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Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 210
Author(s):  
Sooho Yeo ◽  
Il Yoon ◽  
Woo Kyoung Lee

Photodynamic therapy (PDT) is a non-invasive and tumour-specific therapy. Photosensitizers (PSs) (essential ingredients in PDT) aggregate easily owing to their lipophilic properties. The aim of this study was to synthesise a PS (methyl pheophorbide a, MPa) and design a biocompatible lipid-based nanocarrier to improve its bioavailability and pharmacological effects. MPa-loaded nano-transfersomes were fabricated by sonication. The characteristics of synthesised PS and nano-transfersomes were assessed. The effects of PDT were evaluated by 1,3-diphenylisobenzofuran assay and by measuring photo-cytotoxicity against HeLa and A549 cell lines. The mean particle size and zeta potential for nano-transfersomes ranged from 95.84 to 267.53 nm and −19.53 to −45.08 mV, respectively. Nano-transfersomes exhibited sustained drug release for 48 h in a physiological environment (as against burst release in an acidic environment), which enables its use as a pH-responsive drug release system in PDT with enhanced photodynamic activity and reduced side effects. The formulations showed light cytotoxicity, but no dark toxicity, which meant that light irradiation resulted in anti-cancer effects. Additionally, formulations with the smallest size exhibited photodynamic activity to a larger extent than those with the highest loading capacity or free MPa. These results suggest that our MPa-loaded nano-transfersome system is a promising anti-cancer strategy for PDT.


2022 ◽  
Vol 46 ◽  
pp. 100565
Author(s):  
Eunyoung Park ◽  
Donghyun Lee ◽  
Yeeun Lee ◽  
Eunjin Jeong ◽  
Sehee Kim ◽  
...  

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1985
Author(s):  
Mariia R. Mollaeva ◽  
Elena Nikolskaya ◽  
Veronika Beganovskaya ◽  
Maria Sokol ◽  
Margarita Chirkina ◽  
...  

Pheophorbide a 17-diethylene glycol ester (XL-8), is a promising high-active derivative of known photosensitizer chlorin e6 used in photodynamic therapy. However, high lipophilicity and poor tumor accumulation limit XL-8 therapeutic application. We developed a novel XL-8 loaded with poly(D,L-lactide-co-glycolide) nanoparticles using the single emulsion-solvent evaporation method. The nanoparticles possessed high XL-8 loading content (4.6%) and encapsulation efficiency (87.7%) and a small size (182 ± 19 nm), and negative surface charge (−22.2 ± 3.8 mV) contributed to a specific intracellular accumulation. Sustained biphasic XL-8 release from nanoparticles enhanced the photosensitizer photostability upon irradiation that could potentially reduce the quantity of the drug applied. Additionally, the encapsulation of XL-8 in the polymer matrix preserved phototoxic activity of the payload. The nanoparticles displayed enhanced cellular internalization. Flow cytometry and confocal laser-scanning microscopy studies revealed rapid XL-8 loaded nanoparticles distribution throughout the cell and initiation of DNA damage, glutathione depletion, and lipid peroxidation via reactive oxygen species formation. The novel nanoformulated XL-8 simultaneously revealed a significant phototoxicity accompanied with enhanced photostability, in contrast with traditional photosensitizers, and demonstrated a great potential for further in vivo studies.


Author(s):  
Thomas Meunier ◽  
Lowiese Desmarets ◽  
Simon Bordage ◽  
Moussa Bamba ◽  
Kévin Hervouet ◽  
...  

The SARS-CoV-2 outbreak has highlighted the need for broad-spectrum antivirals against coronaviruses (CoVs). Here, pheophorbide a (Pba) was identified as a highly active antiviral molecule against HCoV-229E after bioguided fractionation of plant extracts. The antiviral activity of Pba was subsequently shown for SARS-CoV-2 and MERS-CoV, and its mechanism of action was further assessed, showing that Pba is an inhibitor of coronavirus entry by directly targeting the viral particle. Interestingly, the antiviral activity of Pba depends on light exposure, and Pba was shown to inhibit virus-cell fusion by stiffening the viral membrane as demonstrated by cryo-electron microscopy. Moreover, Pba was shown to be broadly active against several other enveloped viruses, and reduced SARS-CoV-2 and MERS-CoV replication in primary human bronchial epithelial cells. Pba is the first described natural antiviral against SARS-CoV-2 with direct photosensitive virucidal activity that holds potential for COVID-19 therapy or disinfection of SARS-CoV-2 contaminated surfaces.


2021 ◽  
Vol 22 (22) ◽  
pp. 12502
Author(s):  
Shoji Kokubo ◽  
Shinobu Ohnuma ◽  
Megumi Murakami ◽  
Haruhisa Kikuchi ◽  
Shota Funayama ◽  
...  

