Two phthalocyanine derivatives tetra-peripherally substituted with tert-butylsulfonyl groups and coordinating either zinc(II) or platinum(II) ions have been synthesized and subsequently investigated in terms of their optical and photochemical properties, as well as biological activity in cellular, tissue-engineered, and animal models. Our research has revealed that both synthesized phthalocyanines are effective generators of reactive oxygen species (ROS). PtSO₂tBu demonstrated an outstanding ability to generate singlet oxygen (Φ_Δ = 0.87-0.99), while ZnSO₂tBu in addition to ¹O₂ (Φ_Δ = 0.45-0.48) generated efficiently other ROS, in particular ·OH. Considering future biomedical applications, the affinity of the tested phthalocyanines for biological membranes (partition coefficient; log P_ow) and their primary interaction with serum albumin were also determined. To facilitate their biological administration, a water-dispersible formulation of these phthalocyanines was developed using Pluronic triblock copolymers to prevent self-aggregation and improve their delivery to cancer cells and tissues. The results showed a significant increase in cellular uptake and phototoxicity when phthalocyanines were incorporated into the customizable polymeric micelles. Moreover, the improved distribution in the body and photodynamic efficacy of the encapsulated phthalocyanines were investigated in hiPSC-delivered organoids and BALB/c mice bearing CT26 tumors. Both photosensitizers exhibit strong antitumor activity. Notably, vascular-targeted photodynamic therapy (V-PDT) led to complete tumor eradication in 84% of ZnSO₂tBu and 100% of PtSO₂tBu-treated mice, and no recurrence has so far been observed for up to five months after treatment. In the case of PtSO₂tBu, the effect was significantly stronger, offering a wider range of light doses suitable for achieving effective PDT.

Novel hybrid TiO₂-based materials were obtained by adsorption of two different porphyrins on the surface of nanoparticles—commercially available 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (TPPS) and properly modified metalloporphyrin—5,10,15,20-tetrakis(2,6-difluoro-3-sulfophenyl)porphyrin palladium(II) (PdF₂POH). The immobilization of porphyrins on the surface of TiO₂ was possible due to the presence of sulfonyl groups. To further elevate the adsorption of porphyrin, an anchoring linker—4-hydroxybenzoic acid (PHBA)—was used. The synthesis of hybrid materials was proven by electronic absorption spectroscopy, dynamic light scattering (DLS), and photoelectrochemistry. Results prove the successful photosensitization of TiO₂ to visible light by both porphyrins. However, the presence of the palladium ion in the modifier structure played a key role in strong adsorption, enhanced charge separation, and thus effective photosensitization. The incorporation of halogenated metalloporphyrins into TiO₂ facilitates the enhancement of the comprehensive characteristics of the investigated materials and enables the evaluation of their performance under visible light. The effectiveness of reactive oxygen species (ROS) generation was also determined. Porphyrin-based materials with the addition of PHBA seemed to generate ROS more effectively than other composites. Interestingly, modifications influenced the generation of singlet oxygen for TPPS but not hydroxyl radical, in contrast to PdF₂POH, where singlet oxygen generation was not influenced but hydroxyl radical generation was increased. Palladium (II) porphyrin-modified materials were characterized by higher photostability than TPPS-based nanostructures, as TPPS@PHBA-P25 materials showed the highest singlet oxygen generation and may be oxidized during light exposure. Photocatalytic activity tests with two model pollutants—methylene blue (MB) and the opioid drug tramadol (TRML)—confirmed the light dose-dependent degradation of those two compounds, especially PdF₂POH@P25, which led to the virtually complete degradation of MB.

