Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy

The utilization of Photodynamic Therapy (PDT) for the treatment of various types of cancer has gained increasing attention over the last decades. Despite the clinical success of approved photosensitizers (PSs), their application is limited due to poor water solubility, aggregation, photodegradation, and slow clearance from the body. To overcome these drawbacks, research efforts are devoted towards the development of metal complexes and especially Ru(II) polypyridine complexes based on their attractive photophysical and biological properties. Despite the recent research developments, the vast majority of complexes utilize blue or UV-A light to obtain a PDT effect, limiting the penetration depth inside the tissue and therefore, the possibility to treat deep-seated or large tumors. To circumvent these drawbacks, we present the first example of the DFT guided search for efficient PDT PSs with a substantial spectral red shift towards the biological spectral window. Thanks to this design, we have unveiled a Ru(II) polypyridine complex, which causes phototoxicity in the very-low micromolar-to-nanomolar range at clinically relevant 595 nm, in monolayer cells as well as in 3D multicellular tumor spheroids.<br>

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Ruthenium Complexes for 1- and 2-Photon Photodynamic Therapy: From In Silico Prediction to In Vivo Applications

10.26434/chemrxiv.11767995 ◽

2020 ◽

Author(s):

Johannes Karges ◽

Shi Kuang ◽

Federica Maschietto ◽

Olivier Blacque ◽

Ilaria Ciofini ◽

...

Keyword(s):

Photodynamic Therapy ◽

In Silico ◽

Aqueous Solubility ◽

The Body ◽

Photon Absorption ◽

Multicellular Tumor Spheroids ◽

Spectral Window ◽

Photon Excitation ◽

Polypyridine Complexes

<div>The use of photodynamic therapy (PDT) against cancer has received increasing attention overthe recent years. However, the application of the currently approved photosensitizers (PSs) is somehow limited by their poor aqueous solubility, aggregation, photobleaching and slow clearance from the body. To overcome these limitations, there is a need for the development of new classes of PSs with ruthenium(II) polypyridine complexes currently gaining momentum. However, these compounds generally lack significant absorption in the biological spectral window, limiting their application to treat deep-seated or large tumors. To overcome this drawback, ruthenium(II) polypyridine complexes designed in silico with (E,E’)-4,4´-bisstyryl 2,2´-bipyridine ligands showed impressive 1- and 2-Photon absorption up to a magnitude higher than the ones published so far. While non-toxic in the dark, these compounds were found phototoxic in various 2D monolayer cells, 3D multicellular tumor spheroids and be able to eradicate a multiresistant tumor inside a mouse model upon clinically relevant 1-Photon and 2 Photon excitation.</div>

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Ruthenium Complexes for 1- and 2-Photon Photodynamic Therapy: From In Silico Prediction to In Vivo Applications

10.26434/chemrxiv.11767995.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Johannes Karges ◽

Shi Kuang ◽

Federica Maschietto ◽

Olivier Blacque ◽

Ilaria Ciofini ◽

...

Keyword(s):

Photodynamic Therapy ◽

In Silico ◽

Aqueous Solubility ◽

The Body ◽

Photon Absorption ◽

Multicellular Tumor Spheroids ◽

Spectral Window ◽

Photon Excitation ◽

Polypyridine Complexes

<div>The use of photodynamic therapy (PDT) against cancer has received increasing attention overthe recent years. However, the application of the currently approved photosensitizers (PSs) is somehow limited by their poor aqueous solubility, aggregation, photobleaching and slow clearance from the body. To overcome these limitations, there is a need for the development of new classes of PSs with ruthenium(II) polypyridine complexes currently gaining momentum. However, these compounds generally lack significant absorption in the biological spectral window, limiting their application to treat deep-seated or large tumors. To overcome this drawback, ruthenium(II) polypyridine complexes designed in silico with (E,E’)-4,4´-bisstyryl 2,2´-bipyridine ligands showed impressive 1- and 2-Photon absorption up to a magnitude higher than the ones published so far. While non-toxic in the dark, these compounds were found phototoxic in various 2D monolayer cells, 3D multicellular tumor spheroids and be able to eradicate a multiresistant tumor inside a mouse model upon clinically relevant 1-Photon and 2 Photon excitation.</div>

