To effectively combat advanced cancers, next-generation nanomedicines should combine both therapeutic and diagnostic functions. In this study, we developed stimulus-responsive theranostics systems based on micellar nanostructures that deliver derivatives of tetraphenylporphyrins (TPP) bound via tumor microenvironment-sensitive hydrazone bonds. These nanomedicines are engineered using a micelle-forming polymer-TPP conjugate, enabling the pH-sensitive activation of both photodynamic therapy (PDT) and fluorescence. Two pH-sensitive and one stable polymer-TPP conjugates were synthesized and characterized by size exclusion chromatography and TPP release rates. Micelle stability was evaluated using UV/vis spectroscopy, while fluorescence and singlet oxygen production were measured to determine their theranostics potential. Femtosecond transient absorption and time-correlated single photon counting techniques were employed for the photophysical evaluation of micellar systems. Compared to polymer conjugates where TPP is linked through nondegradable amide bonds, the pH-sensitive systems exhibit superior physicochemical properties. These micellar conjugates are highly stable, allowing prolonged circulation in the body while remaining in an "off" state, where fluorescence and singlet oxygen production are minimized. Overall, the hydrazone-linked conjugates display favorable properties that make them strong candidates for future anticancer theranostic applications.

Institute of Inorganic Chemistry Czech Academy of Sciences Řež 1001 Husinec Řež 250 68 Czech Republic

Institute of Macromolecular Chemistry Czech Academy of Sciences Prague 162 00 Czech Republic

Laboratory of Microbiology and Oncology Faculty of Pharmaceutical Sciences Sojo University Kumamoto 860 0082 Japan

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