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

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>

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

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>

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

2019 ◽  
Author(s):  
Johannes Karges ◽  
Franz Heinemann ◽  
Marta Jakubaszek ◽  
Federica Maschietto ◽  
Chloé Subecz ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Water Solubility ◽  
Clinical Success ◽  
Biological Properties ◽  
The Body ◽  
Multicellular Tumor Spheroids ◽  
Spectral Window ◽  
Long Wavelength ◽  
Polypyridine Complexes ◽  
Nanomolar Range

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>

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

2019 ◽  
Author(s):  
Johannes Karges ◽  
Franz Heinemann ◽  
Marta Jakubaszek ◽  
Federica Maschietto ◽  
Chloé Subecz ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Water Solubility ◽  
Clinical Success ◽  
Biological Properties ◽  
The Body ◽  
Multicellular Tumor Spheroids ◽  
Spectral Window ◽  
Long Wavelength ◽  
Polypyridine Complexes ◽  
Nanomolar Range

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>

scholarly journals Two-Photon–NIR-II Antimicrobial Graphene-Nanoagent for Ultraviolet–NIR Imaging and Photoinactivation

2021 ◽  
Author(s):  
WEN-SHUO KUO ◽  
Chia-Yuan Chang ◽  
Ping-Ching Wu ◽  
Jiu-Yao Wang
Keyword(s):  
Photodynamic Therapy ◽  
Quantum Yield ◽  
Chemical Modification ◽  
Near Infrared ◽  
Photon Absorption ◽  
Excitation Wavelength ◽  
Strong Electron ◽  
Two Photon ◽  
Photon Excitation ◽  
Two Photon Excitation

Abstract BackgroundNitrogen doping and amino-group functionalization, which result in strong electron donation, can be achieved through chemical modification. Large π-conjugated systems of graphene quantum dot (GQD)-based materials acting as electron donors can be chemically manipulated with low two-photon excitation energy in a short photoexcitation time for improving the charge transfer efficiency of sorted nitrogen-doped amino acid–functionalized GQDs (sorted amino-N-GQDs). ResultsIn this study, a self-developed femtosecond Ti-sapphire laser optical system (222.7 nJ pixel−1 with 100-170 scans, approximately 0.65-1.11 s of total effective exposure times; excitation wavelength: 960 nm in the near-infrared II region) was used for chemical modification. The sorted amino-N-GQDs exhibited enhanced two-photon absorption, post-two-photon excitation stability, two-photon excitation cross-section, and two-photon luminescence through the radiative pathway. The lifetime and quantum yield of the sorted amino-N-GQDs decreased and increased, respectively. Furthermore, the sorted amino-N-GQDs exhibited excitation-wavelength-independent photoluminescence in the near-infrared region and generated reactive oxygen species after two-photon excitation. An increase in the size of the sorted amino-N-GQDs boosted photochemical and electrochemical efficacy and resulted in high photoluminescence quantum yield and highly efficient two-photon photodynamic therapy. ConclusionThe sorted dots can be used in two-photon contrast probes for tracking and localizing analytes during two-photon imaging in a biological environment and for conducting two-photon photodynamic therapy for eliminating infectious microbes.

scholarly journals Ethanolic Extract of Papaya (Carica papaya) Leaf Exhibits Estrogenic Effects In Vivo and In Silico

2012 ◽  
Vol 3 (2) ◽  
pp. 384
Author(s):  
Raisatun Nisa Sugiyanto ◽  
Rahmi Khamsita ◽  
Marvin Lambertus ◽  
Rohmad Yudi Utomo ◽  
Ratna Asmah Susidarti
Keyword(s):  
Estrogen Receptor ◽  
In Silico ◽  
Carica Papaya ◽  
Ethanolic Extract ◽  
The Body ◽  
Female Rats ◽  
Sprague Dawley ◽  
Docking Score ◽  
Estrogenic Effect

The menopause women have the low level of estrogen in the body. The lack of estrogen changes physiological function in women’s body that affects in health condition. Carica papaya L. leaf contains flavonoid quercetin which exhibits estrogenic effect. The aim of this study is to determine the estrogenic effect of papaya leaves extract (PLE) in vivo, and in silico. Papaya leaves were extracted by ethanol 70% maceration. The in silico study were done by molecular docking between quersetin and Estrogen Receptor (ERα and ERβ) to obtain the docking score. Based on this study, docking score of quercetin was almost similar to the native ligand of ER. The in vivo study was done as follow: 36 female rats Sprague Dawley divided into six groups.  The groups are shame-ovariectomized (S-OVX), control ovariectomized (OVX), CMC-Na control (OVX+CMC-Na), positive control (OVX+Estradiol), and the PLE treatment groups dose 750 mg/kgBW (OVX+750mg/kgBW) and dose 1000 mg/kgBW (OVX+1000 mg/kgBW). Administrations of PLE were done in three weeks orally, while estradiol was administrated intraperitonially. The mammae and uterine were sliced for analysis. Based on the study, the treatment of PLE increased the number of mammae lobules and uterine weight as well as estrogen does.  In summary, PLE can be developed as a source of phytoestrogens.Keywords: Carica papaya L., phytoestrogen, estrogen receptor, mammae lobule, uterine

scholarly journals A self-assembled Ru–Pt metallacage as a lysosome-targeting photosensitizer for 2-photon photodynamic therapy

