Balaji Babu

Photodynamic therapy (PDT) is a minimally invasive cancer treatment that works through the combined use of photosensitizers (PS), light, and molecular oxygen to generate reactive oxygen species. Several porphyrin-based photosensitizers have been clinically developed for PDT, with Photofrin being one of the most commonly used photosensitizers for tumor destruction. Several of the limitations associated with using porphyrins as photodynamic therapeutic agents include weak absorption in the therapeutic window, prolonged skin phototoxicity after photosensitizer administration, and variable composition. Porphyrins remain among the most extensively studied classes of PSs for PDT and aPDT (antimicrobial photodynamic therapy) because of their favorable photophysical characteristics. However, many photosensitizers have limited utility because of poor water solubility, aggregation in biological media, or suboptimal cellular uptake. In response to these challenges, recent efforts have increasingly emphasized rational molecular design to improve intrinsic water solubility while simultaneously enhancing their therapeutic performance. Although significant progress has been made with nanomaterials and hybrid systems, discrete water-soluble porphyrins remain a valuable molecular basis for the development of photosensitizers for both PDT and aPDT. Recent work on water-soluble porphyrin-based photosensitizers is discussed in the context of PDT, antimicrobial PDT, and selected theranostic applications, with emphasis on emerging strategies for their further development.

Multidrug-resistant (MDR) bacterial infections require alternative therapeutic strategies because effective new antibiotics are limited in availability. Skin and soft-tissue infections, in particular, demand surface-specific treatment approaches such as photoantimicrobial chemotherapy (PACT). Here, we report two structurally related pyrene-based photosensitizers, PyB and PyP, and evaluate their photophysical properties and blue-light (440 nm) activated antibacterial activity against Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA). We demonstrate enhanced singlet oxygen–mediated phototoxicity of PyP compared to PyB due to the presence of a triphenylphosphonium (TPP+) moiety. These results highlight how subtle molecular design modifications can be exploited for developing novel photoinduced antibacterial agents.

The photodynamic antimicrobial chemotherapy activity (PACT) properties of 3-pyridyl substituted tetraarylchlorin ( Chl1 ) and tetraarylbacteriochlorin ( BChl1 ) have been assessed against Gram-(+) S. aureus and Gram-(−) E. coli strains. The pyridyl nitrogens were quaternized with methyl iodide to form water-soluble tetracationic species ( Chl1-Q and BChl1-Q ) that are more suitable for use against Gram-(−) bacteria. Metal insertion reactions with a main-group heavy-atom ion, Sn(IV), were attempted to assess whether the singlet oxygen quantum yield and the PACT activity properties could be enhanced in this manner. This proved successful with the chlorin ligand ( Sn ^IV Chl1 ), but purification and characterization was problematic in the context of the bacteriochlorin. Upon photoirradiation with Thorlabs LEDs, Chl1 and Chl1-Q exhibited high Log ₁₀ reduction values of 8.98 against S. aureus , while Sn ^IV Chl1 exhibited Log ₁₀ reduction of 8.96 and 8.98 against both S. aureus and E. coli . This is noteworthy since neutral photosensitizers are normally ineffective against Gram-(−) strains. The cationic BChl1-Q species exhibits favorable photocytotoxicity towards S. aureus with a Log ₁₀ reduction value of 6.61.

Antimicrobial photodynamic therapy is an effective approach to counteract bacterial infections that are not possible to be treated through antibiotics. In this study, three cationic Sn(IV) porphyrins bearing triaryl phosphonium substituents (SnP1, SnP2, and SnP3) were synthesized and evaluated as antibacterial photosensitizers (PSs). All compounds exhibited efficient singlet oxygen generation with quantum yields (Φ_Δ) in the range of 0.72–0.78. Aggregation studies show reduced aggregation of SnP1 and SnP2 than SnP3. Lipophilicity (log P) values indicated that SnP2, containing fluoro substituents, possesses a balanced amphiphilic character favorable for effective bacterial uptake and antimicrobial activity. The photodynamic antibacterial activity (427 nm LED; 22 mW cm⁻²) of SnP1, SnP2 and SnP3 was evaluated against Escherichia coli (E. coli) and clinical methicillin-resistant Staphylococcus aureus (MRSA). SnP2 exhibited significant photoantimicrobial activity against both Gram-negative (E. coli) and Gram-positive (MRSA) bacteria with a log reduction of 8.7 at 10 μM and 8.5 at 20 nM, respectively. Overall, our study highlights the importance of structural tuning of lipophilicity and aggregation in enhancing the efficacy of Sn(IV)-porphyrin-based photosensitizers.

