Phototoxicity of temoporfin-loaded cyclodextrin nanosponges in stroma-rich three-dimensional models of head and neck cancer.

Photodynamic therapy is a multistage treatment, in which cancerous and precancerous cells are destroyed by light activation of a drug (photosensitizer). For a long time, high cellular uptake of the photosensitizer was an important indication of efficient PDT, while the role of photosensitizer penetration was unexplored. Recently, we have demonstrated that nanosponges based on hypercrosslinked β-cyclodextrin polymer (β-CDp) can increase drug penetration at the cost of their cellular uptake in multicellular spheroids, paving the way for studying the impact of penetration on PDT response. In the present work, we used β-CDp nanosponges to deliver temoporfin to the depth of stroma-rich head and neck cancer multicellular spheroids and then assess PDT response. Encapsulation of temoporfin in β-CDp nanosponges resulted in increased penetration and more uniform distribution of temoporfin in spheroids, however, was also associated with a two-fold reduction of cellular uptake compared to the free drug. Nevertheless, we demonstrated that β-CDp nanosponges possess similar PDT efficiency as the free drug in stroma-rich head and neck cancer multicellular spheroids. Overall, this study suggests that β-CDp nanosponges are a strong candidate for in vivo studies as they have fewer "off-target" effects while providing a similar therapeutic response.