Photochemical Internalization Techniques in Cancer Therapy

Photochemical internalisation (PCI) harnesses light-activated photosensitisers to induce transient disruption of endolysosomal membranes, enabling the release of macromolecular therapeutics directly into the cytosol. By combining sub-lethal photodynamic activation with targeted drug carriers, PCI overcomes intracellular sequestration and degradation of endocytosed agents, thereby enhancing the efficacy of cytotoxins, immunoconjugates, nucleic acids and nanoparticle-based medicines. This approach offers precise spatio-temporal control of drug delivery, minimises off-target effects and can potentiate immune responses through the release of danger-associated signals. Advances in photosensitiser chemistry, nanoparticle design and light delivery have expanded the applicability of PCI to deep-seated and complex tumour models. Moreover, integration with immune-checkpoint inhibitors and antitumour vaccines has revealed synergistic opportunities to improve clinical outcomes. Emerging preclinical and early clinical data support the translation of PCI as a versatile platform in oncology, offering renewed potential for drugs previously limited by poor intracellular bioavailability.

Research from Nature Portfolio

Innovative polymeric nanocarriers have been engineered to degrade under both acidic and light stimuli, enabling dual-triggered release of anticancer compounds upon PCI activation. These self-assembling polymers demonstrate tunable photolysis at clinically relevant wavelengths and, when co-delivered with porphyrin photosensitisers, achieve synergistic cytosolic release of drug payloads and reactive oxygen species, resulting in markedly increased tumour cell death in vitro. In a complementary study, a clinically approved chlorin photosensitiser was repurposed for PCI by conjugation to a cell-penetrating peptide. This modification redirected endolysosomal localisation, permitting light-induced membrane rupture and efficient cytosolic release of a nano-sized cytotoxin, thereby enhancing its antitumour potency without altering the photophysical properties of the photosensitiser.

Photochemical Internalization Techniques in Cancer Therapy publication trend

The graph below shows the total number of articles in photochemical internalization techniques in cancer therapy across all publications each year (not limited to Nature Index journals).

Technical terms

Photochemical internalisation (PCI): A technique that uses light-activated photosensitisers to disrupt endolysosomal membranes, releasing trapped therapeutics into the cytosol.

Photosensitiser: A molecule that, upon light activation, generates reactive oxygen species to induce photochemical effects.

Endolysosome: A cellular compartment formed by the fusion of endosomes and lysosomes where internalised molecules are typically degraded.

Reactive oxygen species (ROS): Highly reactive molecules produced by photosensitiser activation that mediate membrane damage.

Tumouroid: A three-dimensional in vitro model that mimics the architecture and microenvironment of solid tumours.

References

1. Light-enhanced VEGF121/rGel induce immunogenic cell death and increase the antitumor activity of αCTLA4 treatment. Frontiers in Immunology (2023).
2. Photochemical Internalization with Fimaporfin: Enhanced Bleomycin Treatment for Head and Neck Cancer. Pharmaceutics (2023).
3. Treatment of 3D In Vitro Tumoroids of Ovarian Cancer Using Photochemical Internalisation as a Drug Delivery Method. Biomedicines (2023).
4. Harnessing photochemical internalization with dual degradable nanoparticles for combinatorial photo–chemotherapy. Nature Communications (2014).
5. Endolysosomal targeting of a clinical chlorin photosensitiser for light-triggered delivery of nano-sized medicines. Scientific Reports (2017).