Antimicrobial resistance has emerged as a global threat to the treatment of infectious diseases. Antibacterial photodynamic therapy (aPDT) is a promising alternative approach and is highly suitable for the treatment of cutaneous bacterial infections through topical applications. aPDT relies on light-responsive compounds called photosensitizer (PS) dyes, which generate reactive oxygen species (ROS) when induced by light, thereby killing bacterial cells. Despite several previous studies in this area, the molecular details of targeting and cell death mediated by PS dyes are poorly understood. In this study, we further investigate the antibacterial properties of two water-soluble Sn(IV) tetrapyridylporphyrins that were quaternized with methyl and hexyl groups (1 and 2). In this follow-up study, we demonstrate that Sn(IV)-porphyrins can be photoexcited by blue light (a 427 nm LED) and exhibit various levels of bactericidal activity against both Gram-(+) and Gram-(-) strains of bacteria. Using localization studies through fluorescence microscopy, we show that 2 targets the bacterial membrane more effectively than 1 and exhibits comparatively higher aPDT activity. Using multiple fluorescence reporters, we demonstrate that photoactivation of 1 and 2 results in extensive collateral damage to the bacterial cells including DNA cleavage, membrane damage, and delocalization of central systems necessary for bacterial growth and division. In summary, this investigation provides deep insights into the mechanism of bacterial killing mediated by the Sn(IV)-porphyrins. Moreover, our approach offers a new method for evaluating the activity of PS, which may inspire the discovery of new PS with enhanced aPDT activity.

A Sn(IV) meso-tetra(4-methylthiolphenyl) N-confused porphyrin (4-Sn) complex was prepared to facilitate a comparison of the photophysicochemical and singlet oxygen photosensitiser properties of a series of Sn(IV) complexes of meso-4-methylthiolphenyl-substituted porphyrin, corrole, chlorin, and N-confused porphyrin. 4-Sn has an unusually high singlet oxygen quantum (Φ_Δ) yield of 0.88, markedly higher than the Φ_Δ values of the other complexes in this series. A Thorlabs M660L4 LED (280 mW · cm⁻²) was used to study the photodynamic activity of Sn-4 against the MCF-7 cancer cell line through irradiation at 660 nm for 30 min. The IC₅₀ value was calculated to be 1.4 (± 0.8) µM, markedly lower than the previously reported values for the rest of the series. Photodynamic antimicrobial activity was also determined against Staphylococcus aureus and Escherichia coli, and 4-Sn was found to deactivate both Gram-(+) and Gram-(−) bacteria despite the absence of cationic charges on the ligand structure.

A series of tetraarylchlorins with 3-methoxy-, 4-hydroxy- and 3-methoxy-4-hydroxyphenyl meso-aryl rings (1-3-Chl) and their Sn(IV) complexes (1-3-SnChl) were synthesized and characterized so that their potential utility as photosensitizer dyes for use in photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) can be assessed. The photophysicochemical properties of the dyes were assessed prior to in vitro PDT activity studies against MCF-7 breast cancer cells through irradiation with Thorlabs 625 or 660 nm LED for 20 min (240 or 280 mW·cm⁻²). PACT activity studies were performed against both planktonic bacteria and biofilms of Gram-(+) S. aureus and Gram-(−) E. coli upon irradiation with Thorlabs 625 and 660 nm LEDs for 75 min. The heavy atom effect of the Sn(IV) ion results in relatively high singlet oxygen quantum yield values of 0.69−0.71 for 1-3-SnChl. Relatively low IC₅₀ values between 1.1−4.1 and 3.8−9.4 µM were obtained for the 1-3-SnChl series with the Thorlabs 660 and 625 nm LEDs, respectively, during the PDT activity studies. 1-3-SnChl were also found to exhibit significant PACT activity against planktonic S. aureus and E. coli with Log₁₀ reduction values of 7.65 and >3.0, respectively. The results demonstrate that the Sn(IV) complexes of tetraarylchlorins merit further in depth study as photosensitizers in biomedical applications.

Photodynamic therapy (PDT) is a mode of treatment for different types of cancers, which involves a nontoxic photosensitizer (PS), a light source to activate the PS, and ground-state molecular oxygen (³O₂). Light activation of the PS leads to the generation of reactive oxygen species (ROS), which initiates a toxic effect on the surrounding cellular substrates, thereby destroying the cancerous cells. The commercially used PDT drug Photofrin^® which is a tetrapyrrolic porphyrin-based photosensitizer has drawbacks such as aggregation in water, prolonged skin photosensitivity, variability in chemical compositions, and minimal absorbance in the red-light region. Metallation of the porphyrin core with diamagnetic metal ions aids the photogeneration of singlet oxygen (ROS). Metalating with Sn(IV) provides a six-coordination octahedral geometry with trans-diaxial ligands. This approach suppresses aggregation in aqueous media and increases ROS generation upon light exposure due to the heavy atom effect. Bulky trans-diaxial ligation hinders the approach of the Sn(IV) porphyrins, thereby suppressing aggregation effects. In this review, we document the recently reported Sn(IV) porphyrinoids and their photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) activity properties. In a similar manner to PDT, the photosensitizer is used to kill the bacteria upon irradiation with light during PACT. Often, bacteria develop resistance against conventional chemotherapeutic drugs over time, decreasing their antibacterial properties. However, in the case of PACT, it is difficult to generate resistance against singlet oxygen produced by the photosensitizer.

A Sn(iv) porphyrin with a mitochondria targeting triphenylphosphonium moiety has a highΦ_Δvalue (ca.0.72) and does not aggregate in aqueous solution. The dye exhibits favorable photodynamic activity against MCF-7 cells with an IC₅₀value of 2.9 μM.