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Synthesis, Characterization, and Biological Evaluation of Red-Absorbing Fe(II) Polypyridine Complexes

Inorganics ◽

10.3390/inorganics7010004 ◽

2019 ◽

Vol 7 (1) ◽

pp. 4 ◽

Cited By ~ 20

Author(s):

Johannes Karges ◽

Philippe Goldner ◽

Gilles Gasser

Keyword(s):

Anticancer Agents ◽

Water Solubility ◽

Photophysical Properties ◽

Biological Evaluation ◽

The Body ◽

Ic50 Values ◽

Polypyridine Complexes ◽

Poor Absorption ◽

Micromolar Range

Cancer is known to be one of the major causes of death nowadays. Among others, chemotherapy with cisplatin is a commonly used treatment. Although widely employed, cisplatin is known to cause severe side effects, such as nerve and kidney damage, nausea, vomiting, and bone marrow suppression. Most importantly, a number of cancer tumors are acquiring resistance to cisplatin, limiting its clinical use. There is therefore a need for the discovery of novel anticancer agents. Complementary to chemotherapy, Photodynamic Therapy (PDT) has expanded the range of treatment opportunities of numerous kinds of cancer. Nonetheless, the currently approved PDT photosensitizers (PSs) suffer from major drawbacks, which include poor water solubility or photobleaching, in addition to a slow clearance from the body that causes photosensitivity. Due to these limitations, there is a need for the development of new PDT PSs. To overcome these problems, a lot of research groups around the world are currently focusing their attention towards the development of new metal complexes as PDT PSs. However, most synthesized compounds reported so far show limited use due to their poor absorption in the phototherapeutic window. Herein, we report on the preparation and characterization of three Fe(II) polypyridine complexes (4–6) and evaluate their potential as both anticancer agents and PDT PSs. Very importantly, these compounds are stable in human plasma, photostable upon continuous LED irradiation, and absorb in the red region of the spectrum. We could demonstrate that through additional sulfonic acid groups on the polypyridine ligand being used (bphen: 4,7-diphenyl-1,10-phenanthroline), the water solubility of the complexes could be highly improved, whereas the photophysical properties did not significantly change. One of these complexes (4) shows interesting toxicity, with IC50 values in the low micromolar range in the dark as well as some phototoxicity upon irradiation at 480 and 540 nm against RPE-1 and HeLa cells.

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Primary screening of substances-photosensibilizers of the bacteriochlorin range for photodynamic therapy of malignant neoplasms

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20186403283 ◽

2018 ◽

Vol 64 (3) ◽

pp. 283-289 ◽

Cited By ~ 1

Author(s):

E.A. Plotnikova ◽

M.A. Grin ◽

P.V. Ostroverkhov ◽

I.V. Pantushenko ◽

R.I. Yakubovskaya ◽

...

Keyword(s):

