Selective antibacterial and antibiofilm activity of chlorinated hemicyanine against gram-positive bacteria.

Antibiotic-free therapies are highly needed due to the limited success of conventional approaches especially against biofilm related infections. In this direction, antimicrobial phototherapy, either in the form of antimicrobial photothermal therapy (aPTT) or antimicrobial photodynamic therapy (aPDT), have appeared to be highly promising candidates in recent years. These are local and promising approaches for antibiotic resistant bacterial infections and biofilms. Organic small photosensitizers (PSs) are extensively preferred in antimicrobial phototherapy applications as they offer a great opportunity to combine therapeutic action (aPTT, aPDT or both) with fluorescence imaging on a single molecule. In this study, the bactericidal effect of cationic chlorinated hemicyanine (Cl-Hem)-based type I PS, which can function as a dual aPDT/aPTT agent, was investigated on both planktonic cells and biofilms of different gram-positive (E. faecalis and S. epidermidis) and gram-negative bacteria (P. aeruginosa and K. pneumoniae) with and without 640 nm laser irradiation. Cl-Hem was shown to induce a selective phototheranostic activity against gram-positive bacteria (E. faecalis and S. epidermidis). Cl-Hem exhibited both dose and laser irradiation time dependent bactericidal effect on planktonic and biofilms of S. epidermidis. These results clearly showed that highly potent Cl-Hem can treat resistant microbial infections, while allowing fluorescence detection at the same time. High biofilm reduction observed with combined aPDT/aPTT action of Cl-Hem together with its non-cytotoxic nature points out that Cl-Hem is a promising PS for antibacterial and antibiofilm treatments.

A mitochondria-targeted chemiluminescent probe for detection of hydrogen sulfide in cancer cells, human serum and in vivo.

Hydrogen sulfide (H2S) as a critical messenger molecule plays vital roles in regular cell function. However, abnormal levels of H2S, especially mitochondrial H2S, are directly correlated with the formation of pathological states including neurodegenerative diseases, cardiovascular disorders, and cancer. Thus, monitoring fluxes of mitochondrial H2S concentrations both in vitro and in vivo with high selectivity and sensitivity is crucial. In this direction, herein we developed the first ever example of a mitochondria-targeted and H2S-responsive new generation 1,2-dioxetane-based chemiluminescent probe (MCH). Chemiluminescent probes offer unique advantages compared to conventional fluorophores as they do not require external light irradiation to emit light. MCH exhibited a dramatic turn-on response in its luminescence signal upon reacting with H2S with high selectivity. It was used to detect H2S activity in different biological systems ranging from cancerous cells to human serum and tumor-bearing mice. We anticipate that MCH will pave the way for development of new organelle-targeted chemiluminescence agents towards imaging of different analytes in various biological models.

Image-Guided Enhanced PDT/PTT Combination Therapy Using Brominated Hemicyanine-Loaded Folate Receptor-Targeting Ag2S Quantum Dots.

Tumor-targeting nanoparticles and phototherapies are the two major trends in tumor-specific, local cancer therapy with minimal side effects. Organic photosensitizers (PSs) usually offer effective photodynamic therapy (PDT) but require enhanced solubility and tumor-targeting, which may be provided by a nanoparticle. Near-infrared (NIR)-emitting Ag2S quantum dots may act as a delivery vehicle for the PS, NIR tracking agent, and as a phototherapy (PTT) agent. A combination of the two provides luminescent dual-phototherapy agents with tumor-specificity and image-guided and enhanced cytotoxicity as a result of synergistic PDT and PTT. In this study, brominated hemicyanine (Hemi-Br), a photosensitizer, was loaded onto folic acid (FA)-tagged, glutathione (GSH)-coated Ag2S quantum dots (AS-GSH QDs) to provide enhanced phototoxicity via a photodynamic and mild photothermal effect in folate receptor(+) cancer cell lines at clinically relevant 640 nm irradiation. Final particles (AS-GSH-FA/Hemi-Br) had a hydrodynamic size of 75.5 nm, dual emission at both 705 and 910 nm, and a 93% light-to-heat conversion efficiency under 640 nm laser irradiation. In vitro cytotoxicity studies were conducted with folate receptor (FR)-positive HeLa and -negative A549 cell lines to differentiate receptor-mediated uptake. Enhanced phototoxicity on HeLa cells was observed with AS-GSH-FA/Hemi-Br compared to free Hemi-Br and AS-GSH-FA QDs due to increased uptake of the photosensitizer via active targeting and combination therapy, which is especially visible at the safe dose of single agents. Upon irradiation with a 640 nm (300 mW, 0.78 W/cm2) laser for 5 min, the viability of the HeLa cells decreased from 64% to 42 and 25% when treated with free Hemi-Br, AS-GSH-FA, and AS-GSH-FA/Hemi-Br, respectively. Overall, AS-GSH-FA/Hemi-Br provides image-guided enhanced PDT/PTT, which may be adopted for different FR(+) tumors.

Development of a cysteine responsive chlorinated hemicyanine for image-guided dual phototherapy.

A cysteine (Cys) activatable chlorinated hemicyanine (Cl-Cys) was introduced as a tumour selective image-guided dual phototherapy agent. Cl-Cys exhibited a significant turn on response in its near-IR emission signal and activated its singlet oxygen generation as well as photothermal conversion potentials upon reacting with Cys. The laser irradiation of Cl-Cys induced significant cell death in cancer cells with high Cys level, while it stayed deactivated and non-emissive in a healthy cell line. A profound synergistic PDT/PTT effect was observed at high doses. Remarkably, Cl-Cys marks the first ever example of Cys-responsive small organic-based therapeutic agent and holds a great promise to develop new activity-based photosensitizers for dual phototherapy action.

Balanced Intersystem Crossing in Iodinated Silicon-Fluoresceins Allows New Class of Red Shifted Theranostic Agents.

Iodination of the silicon-fluorescein core revealed a new class of highly cytotoxic, red-shifted and water-soluble photosensitizer (SF-I) which is also fairly emissive to serve as a theranostic agent. Singlet oxygen generation capacity of SF-I was evaluated chemically, and up to 45% singlet oxygen quantum yield was reported in aqueous solutions. SF-I was further tested in triple negative breast (MDA MB-231) and colon (HCT-116) cancer cell lines, which are known to have limited chemotherapy options as well as very poor prognosis. SF-I induced efficient singlet oxygen generation and consequent photocytotoxicity in both cell lines upon light irradiation with a negligible dark toxicity while allowing cell imaging at the same time. SF-I marks the first ever example of a silicon xanthene-based photosensitizer and holds a lot of promise as a small-molecule-based theranostic scaffold.

Dual laser activatable brominated hemicyanine as a highly efficient and photostable multimodal phototherapy agent.

Dual phototherapy agents have attracted great interest in recent years as they offer enhanced cytotoxicity on cancer cells due to the synergistic effect of photodynamic and photothermal therapies (PDT/PTT). In this study, we demonstrate a brominated hemicyanine (HC-1), which is previously shown as mitochondria targeting PDT agent, can also serve as an effective photosensitizer for PTT for the first time under a single (640 nm or 808 nm) and dual laser (640 nm + 808 nm) irradiation. Generation of reactive oxygen species and photothermal conversion as a function of irradiation wavelength and power were studied. Both single wavelength irradiations caused significant phototoxicity in colon and cervical cancer cells after 5 min of irradiation. However, co-irradiation provided near-complete elimination of cancer cells due to synergistic action. This work introduces an easily accessible small molecule-based synergistic phototherapy agent, which holds a great promise towards the realization of local, rapid and highly efficient treatment modalities against cancer.