Erlotinib-Modified BODIPY Photosensitizers for Targeted Photodynamic Therapy

Photodynamic therapy (PDT) is an innovative, non-invasive and highly selective therapeutic modality for tumours and non-malignant diseases. BODIPY based molecules can function as new generation photosensitizers (PSs) in various PDT applications. Despite numerous conjugated PS systems are available, BODIPYs containing erlotinib lagged behind other photosensitizer units. In this study, smart photosensitizers containing BODIPY, erlotinib and hydrophilic units were prepared for the first time, their physicochemical properties and PDT effects were investigated. Compared with non-halogenated compound, halogenated derivatives possessed much lower fluorescence profile as well as the good ROS generation ability under red light. In vitro PDT studies were performed on both healthy (PNT1a) and prostate cancerous cells (PC3) to determine the selectivity of the compounds on cancerous cells and their effects under light. The halogenated conjugates, exposed to low dose of light illumination exhibited potent activity on cancer cell viability and the calculated IC₅₀ values proved the high phototoxicity of the photosensitizers. It was also determined that the PSs have very low dark toxicity and that the light illumination and ROS formation are required for the initiation of the cell death mechanism. As a result, erlotinib modified BODIPYs could serve as promising agents in anticancer photodynamic therapy.     

hERG Optimization of Benzofuro−Pyridine and Pyrazino−Indole Derivatives as MCHR1 Antagonists

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the antagonists of melanin concentrating hormone receptor 1 (MCHR1). The design, synthesis, and biological studies of novel MCHR1 antagonists based on benzofuro−pyridine and pyrazino−indole scaffold was performed. We confirmed that fine-tuning lipophilicity and basic pK_a by modifying the benzyl group and introducing different substituents on the aliphatic nitrogen sidechain decreases both hERG inhibition and metabolic clearance. We have succeeded to develop excellent in vitro parameters in the case of compounds 17 (4-[(5-chloropyridin-2-yl)methoxy]-1-[4-(2-hydroxyethyl)-8-oxa-4-azatricyclo[7.4.0.0²,⁷]trideca-1(13),2(7),9,11-tetraen-11-yl]-1,2-dihydropyridin-2-one monohydrochloride) and 23 g (4-[(5-chloropyridin-2-yl)methoxy]-1-(1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)pyridin-2(1H)-one monohydrochloride), which can be considered as valuable tools for further pharmacological investigation.     

A Novel Strategy as a Potential Rapid Therapy Modality in the Treatment of Corneal Ulcers: Fluconazole/Vancomycin Dual Drug-Loaded Nanofibrous Patches

Corneal ulcer, which is brought on by a breach in the epithelial barrier, is a dangerous infection of the avascular corneal stroma. New treatment strategies are needed, suppressing the aggressive nature of the disease and including a combination of different drugs. In this study, vancomycin (VAN) and fluconazole (FLU) dual-drug loaded dual-layered polyvinyl alcohol and gelatin (PVA/GEL) nanofibrous patches are produced by electrospinning. Scanning electron microscopy (SEM) images show smooth surfaces are obtained for both pure and drug-loaded nanofibrous patches. The tensile test results report that loading the FLU and VAN separately into the PVA/GEL patches decrease both the tensile strength and elongation at break and it is further reduced when combining two drug-loaded layers in one patch. According to drug release results, the FLU and VAN-loaded nanofibrous patches show a controlled release profile extending up to 96 h. Moreover, PVA/GEL/FLU, PVA/GEL/VAN, and PVA/GEL/FLU/VAN nanofibrous patches display significant antimicrobial activity against Candida albicans and Staphylococcus aureus. SEM, 4'-6diamidynofenyloindol (DAPI) staining, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay show that PVA/FLU and PVA/GEL/FLU/VAN nanofibrous patches have a superior effect on NIH3T3 cell spreading and proliferation. The novelty of this study lays in the development of a potential dual drug rapid treatment for corneal ulcers of aggressive nature.