated in oncology</td>
<td>Better red/NIR absorption; shorter photosensitivity window.</td>
</tr>
<tr>
<td>Talcaporfin sodium (Laserphyrin®)</td>
<td>Chlorin derivative</td>
<td>~664 nm</td>
<td>Moderate (~5–10 mm)</td>
<td>Short (~1–2 weeks)</td>
<td>Lung, brain tumors (Japan)</td>
<td>Improved safety vs first-generation porphyrins.</td>
</tr>
<tr>
<td>Methylene Blue</td>
<td>Phenothiazine dye</td>
<td>~660–670 nm</td>
<td>Shallow–Moderate</td>
<td>Short</td>
<td>Experimental oncology; antimicrobial PDT</td>
<td>Strong Type I ROS contribution; also has redox cycling effects without light.</td>
</tr>
<tr>
<td>Hypericin</td>
<td>Natural anthraquinone</td>
<td>~590–600 nm</td>
<td>Shallow</td>
<td>Variable</td>
<td>Investigational</td>
<td>High singlet oxygen yield; hydrophobic; not widely used clinically.</td>
</tr>
</table>
<p><small>
*Penetration depth depends on wavelength, tissue optical properties, and light delivery method. Red/NIR light (~650–700 nm) penetrates deeper than blue/green light.
</small></p>