Showing papers on "Protoporphyrin IX published in 2019"
TL;DR: This immune-stimulating PM-PDT strategy also exhibited the inhibition of distant metastatic tumors when combined with programmed cell death receptor 1 blockade therapy.
Abstract: Here, a protein farnesyltransferase (PFTase)-driven plasma membrane (PM)-targeted chimeric peptide, PpIX-C6-PEG8-KKKKKKSKTKC-OMe (PCPK), was designed for PM-targeted photodynamic therapy (PM-PDT) and enhanced immunotherapy via tumor cell PM damage and fast release of damage-associated molecular patterns (DAMPs). The PM targeting ability of PCPK originates from the cellular K-Ras signaling, which occurs exclusively to drive the corresponding proteins to PM by PFTase. With the conjugation of the photosensitizer protoporphyrin IX (PpIX), PCPK could generate cytotoxic reactive oxygen species to deactivate membrane-associated proteins, initiate lipid peroxidation, and destroy PM with an extremely low concentration (1 μM) under light irradiation. The specific PM damage further induced the fast release of DAMPs (high-mobility group box 1 and ATP), resulting in antitumor immune responses stronger than those of conventional cytoplasm-localized PDT. This immune-stimulating PM-PDT strategy also exhibited the inhibition effect for distant metastatic tumors when combined with programmed cell death receptor 1 blockade therapy.
93 citations
TL;DR: This review focuses on alterations in the haem pathway in cancer and considers the unique features of the cancer environment, such as altered glucose metabolism, oncogenic mutations and hypoxia, and their potential effects on the protoporphyrin IX phenomenon.
Abstract: Photodynamic diagnosis and therapy have emerged as a promising tool in oncology. Using the visible fluorescence from photosensitisers excited by light, clinicians can both identify and treat tumour cells in situ. Protoporphyrin IX, produced in the penultimate step of the haem synthesis pathway, is a naturally occurring photosensitiser that visibly fluoresces when exposed to light. This fluorescence is enhanced considerably by the exogenous administration of the substrate 5-aminolaevulinic acid (5-ALA). Significantly, 5-ALA-induced protoporphyrin IX accumulates preferentially in cancer cells, and this enhanced fluorescence has been harnessed for the detection and photodynamic treatment of brain, skin and bladder tumours. However, surprisingly little is known about the mechanistic basis for this phenomenon. This review focuses on alterations in the haem pathway in cancer and considers the unique features of the cancer environment, such as altered glucose metabolism, oncogenic mutations and hypoxia, and their potential effects on the protoporphyrin IX phenomenon. A better understanding of why cancer cells fluoresce with 5-ALA would improve its use in cancer diagnostics and therapies.
42 citations
TL;DR: The preparation of light-activated hybrid antibacterial agent combining the porphyrin molecules, bound to the silver nanoparticles (AgNPs) surface is reported and the synergetic effect and light activation of the created antibacterial conjugates were observed.
34 citations
TL;DR: In human in Situ brain tumor tissue, fluorescence after 5-ALA administration is determined to be maximal later than previously thought, with timing adjusted to internal logistical circumstances and factors related to approaching the tumor.
Abstract: Background Five-aminolevulinic acid (5-ALA) is well established for fluorescence-guided resections of malignant gliomas by eliciting the accumulation of fluorescent protoporphyrin IX (PpIX) in tumors. Because of the assumed time point of peak fluorescence, 5-ALA is recommended to be administered 3 h before surgery. However, the actual time dependency of tumor fluorescence has not yet been evaluated in humans and may have important implications. Objective To investigate the time dependency of PpIX by measuring fluorescence intensities in tumors at various time points during surgery. Methods Patients received 5-ALA (20 mg/kg b.w.) 3 to 4 h before surgery. Fluorescence intensities (FI) and estimated tumor PpIX concentrations (CPPIX) were measured in the tumors over time with a hyperspectral camera. CPPIX was assessed using hyperspectral imaging and by evaluating fluorescence phantoms with known CPPIX. Results A total of 201 samples from 68 patients were included in this study. On average, maximum values of calculated FI and CPPIX were observed between 7 and 8 h after 5-ALA administration. FI and CPPIX both reliably distinguished central strong and marginal weak fluorescence, and grade III compared to grade IV gliomas. Interestingly, marginal (weak) fluorescence was observed to peak later than strong fluorescence (8-9 vs 7-8 h). Conclusion In human in Situ brain tumor tissue, we determined fluorescence after 5-ALA administration to be maximal later than previously thought. In consequence, 5-ALA should be administered 4 to 5 h before surgery, with timing adjusted to internal logistical circumstances and factors related to approaching the tumor.