Photodynamic Therapy ◽

Malignant Tumors ◽

Light Exposure ◽

Spectral Characteristics ◽

Red Light ◽

Wavelength Region ◽

Biological Properties ◽

Malignant Neoplasms ◽

Long Wavelength ◽

Primary Screening

This paper presents a primary screening of bacteriochlorin-type compounds with aminoamide, propyl and carbohydrate substituents aimed for development a new generation photosensitizers (PS) for photodynamic therapy of malignant tumors. Absorption and fluorescence spectral characteristics of the compounds, their storage stability in solutions under dark conditions and light exposure, photo-induced and dark cytotoxicity against human HEp2 tumor cells have been studied. It has been shown that the dyes with aminoamide substituents have an absorbtion maximum at 754±2 nm in the long wavelength region and they are not stable during storage (the specific fluorescence intensity decreased by 33-56% during 24 hours). The long wavelength region absorption of the propyl and carbohydrate substituted compounds varied in the range 780-831 nm, they were stable in solutions during storage and under light irradiation. Except the dye with a carbohydrate residue in the exocycle E, all PS exhibited the high photo-induced activity and low level of the dark cytotoxicity. The highest photo-induced cytotoxicity was observed for compounds with aminoamide substituents inthe macrocyclic ring (IC 50 values ranged from 17 nM to49 nM after 2 hour incubation with PS followed by exposure to the 10 J/cm 2 dose of red light). Taking into account the totality of the physico-chemical and biological properties, as well as manufacturability of production, O-propyloxime-N-propoxybacteriopurinimide methyl ester was chosen as the most promising candidate compound for further investigations.

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5,15-Diphenyl-7-oxobenzochlorins. Novel long-wavelength absorbing photosensitizers for photodynamic therapy

Journal of the Chemical Society Chemical Communications ◽

10.1039/c39940002463 ◽

1994 ◽

pp. 2463 ◽

Cited By ~ 18

Author(s):

Ross W. Boyle ◽

David Dolphin

Keyword(s):

Photodynamic Therapy ◽

Long Wavelength

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Current Status of Putative Animal Sources of SARS-CoV-2 Infection in Humans: Wildlife, Domestic Animals and Pets

Microorganisms ◽

10.3390/microorganisms9040868 ◽

2021 ◽

Vol 9 (4) ◽

pp. 868

Author(s):

Max Maurin ◽

Florence Fenollar ◽

Oleg Mediannikov ◽

Bernard Davoust ◽

Christian Devaux ◽

...

Keyword(s):

Animal Species ◽

Biological Properties ◽

Experimental Models ◽

Current Data ◽

The Body ◽

Receptor Expression ◽

Current Status ◽

Susceptible Animal

SARS-CoV-2 is currently considered to have emerged from a bat coronavirus reservoir. However, the real natural cycle of this virus remains to be elucidated. Moreover, the COVID-19 pandemic has led to novel opportunities for SARS-CoV-2 transmission between humans and susceptible animal species. In silico and in vitro evaluation of the interactions between the SARS-CoV-2 spike protein and eucaryotic angiotensin-converting enzyme 2 (ACE2) receptor have tentatively predicted susceptibility to SARS-CoV-2 infection of several animal species. Although useful, these data do not always correlate with in vivo data obtained in experimental models or during natural infections. Other host biological properties may intervene such as the body temperature, level of receptor expression, co-receptor, restriction factors, and genetic background. The spread of SARS-CoV-2 also depends on the extent and duration of viral shedding in the infected host as well as population density and behaviour (group living and grooming). Overall, current data indicate that the most at-risk interactions between humans and animals for COVID-19 infection are those involving certain mustelids (such as minks and ferrets), rodents (such as hamsters), lagomorphs (especially rabbits), and felines (including cats). Therefore, special attention should be paid to the risk of SARS-CoV-2 infection associated with pets.

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Synthesis of Y2O3: Eu Luminescent Phosphor with Increased Dispersion for Use in Medical Purposes

Materials Science Forum ◽

10.4028/www.scientific.net/msf.1040.61 ◽

2021 ◽

Vol 1040 ◽

pp. 61-67

Author(s):

Anna B. Vlasenko ◽

Vadim V. Bakhmetyev ◽

Sergey V. Mjakin

Keyword(s):