The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is involved in the development of multidrug resistance in cancer patients. Many inhibitors of ABCG2 have been reported to enhance the chemosensitivity of cancer cells. However, none of these inhibitors are being used clinically. The aim of this study was to identify novel ABCG2 inhibitors by high-throughput screening of a chemical library. Among the 5812 compounds in the library, 23 compounds were selected in the first screening, using a fluorescent plate reader-based pheophorbide a (PhA) efflux assay. Thereafter, to validate these compounds, a flow cytometry-based PhA efflux assay was performed and 16 compounds were identified as potential inhibitors. A cytotoxic assay was then performed to assess the effect these 16 compounds had on ABCG2-mediated chemosensitivity. We found that the phenylfurocoumarin derivative (R)-9-(3,4-dimethoxyphenyl)-4-((3,3-dimethyloxiran-2-yl)methoxy)-7H-furo [3,2-g]chromen-7-one (PFC) significantly decreased the IC50 of SN-38 in HCT-116/BCRP colon cancer cells. In addition, PFC stimulated ABCG2-mediated ATP hydrolysis, suggesting that this compound interacts with the substrate-binding site of ABCG2. Furthermore, PFC reversed the resistance to irinotecan without causing toxicity in the ABCG2-overexpressing HCT-116/BCRP cell xenograft mouse model. In conclusion, PFC is a novel inhibitor of ABCG2 and has promise as a therapeutic to overcome ABCG2-mediated MDR, to improve the efficiency of cancer chemotherapy.


Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6241
Author(s):  
Jordan Bouilloux ◽  
Martin Kiening ◽  
Sopie Yapi ◽  
Norbert Lange

Cyclopeptidic photosensitizer prodrugs (cPPPs) are compounds designed to specifically target overexpressed hydrolases such as serine proteases, resulting in their specific activation in close proximity to tumor cells. In this study, we explored a series of conjugates that can be selectively activated by the urokinase plasminogen activator (uPA). They differ from each other by their pheophorbide a (Pha) loading, their number of PEG chains and the eventual presence of black hole quenchers (BHQ3). The involvement of a peptidic linker between the drugs and the cyclopeptidic carrier allows specific cleavage by uPA. Restoration of the photophysical activity was observed in vitro on A549 lung and MCF7 breast cancer cells that exhibited an increase in red fluorescence emission up to 5.1-fold and 7.8-fold, respectively for uPA-cPPQ2+2/5. While these cPPP conjugates do not show dark toxicity, they revealed their phototoxic potential in both cell lines at 5 µM of Phaeq and a blue light fluence of 12.7 J/cm2 that resulted in complete cell death with almost all conjugates. This suggests, in addition to the promising use for cancer diagnosis, a use as a PDT agent. Intravenous injection of tetrasubstituted conjugates in fertilized hen eggs bearing a lung cancer nodule (A549) showed that a double PEGylation was favorable for the selective accumulation of the unquenched Pha moieties in the tumor nodules. Indeed, the diPEGylated uPA-cPPP4/52 induced a 5.2-fold increase in fluorescence, while the monoPEGylated uPA-cPPP4/5 or uPA-cPPQ2+2/5 led to a 0.4-fold increase only.


2021 ◽  
Vol 14 (10) ◽  
pp. 1048
Author(s):  
Guillermo H. Jimenez-Aleman ◽  
Victoria Castro ◽  
Addis Longdaitsbehere ◽  
Marta Gutierrez-Rodríguez ◽  
Urtzi Garaigorta ◽  
...  

SARS-CoV-2 pandemic is having devastating consequences worldwide. Although vaccination advances at good pace, effectiveness against emerging variants is unpredictable. The virus has displayed a remarkable resistance to treatments and no drugs have been proved fully effective against COVID-19. Thus, despite the international efforts, there is still an urgent need for new potent and safe antivirals against SARS-CoV-2. Here, we exploited the enormous potential of plant metabolism using the bryophyte Marchantia polymorpha L. and identified a potent SARS-CoV-2 antiviral, following a bioactivity-guided fractionation and mass-spectrometry approach. We found that the chlorophyll derivative Pheophorbide a (PheoA), a porphyrin compound similar to animal Protoporphyrin IX, has an extraordinary antiviral activity against SARS-CoV-2, preventing infection of cultured monkey and human cells, without noticeable cytotoxicity. We also show that PheoA targets the viral particle, interfering with its infectivity in a dose- and time-dependent manner. Besides SARS-CoV-2, PheoA also displayed a broad-spectrum antiviral activity against enveloped RNA viral pathogens such as HCV, West Nile, and other coronaviruses. Our results indicate that PheoA displays a remarkable potency and a satisfactory therapeutic index, which together with its previous use in photoactivable cancer therapy in humans, suggest that it may be considered as a potential candidate for antiviral therapy against SARS-CoV-2.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1399
Author(s):  
Ben Chung Lap Chan ◽  
Priyanga Dharmaratne ◽  
Baiyan Wang ◽  
Kit Man Lau ◽  
Ching Ching Lee ◽  
...  

