Amphiphilic Chlorin‐β‐cyclodextrin Conjugates in Photo‐Triggered Drug Delivery: The Role of Aggregation

• Published in: ChemPlusChem (Weinheim, Germany) Vol. 89; no. 6; pp. e202300743 - n/a
• Main Authors: Panagiotakis, Stylianos, Mavroidi, Barbara, Athanasopoulos, Alexandros, Charalambidis, Georgios, Coutsolelos, Athanassios G., Pelecanou, Maria, Yannakopoulou, Konstantina
• Format: Journal Article
• Language: English
• Published: Germany 01.06.2024
• Subjects: Aggregation; beta-Cyclodextrins - chemistry; Cell Survival - drug effects; chlorin; conjugates; cyclodextrins; Drug Carriers - chemistry; drug delivery; Drug Delivery Systems; Humans; Light; MCF-7 Cells; PCI; Photosensitizing Agents - chemistry; Photosensitizing Agents - pharmacology; Porphyrins - chemistry; Singlet Oxygen - chemistry; Singlet Oxygen - metabolism; Tamoxifen - chemistry; Tamoxifen - pharmacology; Aggregation; chlorin; conjugates; drug delivery; cyclodextrins; PCI
• ISSN: 2192-6506; 2192-6506
• DOI: 10.1002/cplu.202300743

Conjugates of chlorins with β‐cyclodextrin connected either directly or via a flexible linker were prepared. In aqueous medium these amphiphilic conjugates were photostable, produced singlet oxygen at a rate similar to clinically used temoporfin and formed irregular nanoparticles via aggregation. Successful loading with the chemotherapeutic drug tamoxifen was evidenced in solution by the UV‐Vis spectral changes and dynamic light scattering profiles. Incubation of MCF‐7 cells with the conjugates revealed intense spotted intracellular fluorescence suggestive of accumulation in endosome/lysosome compartments, and no dark toxicity. Incubation with the tamoxifen‐loaded conjugates revealed also practically no dark toxicity. Irradiation of cells incubated with empty conjugates at 640 nm and 4.18 J/cm2 light fluence caused >50 % cell viability reduction. Irradiation following incubation with tamoxifen‐loaded conjugates resulted in even higher toxicity (74 %) indicating that the produced reactive oxygen species had triggered tamoxifen release in a photochemical internalization (PCI) mechanism. The chlorin‐β‐cyclodextrin conjugates displayed less‐lasting effects with time, compared to the corresponding porphyrin‐β‐cyclodextrin conjugates, possibly due to lower tamoxifen loading of their aggregates and/or their less effective lodging in the cell compartments’ membranes. The results suggest that further to favorable photophysical properties, other parameters are important for the in vitro effectiveness of the photodynamic systems. Differently aggregated chlorin‐βCD conjugates loaded with the drug tamoxifen accumulate in MCF‐7 cells’ endosome/lysosome compartments. Upon irradiation, ROS generation and photo‐release of tamoxifen ensues. The combined photo‐/chemo‐ toxicity reduces the cell viability up to 74 %. Comparison with the corresponding porphyrin‐βCD conjugates highlights the formation of aggregates as a factor that impacts the in vitro effectiveness of the photodynamic systems.