ADDRESSING CHALLENGES IN PHOTODYNAMIC THERAPY: FROM TUMOR HYPOXIA TO MULTIDRUG-RESISTANT BACTERIA

Photodynamic therapy (PDT) is often described as the outcome of a simple triad: photosensitizer (PS), light, and oxygen. However, its efficacy can be limited by oxygen deprivation in solid tumors and by insufficient PS activity against drug-resistant bacteria. Here, we discuss how molecular design and formulation can tune photodynamic performance to address these distinct biological challenges. Manganese carbonyl complexes (Mn-pbiH and Mn-pby) and liposomal metalloporphyrazines (MgCF₃Pz and ZnCF₃Pz) were evaluated in hypoxic breast cancer cells (MDA-MB-231 and MCF-7). Both manganese complexes showed enhanced phototoxicity under hypoxia. In MDA-MB-231 cells, the phototoxicity index (PI; dark IC₅₀/irradiated IC₅₀) increased from 2.08 to 10.87 for Mn-pbiH and from 1.95 to 7.91 for Mn-pby. Corresponding increases in MCF-7 cells were from 2.74 to 4.83 and from 1.67 to 3.48, respectively. In contrast, the PI of protoporphyrin IX (PpIX) decreased approximately 20-fold in hypoxic MCF-7 cells, from 89.48 to 4.46, consistent with the expected loss of efficacy for an oxygen-dependent PS. Metalloporphyrazines showed cell-dependent responses: PI decreased under hypoxia in MDA-MB-231 cells but increased in MCF-7 cells, where ZnCF₃Pz increased from 40.1 to 113. Methylene blue (MB) derivatives bearing pyrrolidine, piperidine, dibutylamine, methylpiperazine, or naphthylmethylpiperazine side chains were evaluated against methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Neisseria gonorrhoeae. At 630 ± 20 nm and 100 J cm⁻², MB-piperidine and MB-dibutylamine produced ≥3-log₁₀ reductions in viable counts for all species. This effect was achieved at 2.5 μM in P. aeruginosa and N. gonorrhoeae, but required 20 μM in MRSA. At 1 μM, MB-naphthylmethylpiperazine selectively produced ≥4-log₁₀ reductions in the Gram-negative strains P. aeruginosa and N. gonorrhoeae, but not against Gram-positive MRSA. Remarkably, MB–methylpiperazine (1 μM) achieved a ≥5-log₁₀ reduction against P. aeruginosa only, with no comparable photoinactivation observed for other gram-negative or gram-positive strains tested. Overall, these results show that PS structure and formulation dictate photodynamic performance in a target-dependent manner, supporting the rational design of systems for hypoxic tumors and drug-resistant bacterial infections.