Glycosylated Porphyrin Derivatives for Sonodynamic Therapy: ROS Generation and Cytotoxicity Studies in Breast Cancer Cells.

Sonodynamic therapy (SDT) is a promising alternative to photodynamic therapy for achieving site-specific cytotoxic therapy. Porphyrin derivative molecules have been reported extensively in photodynamic therapy. We have previously shown that the glycosylation of porphyrin-based sonosensitizers can enhance their cellular uptake. However, the sonodynamic potential of these water-soluble glycosylated porphyrins has not been investigated. In this study, we characterized the sonodynamic response of two water-soluble glycosylated porphyrin derivatives. Ultrasound (US) exposure was performed (1 MHz frequency, intensities of 0.05-1.1 W/cm2) for 0-3 min in continuous mode. Reactive oxygen species (ROS) generation was quantified via ultraviolet-visible (UV-vis) spectrophotometry. MTT assay was used to quantify cytotoxicity caused by sonodynamic effects from these derivatives in the human mammary carcinoma (SUM-159) cell line in vitro. ROS generation from the porphyrin derivatives was demonstrated at a concentration of 15 µM. No significant cytotoxic effects were observed with the sonosensitizer alone or US exposure alone over the tested range of intensities and duration. The free base porphyrin derivative caused 60-70% cell death, whereas the zinc-porphyrin derivative with Zn metal conjugation caused nearly 50% cytotoxicity when exposed at 0.6 W/cm2 intensity for 3 min. These studies demonstrate the potential of anticancer SDT with soluble glycosylated porphyrins.

Antibacterial Sonodynamic Therapy: Current Status and Future Perspectives.

Multidrug-resistant bacteria have emerged in both community and hospital settings, partly due to the misuse of antibiotics. The inventory of viable antibiotics is rapidly declining, and efforts toward discovering newer antibiotics are not yielding the desired outcomes. Therefore, alternate antibacterial therapies based on physical mechanisms such as light and ultrasound are being explored. Sonodynamic therapy (SDT) is an emerging therapeutic approach that involves exposing target tissues to a nontoxic sensitizing chemical and low-intensity ultrasound. SDT can enable site-specific cytotoxicity by producing reactive oxygen species (ROS) in response to ultrasound, which can be harnessed for treating bacterial infections. This approach can potentially be used for both superficial and deep-seated microbial infections. The majority of the sonosensitizers reported are nonpolar, exhibiting limited bioavailability and a high clearance rate in the body. Therefore, targeted delivery agents such as nanoparticle composites, liposomes, and microbubbles are being investigated. This article reviews recent developments in antibacterial sonodynamic therapy, emphasizing biophysical and chemical mechanisms, novel delivery agents, ultrasound exposure and image guidance strategies, and the challenges in the pathway to clinical translation.

BODIPY based red emitters: Synthesis, computational and biological studies.

Donor-Acceptor type BODIPYs with strong absorption and fluorescence in the red region (550-800 nm) are reported. The aromatic groups like N-butylcarbazole/ N-butylphenothiazine/ benzothiadiazole were attached to the C-8 position of the BODIPY core with furan or thiophene spacers. TD-DFT studies indicated significant charge distribution between C-8 aromatic heterocycles and BODIPY core in all the molecules. The in-vitro studies of the N-butylcarbazole substituted BODIPYs indicated significant localization in the endoplasmic reticulum and lysosomes of the cancer cells. The BODIPYs showed decent cytotoxicity after 48 h incubation period (14.9 to 31.8 µM) in HeLa and A549 cancer cells, indicating their potential application as theranostic agents.

Synthesis, Photophysical Properties and Computational Studies of beta-Substituted Porphyrin Dyads.

Beta-pyrrole-substituted porphyrin dyads connected by ethynyl linkage to N-butylcarbazole or triphenylamine donors are reported. Donor-π-acceptor type beta-substituted porphyrin dyads and their Zn(II) and Pd(II) complexes were characterized by MALDI-MS, NMR, UV-vis absorption, fluorescence and cyclic voltammetry techniques. The S1 emission dynamics were analyzed by time-resolved spectroscopy (TCSPC); dyads exhibited efficient energy transfer up to 93% from beta-donors (N-butylcarbazole or triphenylamine group) to the porphyrin core. The efficiency of energy transfer for the beta-substituted porphyrin dyads were much higher than those of the corresponding meso-substituted porphyrin dyads, reflecting enhanced communications between the beta-donors and the porphyrin core. The Pd(II) dyads, showed characteristic phosphorescence in the near IR region and very efficient singlet oxygen quantum yields (53-60%); these dyads are promising candidates for photocatalytic oxidations of organic compounds. The donor-acceptor interaction between the porphyrin core and the beta-donors was supported by the DFT studies in the porphyrin dyads.

Synthesis of Water-Soluble Thioglycosylated trans-A2B2 Type Porphyrins: Cellular Uptake Studies and Photodynamic Efficiency.

The synthesis of water-soluble thioglycosylated A2B2 type porphyrins and their zinc(II) complexes is reported. The water-soluble trans-A2B2 porphyrins were synthesized in two steps, via [2+2] condensation between thioglycosylated dipyrromethanes and aromatic aldehydes in 15-21% yields. The thioglycosylated trans-A2B2 porphyrins showed decent in vitro singlet oxygen generation, which was supported by the intracellular DCFDA study. The in vitro cellular investigations of thioglycosylated A2B2 porphyrins were carried out in lung cancer cells (A549) to test their photodynamic therapeutic (PDT) activity. The PDT study revealed significant cytotoxicities of porphyrins with IC50 values between 23.3 and 44.2 µM in the dark, whereas, after visible light exposure, the photosensitizers exhibited IC50 values around 11.1-23.8 µM. The water-soluble thioglycosylated zinc(II) porphyrins having two meso-N-butylcarbazole groups exhibited an excellent degree of photocytotoxicity (IC50 = 4.6-8.8 µM). The flow cytometry analysis revealed that cellular uptake and ROS (reactive oxygen species) generation efficiency of water-soluble thioglycosylated zinc(II) porphyrins were considerably higher than nonmetalated porphyrins. Confocal microscopy images displayed substantial distribution in the endoplasmic reticulum with partial colocalization in mitochondria and lysosomes of water-soluble thioglycosylated zinc(II) porphyrins in A549 cells.

Water soluble thioglycosylated BODIPYs for mitochondria targeted cytotoxicity.

The facile synthesis of water-soluble mitochondria targeting thioglycosylated BODIPYs is reported. Thioglycosylated BODIPYs were synthesized in 25-26% yields via thioglycosylated dipyrromethanes in four steps. The dipyrromethanes and thioglycosylated BODIPYs were characterized by various techniques including HRMS, NMR spectroscopy and X-ray crystallography. In-vitro cellular investigations in skin keratinocyte (HaCaT) and cervical (HeLa) cancer cells revealed significant cytotoxicities with IC50 values between 23.83 to 48.61 µM. The flow cytometry experiments revealed significant cellular uptake of thioglycosylated BODIPYs into HaCaT cells and thioglucosyl substituted BODIPY (9) showed higher cellular uptake and ROS generation than the rest of the molecules. The highlight of this study is the mitochondrial targeting by the neutral BODIPYs, as judged by the colocalization experiments using confocal microscopy.