30 citations
TL;DR: The use of 5-ALA-PpIX in meningiomas holds promising potential so neurosurgeons can improve surgical outcomes for patients with mening iomas as well as be pioneers in developing improved fluorescence imaging technologies.
Abstract: 5-aminolevulinic acid induced protoporphyrin IX (5-ALA-PpIX) fluorescence guidance has emerged as a valuable surgical adjunct for resection of intracranial tumors. Here we present a focused review on 5-ALA-PpIX fluorescence guidance for meningiomas. We discuss the clinical studies and specific applications to date as well as the two main intraoperative fluorescence technologies applied to meningiomas. The use of 5-ALA-PpIX in meningiomas holds promising potential so neurosurgeons can improve surgical outcomes for patients with meningiomas as well as be pioneers in developing improved fluorescence imaging technologies.
27 citations
TL;DR: The findings suggested that the results of 5-ALA-PDD might be predictive for 5-ala-PDT therapeutic effects for carcinomas, with 5- ALA- PDT plus chemotherapy potentially increasing the probability of tumor control in veterinary medicine.
Abstract: 5-Aminolevulinic acid (5-ALA), a commonly used photosensitizer in photodynamic detection (PDD) and therapy (PDT), is converted in situ to the established photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway. To extend 5-ALA-PDT application, we evaluated the PpIX fluorescence induced by exogenous 5-ALA in various veterinary tumors and treated canine and feline tumors. 5-ALA-PDD sensitivity and specificity in the whole sample group for dogs and cats combined were 89.5 and 50%, respectively. Notably, some small tumors disappeared upon 5-ALA-PDT. Although single PDT application was not curative, repeated PDT+/−chemotherapy achieved long-term tumor control. We analyzed the relationship between intracellular PpIX concentration and 5-ALA-PDT in vitro cytotoxicity using various primary tumor cells and determined the correlation between intracellular PpIX concentration and 5-ALA transporter and metabolic enzyme mRNA expression levels. 5-ALA-PDT cytotoxicity in vitro correlated with intracellular PpIX concentration in carcinomas. Ferrochelatase mRNA expression levels strongly negatively correlated with PpIX accumulation, representing the first report of a correlation between mRNA expression related to PpIX accumulation and PpIX concentration in canine tumor cells. Our findings suggested that the results of 5-ALA-PDD might be predictive for 5-ALA-PDT therapeutic effects for carcinomas, with 5-ALA-PDT plus chemotherapy potentially increasing the probability of tumor control in veterinary medicine.
26 citations
TL;DR: It is demonstrated that the PPIX efflux transporter ABCG2 (also called BCRP) determines EPP-associated phototoxicity and hepatotoxicity, and it is found thatABCG2 deficiency decreases PPIX distribution to the skin and therefore prevents E PP-associatedPhototoxicity.
Abstract: Erythropoietic protoporphyria (EPP) is an inherited disease caused by loss-of-function mutations of ferrochelatase, an enzyme in the heme biosynthesis pathway that converts protoporphyrin IX (PPIX) into heme. PPIX accumulation in patients with EPP leads to phototoxicity and hepatotoxicity, and there is no cure. Here, we demonstrated that the PPIX efflux transporter ABCG2 (also called BCRP) determines EPP-associated phototoxicity and hepatotoxicity. We found that ABCG2 deficiency decreases PPIX distribution to the skin and therefore prevents EPP-associated phototoxicity. We also found that ABCG2 deficiency protects against EPP-associated hepatotoxicity by modulating PPIX distribution, metabolism, and excretion. In summary, our work has uncovered an essential role of ABCG2 in the pathophysiology of EPP, which suggests the potential for novel strategies in the development of therapy for EPP.
25 citations
TL;DR: It is demonstrated that hydrazine upregulates ALAS1, whereas PIH downregulates FECH, suggesting that the metabolites of isoniazid mediate its disruption of heme biosynthesis by contributing to protoporphyrin IX accumulation.
