Highly Efficient Singlet Oxygen Generators Based on Ruthenium Phthalocyanines: Synthesis, Characterization and in vitro Evaluation for Photodynamic Therapy.

Invited for the cover of this issue is the group of Torres at the University of Madrid. The image of the cover of this issue depicts cancer cells being destroyed by reactive singlet oxygen produced by ruthenium phthalocyanine glycoconjugates under red light. The work, developed at the Universities of Madrid, Aveiro, Lisbon and Coimbra, describes ruthenium phthalocyanines as powerful bladder cancer PDT agents. Read the full text of the article at 10.1002/chem.201903546.

Highly Efficient Singlet Oxygen Generators Based on Ruthenium Phthalocyanines: Synthesis, Characterization and in vitro Evaluation for Photodynamic Therapy.

The synthesis of ruthenium(II) phthalocyanines (RuPcs) endowed with one carbohydrate unit-that is, glucose, galactose and mannose-and a dimethylsulfoxide (DMSO) ligand at the two axial coordination sites, respectively, is described. Two series of compounds, one unsubstituted at the periphery, and the other one bearing eight PEG chains at the isoindole meta-positions, have been prepared. The presence of the axial DMSO unit significantly increases the phthalocyanine singlet oxygen quantum yields, related to other comparable RuPcs. The compounds have been evaluated for PDT treatment in bladder cancer cells. In vitro studies have revealed high phototoxicity for RuPcs unsubstituted at their periphery. The phototoxicity of PEG-substituted RuPcs has been considerably improved by repeated light irradiation. The choice of the axial carbohydrate introduced little differences in the cellular uptake for both series of photosensitizers, but the phototoxic effects were considerably higher for compounds bearing mannose units.

Mitochondria-Targeted Photodynamic Therapy with a Galactodendritic Chlorin to Enhance Cell Death in Resistant Bladder Cancer Cells.

Here, we report the rational design of a new third-generation photosensitizer (PS), a chlorin conjugated with galactodendritic units, ChlGal8, to improve the effectiveness of bladder cancer treatment. ChlGal8 shows better photochemical and photophysical properties than a recently reported homologous porphyrin, PorGal8. In addition to inheriting excellent photostability, the ability to generate singlet oxygen, and the ability to interact with the proteins galectin-1 and human serum albumin (HSA), ChlGal8 exhibits high absorption in the red region of the electromagnetic spectrum. In vitro studies of anticancer activity of ChlGal8 revealed that once this PS is taken up by UM-UC-3 bladder cancer cells, it induces high cytotoxicity after a single dose of light irradiation. In HT-1376 bladder cancer cells resistant to therapy, a second light irradiation treatment enhanced in vitro and in vivo photodynamic efficacy. The enhanced phototoxicity in HT-1376 cancer cells seems to be due to the ability of ChlGal8 to accumulate in the mitochondria, via facilitative glucose transporter 1 (GLUT1), in the period between single and repeated irradiation. A photodynamic therapy (PDT) regimen using an extra dose of light irradiation and ChlGal8 as PS represents a promising strategy in treating resistant cancers in a clinical setting.

The role of galectin-1 in in vitro and in vivo photodynamic therapy with a galactodendritic porphyrin.

Conventional photodynamic agents used in clinic are porphyrin-based photosensitizers. However, they have low tumour selectivity, which may induce unwanted side-effects and damage to healthy tissues. In this study, we used a porphyrin with dendritic units of galactose (PorGal8) developed by us, which can target the galactose-binding protein, galectin-1, known to be overexpressed in many tumour tissues. In vitro and in vivo studies had been conducted for the validation of PorGal8 effectiveness. We showed a specific uptake of PorGal8 and induction of apoptotic cell death by generating oxidative stress and alterations in the cytoskeleton of bladder cancer cells overexpressing galectin-1. We further validated the photodynamic efficiency of PorGal8 in athymic nude mice (Balb/c nu/nu) bearing subcutaneously implanted luciferase-positive bladder cancer xenografts, overexpressing galectin-1 protein. PorGal8 (5 µmol/kg, intraperitoneal), injected 24 h before light delivery (50.4 J/cm2), inhibited tumour growth. We conclude that the use of PorGal8 enables selective target and cytotoxicity by photodynamic therapy in cancer cells overexpressing galectin-1, preventing undesired phototoxicity in the surrounding healthy tissues.

Dual functionality of phosphonic-acid-appended phthalocyanines: inhibitors of urokinase plasminogen activator and anticancer photodynamic agents.

Phthalocyanines (Pcs) bearing phosphonic acid groups at the periphery exhibit a potential photodynamic effect to induce phototoxicity on human bladder cancer epithelial cells (UM-UC-3). In vitro photophysical and biological studies show high intrinsic ability to inhibit the activity of urokinase plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9).

Galactodendritic phthalocyanine targets carbohydrate-binding proteins enhancing photodynamic therapy.

Photosensitizers (PSs) are of crucial importance in the effectiveness of photodynamic therapy (PDT) for cancer. Due to their high reactive oxygen species production and strong absorption in the wavelength range between 650 and 850 nm, where tissue light penetration is rather high, phthalocyanines (Pcs) have been studied as PSs of excellence. In this work, we report the evaluation of a phthalocyanine surrounded by a carbohydrate shell of sixteen galactose units distributed in a dendritic manner (PcGal16) as a new and efficient third generation PSs for PDT against two bladder cancer cell lines, HT-1376 and UM-UC-3. Here, we define the role of galacto-dendritic units in promoting the uptake of a Pc through interaction with GLUT1 and galectin-1. The photoactivation of PcGal16 induces cell death by generating oxidative stress. Although PDT with PcGal16 induces an increase on the activity of antioxidant enzymes immediately after PDT, bladder cancer cells are unable to recover from the PDT-induced damage effects for at least 72 h after treatment. PcGal16 co-localization with galectin-1 and GLUT1 and/or generation of oxidative stress after PcGal16 photoactivation induces changes in the levels of these proteins. Knockdown of galectin-1 and GLUT1, via small interfering RNA (siRNA), in bladder cancer cells decreases intracellular uptake and phototoxicity of PcGal16. The results reported herein show PcGal16 as a promising therapeutic agent for the treatment of bladder cancer, which is the fifth most common type of cancer with the highest rate of recurrence of any cancer.

Plants with neurobiological activity as potential targets for drug discovery.

Significant number of studies has been performed to find alternatives or treatments for diseases of the nervous forum by identifying structures with activity at the central nervous system (CNS). However most of the screenings are usually conducted on an ad hoc basis and not systematically. The initial purpose of this review was to screen plants with neurological bioactivity, in particular those that have not been fully studied and that have molecular mechanisms whose active constituents responsible for the activity remain to be identified. The second purpose was to identify potential target plants for future studies of new and alternative therapies for the treatment of neurological disorders and neurodegenerative diseases. All plants considered in this review were selected for three qualities: possible molecular requirements to act at the CNS; representative of the main classes of compounds with the referred bioactivity and the major families containing species with those compounds; and diffuse world distribution. We identified several examples of plants that have potential for further study. We have included the main families of these plants, their known molecular mechanisms involved in neurological bioactivity, and the active constituents responsible for such activity. Also included is a brief discussion about the requirements of the different compounds to reach the CNS. These requirements may be less limited than what researchers have previously thought.