2019 ◽  
Vol 116 (41) ◽  
pp. 20296-20302 ◽  
Author(s):  
Zhixuan Zhou ◽  
Jiangping Liu ◽  
Juanjuan Huang ◽  
Thomas W. Rees ◽  
Yiliang Wang ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Near Infrared ◽  
Building Blocks ◽  
Cell Uptake ◽  
Photon Absorption ◽  
In Vivo Studies ◽  
Infrared Light ◽  
Ros Generation ◽  
Multicellular Spheroids

Photodynamic therapy (PDT) is a treatment procedure that relies on cytotoxic reactive oxygen species (ROS) generated by the light activation of a photosensitizer. The photophysical and biological properties of photosensitizers are vital for the therapeutic outcome of PDT. In this work a 2D rhomboidal metallacycle and a 3D octahedral metallacage were designed and synthesized via the coordination-driven self-assembly of a Ru(II)-based photosensitizer and complementary Pt(II)-based building blocks. The metallacage showed deep-red luminescence, a large 2-photon absorption cross-section, and highly efficient ROS generation. The metallacage was encapsulated into an amphiphilic block copolymer to form nanoparticles to encourage cell uptake and localization. Upon internalization into cells, the nanoparticles selectively accumulate in the lysosomes, a favorable location for PDT. The nanoparticles are almost nontoxic in the dark, and can efficiently destroy tumor cells via the generation of ROS in the lysosomes under 2-photon near-infrared light irradiation. The superb PDT efficacy of the metallacage-containing nanoparticles was further validated by studies on 3D multicellular spheroids (MCS) and in vivo studies on A549 tumor-bearing mice.

scholarly journals Utilization of Gelling Polymer to Formulate Nanoparticles Loaded with Epalrestat-Cyclodextrin Inclusion Complex: Formulation, Characterization, In-Silico Modelling and In-Vivo Toxicity Evaluation

Polymers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 4350
Author(s):  
Zunaira Alvi ◽  
Muhammad Akhtar ◽  
Nisar U. Rahman ◽  
Khaled M. Hosny ◽  
Amal M. Sindi ◽  
...  
Keyword(s):  
In Silico ◽  
Sodium Tripolyphosphate ◽  
Polymeric Nanoparticles ◽  
Chitosan Nanoparticles ◽  
Chemical Properties ◽  
Aqueous Solubility ◽  
Acute Oral Toxicity ◽  
Oral Toxicity ◽  
Cross Linker

Epalrestat (EPL) is an aldose reductase inhibitor with poor aqueous solubility that affects its therapeutic efficacy. The research study was designed to prepare epalrestat-cyclodextrins (EPL-CDs) inclusion complexes to enhance the aqueous solubility by using beta-cyclodextrin (β-CD) and sulfobutyl ether₇ β-CD (SBE7 β-CD). Furthermore, polymeric nanoparticles (PNPs) of EPL-CDs were developed using chitosan (CS) and sodium tripolyphosphate (sTPP). The EPL-CDs complexed formulations were then loaded into chitosan nanoparticles (CS NPs) and further characterized for different physico-chemical properties, thermal stability, drug-excipient compatibility and acute oral toxicity studies. In-silico molecular docking of cross-linker with SBE7 β-CD was also carried out to determine the binding site of the CDs with the cross-linker. The sizes of the prepared NPs were laid in the range of 241.5–348.4 nm, with polydispersity index (PDI) ranging from 0.302–0.578. The surface morphology of the NPs was found to be non-porous, smooth, and spherical. The cumulative percentage of drug release from EPL-CDs loaded CS NPs was found to be higher (75–88%) than that of the pure drug (25%). Acute oral toxicity on animal models showed a biochemical, histological profile with no harmful impact at the cellular level. It is concluded that epalrestat-cyclodextrin chitosan nanoparticles (EPL-CDs-CS NPs) with improved solubility are safe for oral administration since no toxicity was reported on vital organs in rabbits.