Tetraphenyloporphyrin derivatives are a useful scaffold for developing new pharmaceuticals for photodynamic therapy (PDT) and the photodiagnosis (PD) of cancer. We synthesized new sulfonamide fluorinated porphyrin derivatives and investigated their potential as photosensitizers and real-time bioimaging agents for cancer. We found that 5,10,15,20-tetrakis-[2 ',3 ',5 ',6 '-tetrafluoro-4 '-methanesulfamidyl)phenyl]bacteriochlorin (F(4)BMet) has intense absorption and fluorescence in the near-infrared, efficiently generates singlet oxygen and hydroxyl radicals, has low toxicity in the dark, and high phototoxicity. We increased its bioavailability with encapsulation in Pluronic-based micelles, which also improved the photodynamic effect. F(4)BMet exhibits pH-dependent properties (lower pH promoted its aggregation), and a GlyGly buffer was used to effectively solubilize the compound. In vitro findings with 2D cell culture were complemented with human-induced pluripotent stem cell (hiPSC)-derived organoids. F(4)BMet in P123 micelles showed enhanced efficacy compared to F(4)BMet in the GlyGly formulation. F(4)BMet was further evaluated in real-time bioimaging and PDT of BALB/c mice bearing CT26 tumors. After i.v. injection, the photosensitizer was visible in the tumor area 3 h after injection. The most successful therapeutic approach proved to be tumor-targeted PDT using P123-encapsulated F(4)BMet illuminated 24 h after administration with a light dose of 42 J/cm(2), which led to a 30% long-term cure rate.

Biomolecule–photosensitizer conjugates have rapidly evolved into one of the most powerful strategies for improving the selectivity, efficacy, and translational potential of photodynamic therapy (PDT). By integrating photosensitizers (PSs) with carbohydrates, amino acids, peptides, aptamers, proteins, cofactors, vitamins or antibodies, these constructs overcome long-standing limitations of classical PDT, including poor solubility, insufficient tumour accumulation, and strong dependence on oxygen availability. Beyond enhancing receptor-mediated uptake and enabling precise interactions with the tumour microenvironment (TME), bioconjugation also modulates aggregation, photochemical properties, intracellular accumulation, and immune system activation. A particularly transformative trend is the emergence of supramolecular architectures in which photosensitizers form defined nanostructured aggregates with peptides or proteins. Once considered an undesirable phenomenon, aggregation is now recognized as a tenable feature that governs photochemical behaviour. Engineered aggregates can undergo environment-triggered disassembly to monomeric, photoactive states, or operate as semiconductor-like nanodomains capable of Type I reaction through symmetry-breaking charge separation. This shift toward oxygen-independent radical pathways offers a promising solution to the challenge of hypoxia, a hallmark of the TME that severely compromises conventional Type II PDT. Parallel advances in 3D experimental platforms such as tumour organoids and organ-on-chip systems provide physiologically relevant validation of these conjugates, enabling the assessment of penetration, subcellular localization, immunogenic cell death, and therapeutic synergy within realistic TME conditions. Collectively, the integration of biomolecular targeting with controlled supramolecular design is redefining the landscape of PDT. Future progress will depend on designing conjugates that retain high activity under hypoxia, engineering dynamic aggregate states, and systematically validating these systems in advanced TME-mimetic models. Together, these developments position biomolecule–photosensitizer conjugates as a versatile and increasingly less oxygen-dependent class of next-generation phototherapeutic agents.

Difluorinated sulfonamide porphyrin (F₂PGly) and bacteriochlorin (F₂BGly), modified by glycine residues, were synthesized and evaluated for photodynamic therapy (PDT). F₂PGly exhibits superior stability and singlet oxygen generation efficiency but features a low-intensity band in the red range (λ_max = 639 nm). In contrast, F₂BGly shows a favorable, red-shifted absorption spectrum (λ_max = 746 nm) that aligns well with phototherapeutic window, facilitating deeper tissue penetration. Moreover, it demonstrates reasonable photostability, necessary for the efficient generation of both singlet oxygen (type II) and oxygen-centered radicals (type I mechanism) which contributes to enhanced therapeutic efficacy. Importantly, the glycine modifications in F₂BGly enhance its uptake in MCF-7 cells, known for their resistance to PDT due to efflux transport proteins like LAT1, showing great potential in the cancer cell-targeted PDT. The glycine groups potentially enable F₂BGly to bypass these barriers, resulting in increased intracellular accumulation and more effective Reactive Oxygen Species (ROS) generation under illumination. In vivo studies indicated promising vascular-targeted PDT results, with real-time fluorescence imaging used to monitor photosensitizer distribution prior to irradiation. These findings suggest that F₂BGly is a promising photosensitizer candidate with enhanced cancer cell selectivity and photodynamic efficiency, meriting further exploration in targeted PDT applications for multiple types of cancers.