High prevalence rates of methicillin-resistant Staphylococcus aureus (MRSA) and lack of effective antibacterial treatments urge discovery of alternative therapeutic modalities. The advent of antibacterial photodynamic therapy (aPDT) is a promising alternative, composing rapid, nonselective cell destruction without generating resistance. We used a panel of clinically relevant MRSA to evaluate hypericin (Hy) and pheophobide a (Pa)-mediated PDT with clinically approved methylene blue (MB). We translated the promising in vitro anti-MRSA activity of selected compounds to a full-thick MRSA wound infection model in mice (in vivo) and the interaction of aPDT innate immune system (cytotoxicity towards neutrophils). Hy-PDT consistently displayed lower minimum bactericidal concentration (MBC) values (0.625–10 µM) against ATCC RN4220/pUL5054 and a whole panel of community-associated (CA)-MRSA compared to Pa or MB. Interestingly, Pa-PDT and Hy-PDT topical application demonstrated encouraging in vivo anti-MRSA activity (>1 log10 CFU reduction). Furthermore, histological analysis showed wound healing via re-epithelization was best in the Hy-PDT group. Importantly, the dark toxicity of Hy was significantly lower (p < 0.05) on neutrophils compared to Pa or MB. Overall, Hy-mediated PDT is a promising alternative to treat MRSA wound infections, and further rigorous mechanistic studies are warranted.


Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1143
Author(s):  
Xueyun Hu ◽  
Chu Zeng ◽  
Jinling Su ◽  
Imran Khan ◽  
Ahmad Zada ◽  
...  

Leaf senescence, the last stage of leaf development, is a well-regulated and complex process for investigation. For simplification, dark-induced leaf senescence has frequently been used to mimic the natural senescence of leaves because many typical senescence symptoms, such as chlorophyll (Chl) and protein degradation, also occur under darkness. In this study, we compared the phenotypes of leaf senescence that occurred when detached leaves or intact plants were incubated in darkness to induce senescence. We found that the symptoms of non-programmed cell death (non-PCD) with remaining green coloration occurred more heavily in the senescent leaves of whole plants than in the detached leaves. The pheophorbide a (Pheide a) content was also shown to be much higher in senescent leaves when whole plants were incubated in darkness by analyses of leaf Chl and its metabolic intermediates. In addition, more serious non-PCD occurred and more Pheide a accumulated in senescent leaves during dark incubation if the soil used for plant growth contained more water. Under similar conditions, the non-PCD phenotype was alleviated and the accumulation of Pheide a was reduced by overexpressing 7-hydroxymethyl Chl a (HMChl a) reductase (HCAR). Taken together, we conclude that a high soil water content induced non-PCD by decreasing HCAR activity when whole plants were incubated in darkness to induce senescence; thus, the investigation of the fundamental aspects of biochemistry and the regulation of leaf senescence are affected by using dark-induced leaf senescence.


2021 ◽  
Author(s):  
Guillermo H Jimenez-Aleman ◽  
Victoria Castro ◽  
Addis Longdaitsbehere ◽  
Marta Gutierrez-Rodriguez ◽  
Urtzi Garaigorta ◽  
...  

The SARS-CoV-2 pandemic is having devastating consequences worldwide. Although vaccination advances at good pace, effectiveness against emerging variants of the virus is unpredictable. The virus has displayed a remarkable resistance to treatments and no drugs have been proved fully effective against Covid-19. Thus, despite the international efforts, there is still an urgent need for new potent and safe antivirals against SARS-CoV-2. Here we exploited the enormous potential of plant metabolism, in particular the bryophyte Marchantia polymorpha, and following a bioactivity-guided fractionation and mass-spectrometry approach, identified a potent SARS-CoV-2 antiviral. We found that the chlorophyll derivative Pheophorbide a (PheoA), a natural porphyrin similar to animal Protoporphyrin IX, has an extraordinary antiviral activity against SARS-CoV-2 preventing infection of cultured monkey and human cells, without noticeable citotoxicity. We also show that PheoA prevents coronavirus entry into the cells by directly targeting the viral particle. Besides SARS-CoV-2, PheoA also displayed a broad-spectrum antiviral activity against (+)strand RNA viral pathogens such as HCV, West Nile, and other coronaviruses, but not against (-)strand RNA viruses, such as VSV. Our results indicate that PheoA displays a remarkable potency and a satisfactory therapeutic index, and suggest that it may be considered as a potential candidate for antiviral therapy against SARS-CoV-2. Moreover, PheoA adds to remdesivir's efficiency and is currently employed in photoactivable cancer therapies in humans.


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