Particle Size ◽

Photodynamic Therapy ◽

Visible Light ◽

Modern Method ◽

The Body ◽

Hydrothermal Processing ◽

X Ray ◽

Microwave Annealing ◽

Body Tissues ◽

Pyrogenic Silica

Photodynamic therapy (PDT) is a promising modern method for treatment of oncological, bacterial, fungal and viral diseases. However, its application is limited to diseases with superficial localization since the body tissues are not transparent for visible light. To address this problem and extend PDT application to abdominal diseases, an enhanced method of X-ray photodynamic therapy (XRPDT) is suggested, involving X-ray radiation easily penetrating the body tissues. The implementation of this approach requires the development of a pharmacological drug including a photosensitizer stimulated by visible light to yield active oxygen and a nanosized phosphor converting X-ray radiation into visible light with the wavelength required for the photosensitizer activation. This study is aimed at obtaining X-ray stimulated phosphors with nanosized particles suitable for XRPDT application. For this purpose, Y2O3:Eu phosphors were synthesized via hydrothermal processing of the corresponding mixed acetate followed by annealing. To prevent from the undesirable agglomeration of the particles in the course of hydrothermal synthesis and subsequent annealing, different techniques were used, including rapid thermal annealing (RTA), microwave annealing and addition of finely dispersed pyrogenic silica (aerosil) to the phosphor. The microwave annealing was carried out using a special installation including a resonance chamber for maintaining a standing wave of microwave radiation. The performed research allowed the determination of hydrothermal processing optimal duration affording the synthesis of phosphors with the highest luminescence brightness. The application of microwave annealing is found to provide phosphors with a more perfect crystal structure compared with RTA. The developed method of Y2O3:Eu phosphor synthesis involving pyrogenic silica addition to the autoclave allowed the preparation of samples with the amorphous structure and significantly reduced the particle size without a considerable decrease in the luminescence brightness. The particle size of the phosphor synthesized with aerosil addition is less than 100 nm that allows its implementation in pharmacological drugs for XRPDT.

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Expression of a novel FGF in the Xenopus embryo. A new candidate inducing factor for mesoderm formation and anteroposterior specification

Development ◽

10.1242/dev.114.3.711 ◽

1992 ◽

Vol 114 (3) ◽

pp. 711-720 ◽

Cited By ~ 46

Author(s):

H.V. Isaacs ◽

D. Tannahill ◽

J.M. Slack

Keyword(s):

Specific Activity ◽

Biological Properties ◽

The Body ◽

Mesoderm Induction ◽

Gastrula Stage ◽

Blastula Stage ◽

Mesoderm Formation ◽

Low Levels

We have cloned and sequenced a new member of the fibroblast growth factor family from Xenopus laevis embryo cDNA. It is most closely related to both mammalian kFGF (FGF-4) and FGF-6 but as it is not clear whether it is a true homologue of either of these genes we provisionally refer to it as XeFGF (Xenopus embryonic FGF). Two sequences were obtained, differing by 11% in derived amino acid sequence, which probably represent pseudotetraploid variants. Both the sequence and the behaviour of in vitro translated protein indicates that, unlike bFGF (FGF-2), XeFGF is a secreted molecule. Recombinant XeFGF protein has mesoderm-inducing activity with a specific activity similar to bFGF. XeFGF mRNA is expressed maternally and zygotically with a peak during the gastrula stage. Both probe protection and in situ hybridization showed that the zygotic expression is concentrated in the posterior of the body axis and later in the tailbud. Later domains of expression were found near the midbrain/hindbrain boundary and at low levels in the myotomes. Because of its biological properties and expression pattern, XeFGF is a good candidate for an inducing factor with possible roles both in mesoderm induction at the blastula stage and in the formation of the anteroposterior axis at the gastrula stage.

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Structural Diversity of Nanoscale Zirconium Porphyrin MOFs and Their Photoactivities and Biological Performances

Journal of Materials Chemistry B ◽

10.1039/d1tb01311d ◽

2021 ◽

Author(s):

Zhigang Xie ◽

Lei Wang ◽

YiTe Li ◽

Junli Zhou

Keyword(s):

Photodynamic Therapy ◽

Structural Parameters ◽

Structural Diversity ◽

Biological Properties ◽

Delivery Systems

Photoactive MOFs-based delivery systems are highly attractive for photodynamic therapy (PDT), but the fundamental interplay among structural parameters and photoactivity and biological properties of those MOFs remains unclear. Herein, porphyrinic...

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