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 beta-cyclodextrin polymer (beta-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 beta-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 beta-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. Never-theless, we demonstrated that beta-CDp nanosponges possess similar PDT efficiency as the free drug in stroma-rich head and neck cancer multicellular spheroids. Overall, this study suggests that beta-CDp nanosponges are a strong candidate for in vivo studies as they have fewer off-target effects while providing a similar therapeutic response.

Automated summary

Photodynamic therapy is a multi-stage treatment that destroys cancerous and precancerous cells through light activation of a drug. The role of drug penetration in therapy has been unexplored until recently. This study demonstrates that nanosponges based on hypercrosslinked beta-cyclodextrin polymer can increase drug penetration in multicellular spheroids, providing a potential candidate for effective PDT.