Polymeric Encapsulation of a Ruthenium Polypyridine Complex for Tumor Targeted 1- and 2-Photon Photodynamic Therapy

2020 ◽  
Author(s):  
Johannes Karges ◽  
Jia Li ◽  
Leli Zeng ◽  
Hui Chao ◽  
Gilles Gasser
Keyword(s):  
Photodynamic Therapy ◽  
Cancer Cell ◽  
Polymeric Nanoparticles ◽  
Multicellular Tumor Spheroid ◽  
Epithelial Tumor ◽  
Ru Complex ◽  
Cell Selectivity ◽  
Polypyridine Complexes ◽  
Ruthenium Polypyridine

Photodynamic therapy is a medical technique, which is gaining increasing attention to treat various types of cancer. Among the investigated classes of photosensitizers, the use of Ru(II) polypyridine complexes is gaining momentum. However, the currently investigated compounds generally show poor cancer cell selectivity. As a consequence, high drug doses are needed, which can cause side effects. To overcome this limitation, there is a need for the development of a suitable drug delivery system to increase the amount of PS delivered to the tumor. Herein, we report on the encapsulation of a promising Ru(II) polypyridyl complex into polymeric nanoparticles with terminal biotin groups. Thanks to this design, the particles showed much higher selectivity for cancer cells in comparison to non-cancerous cells in a 2D monolayer and 3D multicellular tumor spheroid model. As a highlight, upon intravenous injection of an identical amount of the Ru(II) polypyridine complex, an improved accumulation inside an adenocarcinomic human alveolar basal epithelial tumor of a mouse by a factor of 8.7 compared to the Ru complex itself was determined. The nanoparticles were found to have a high phototoxic effect upon 1-photon (500 nm) or 2-photon (800 nm) excitation with an eradication of an adenocarcinomic human alveolar basal epithelial tumor inside a mouse. Overall, this work describes, to the best of our knowledge, the first <i>in vivo</i> study demonstrating the cancer cell selectivity of a very promising Ru(II)-based PDT photosensitizer encapsulated into polymeric nanoparticles with terminal biotin groups.

scholarly journals Can nanotechnology potentiate photodynamic therapy?

2012 ◽  
Vol 1 (2) ◽  
pp. 111-146 ◽  
Author(s):  
Ying-Ying Huang ◽  
Sulbha K. Sharma ◽  
Tianhong Dai ◽  
Hoon Chung ◽  
Anastasia Yaroslavsky ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Photodynamic Therapy ◽  
Plasmonic Enhancement ◽  
Gold And Silver Nanoparticles ◽  
Drug Delivery Vehicles ◽  
Two Photon ◽  
Photon Excitation ◽  
Poorly Soluble ◽  
Delivery Vehicles

AbstractPhotodynamic therapy (PDT) uses the combination of nontoxic dyes and harmless visible light to produce reactive oxygen species that can kill cancer cells and infectious microorganisms. Due to the tendency of most photosensitizers (PS) to be poorly soluble and to form nonphotoactive aggregates, drug-delivery vehicles have become of high importance. The nanotechnology revolution has provided many examples of nanoscale drug-delivery platforms that have been applied to PDT. These include liposomes, lipoplexes, nanoemulsions, micelles, polymer nanoparticles (degradable and nondegradable), and silica nanoparticles. In some cases (fullerenes and quantum dots), the actual nanoparticle itself is the PS. Targeting ligands such as antibodies and peptides can be used to increase specificity. Gold and silver nanoparticles can provide plasmonic enhancement of PDT. Two-photon excitation or optical upconversion can be used instead of one-photon excitation to increase tissue penetration at longer wavelengths. Finally, after sections on in vivo studies and nanotoxicology, we attempt to answer the title question, “can nanotechnology potentiate PDT?”

scholarly journals X-ray induced photodynamic therapy with copper-cysteamine nanoparticles in mice tumors

2019 ◽  
Vol 116 (34) ◽  
pp. 16823-16828 ◽  
Author(s):  
Samana Shrestha ◽  
Jing Wu ◽  
Bindeshwar Sah ◽  
Adam Vanasse ◽  
Leon N Cooper ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Treatment Method ◽  
The Body ◽  
Target Cells ◽  
X Rays ◽  
X Ray ◽  
Mouse Tumors ◽  
Study Results ◽  
New Type

Photodynamic therapy (PDT), a treatment that uses a photosensitizer, molecular oxygen, and light to kill target cells, is a promising cancer treatment method. However, a limitation of PDT is its dependence on light that is not highly penetrating, precluding the treatment of tumors located deep in the body. Copper-cysteamine nanoparticles are a new type of photosensitizer that can generate cytotoxic singlet oxygen molecules upon activation by X-rays. In this paper, we report on the use of copper-cysteamine nanoparticles, designed to be targeted to tumors, for X-ray–induced PDT. In an in vivo study, results show a statistically significant reduction in tumor size under X-ray activation of pH-low insertion peptide–conjugated, copper-cysteamine nanoparticles in mouse tumors. This work confirms the effectiveness of copper-cysteamine nanoparticles as a photosensitizer when activated by radiation and suggests that these Cu-Cy nanoparticles may be good candidates for PDT in deeply seated tumors when combined with X-rays and conjugated to a tumor-targeting molecule.

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