Polymeric Theranostics with Tetraphenylporphyrin for Effective Low-Dose Photodynamic Cancer Therapy

Background/Objectives: Photodynamic therapy (PDT) relies on light activation of photosensitizers to generate reactive oxygen species for tumor ablation; however, limited tumor selectivity and systemic toxicity of free photosensitizers remain challenges. This study aimed to develop polymer-based nanotheranostics carrying tetraphenylporphyrin (TPPc) derivatives and to evaluate how linker structure impacts their performance. Methods: TPPc derivatives were covalently conjugated to N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymers via either pH-sensitive hydrazone linkages (using aliphatic 5-hydroxy-2-pentanone or aromatic 1-(4-hydroxymethyl)phenyl)ethanone spacer) or stable amide bonds, forming amphiphilic polymer conjugates. The conjugates were characterized based on their physicochemical and in vitro and in vivo biological behavior. Results: Polymer conjugation reduced dark toxicity while preserving photodynamic activity. Linker structure influenced intracellular behavior and singlet oxygen production, with hydrazone systems showing faster activation-related responses under acidic conditions in vitro. All conjugates accumulated in tumors and induced significant tumor growth inhibition after irradiation at low doses (2.5 mg kg−1 TPPc equivalent), while the amide-linked conjugate showed the strongest overall in vivo therapeutic effect, likely due to more favorable biodistribution and sustained delivery. Conclusions: The developed HPMA-based polymer–TPPc conjugates improve the therapeutic profile of photosensitizers by reducing toxicity and enabling effective PDT. These findings highlight the importance of linker design in balancing photosensitizer activation, circulation stability, and biodistribution, which together determine the overall therapeutic outcome.