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It remains a therapeutic challenge due to its high recurrence rate and resistance to conventional treatments. Photodynamic therapy (PDT) is an attractive, minimally invasive alternative that enables spatially controlled tumor ablation by activating photosensitizers (PS) with visible light, generating reactive oxygen species (ROS), mainly singlet oxygen (1O2), and inducing the targeted death of tumor cancer cells. However, due to poor aqueous solubility and aggregation of porphyrin-based PS, their clinical application is often limited. In this study, we report the biological evaluation of three thiopyridinium porphyrin\u2212cyclodextrin conjugates (Por-CD 1a\u22123a) designed to enhance solubility and cellular delivery while preserving photodynamic activity. In the UM-UC-3 human bladder cancer cell line, we demonstrate that these conjugates exhibit distinct cellular uptake kinetics. PS 1a was rapidly internalized, reaching early saturation within 2 h; PS 2a displayed a gradual and sustained accumulation up to 4 h; and PS 3a demonstrated significant uptake within 30\u201360 min followed by stabilization. None of the compounds induced significant cytotoxicity in the absence of light at concentrations of 5 or 10 \u03bcM, confirming their dark safety profile. After light irradiation, PS 1a\u22123a produced strong PDT effect, with cytotoxicity profiles directly linked to their absorption properties. PS 1a showed rapid and stable phototoxicity, PS 2a exhibited a slower cytotoxic response, and PS 3a caused intense early phototoxicity even after short incubation periods. These findings indicate that Por-CD conjugates possess favorable cellular internalization and strong PDT efficacy. The three derivatives emerge as promising candidates for optimizing PDT strategies targeting bladder cancer cells.<\/jats:p>","DOI":"10.1021\/acsabm.6c00053","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T15:08:04Z","timestamp":1773846484000},"page":"6880-6886","source":"Crossref","is-referenced-by-count":0,"title":["Smart Macrocycles: Cyclodextrin\u2212Porphyrin Photosensitizers for Photodynamic Therapy in Human Bladder Cancer Cells"],"prefix":"10.1021","volume":"9","author":[{"given":"Cl\u00e1udia P. S.","family":"Ribeiro","sequence":"first","affiliation":[{"name":"University of Aveiro , , ,","place":["Aveiro, Portugal, 3810-193"]},{"name":"Universidade de Lisboa , , ,","place":["Lisboa, Portugal, 1049-001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7828-2296","authenticated-orcid":true,"given":"Rosa","family":"Fernandes","sequence":"additional","affiliation":[{"name":"University of Coimbra , , ,","place":["Coimbra, Portugal, 3000-548"]},{"name":"University of Coimbra , , ,","place":["Coimbra, Portugal, 3000-548"]},{"name":"University of Coimbra , , ,","place":["Coimbra, Portugal, 3004-504"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1624-6825","authenticated-orcid":true,"given":"Leandro M. 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