25 citations
TL;DR: This fluorescent imaging-guided fractional PDT process of FSNC on HeLa cells performed a higher phototoxicity than traditional photosensitizer Protoporphyrin IX and can be visually captured by confocal laser scanning microscope via monitoring fluorescent bleaching of 1O2 self-monitoring unit.
Abstract: At present, the intermittent photodynamic therapy (fractional PDT) for overcoming tumor hypoxia still have their own defects, such as irradiation-dependence and rapid metabolism of organic photosensitizers. Therefore, it is still a really formidable challenge to achieve efficient fractional PDT. Herein, a three-in-one functional silica nanocarrier (FSNC) with singlet oxygen (1O2) generating unit (protoporphyrin IX derivative), 1O2 storage/release unit (2-pyridone derivative), and 1O2 self-monitoring unit (cyanine derivative) was prepared by reverse microemulsion method. Also, it could be efficiently internalized in the HeLa cells because of an appropriate particle size (∼44.8 nm). In the presence of light, the endoperoxide is formed to achieve 1O2 storage together with 1O2 generated by 1O2 generating unit for traditional PDT. In the absence of light, the endoperoxide produces 1O2 through cycloreversion for continuous PDT. As a result, the fractional PDT process of the FSNC on the HeLa cells performed a higher phototoxicity than traditional photosensitizer protoporphyrin IX. Furthermore, this real-time release behavior of 1O2 can be visually captured by confocal laser scanning microscope via monitoring fluorescent bleaching of 1O2 self-monitoring unit. Therefore, this fluorescent imaging-guided fractional PDT process could effectively enhance the PDT effect compared with traditional PDT.
24 citations
TL;DR: The results demonstrate the variations between cross-linking strategies in CD-based conjugates, highlighting their potential as carriers in drug delivery and bioimaging applications.
Abstract: Photodynamic therapy (PDT) uses photosensitisers such as protoporphyrin IX (PpIX) to target tumours via the release of toxic singlet oxygen when irradiated. The effectivity of the treatment is limited by the innate properties of the photosensitizers; they typically exhibit inefficient accumulation in target tissue and high dark toxicity. Carbon dots (CDs) are biocompatible fluorescent nanoparticles which can improve PpIX cellular uptake and solubility. In this work, we present conjugates synthesised by host-guest encapsulation (PpIX@CD) and amide cross-linking (PpIX-CD). Characterization demonstrated conjugates have a loading efficiency of 34–48% and similar singlet oxygen production to PpIX. PpIX-containing CDs showed a 2.2 to 3.7-fold decrease in dark toxicity. PpIX-CD and PpIX@CD showed equivalent light-induced toxicity to PpIX in concentrations >1 μg/ml, leading to a 3.2 to 4.1-fold increase in photo-toxicity index (PI). The less soluble fraction of cross-linked conjugates (PpIX-CD)p did not show significant difference from PpIX. Confocal light scanning microscopy demonstrated rapid intracellular uptake and accumulation of conjugates. Our results demonstrate the variations between cross-linking strategies in CD-based conjugates, highlighting their potential as carriers in drug delivery and bioimaging applications.
23 citations
TL;DR: The BLS-induced PDT system can produce the singlet oxygen and provide a certain efficient therapy in SMMC-7721 hepatocellular carcinoma cells through fluorescence resonance energy transfer (FRET), which demonstrates the firefly BLS has already functioned in some extent, but not perfect.
Abstract: Various external lights and improved illumination methods, such as near-infrared light, X-ray, and two-photon excitation, have been tried to enhance the efficiency of photodynamic therapy (PDT) in deep-seated tumors. However, the penetration depth of light required for photosensitizers’ (PSs) activation still remains a major problem in clinic. Herein, bioluminescence (BLS), a kind of inner light induced from the firefly luciferase, is attempted to activate the treatment in deep lesions. To obtain a better therapeutic effect, carbon dots (CDs) with an excitation-independent photoluminescence are prepared by a facile hydrothermal method, and the as-prepared CDs are designed to conjugate protoporphyrin IX (PIX) to construct the PDT agents (CDs-PIX). Results indicate the nano-carrier of CDs enhances the limitations of PIX and bridges the excitation between BLS and PIX. The BLS-induced PDT system can produce the singlet oxygen and provide a certain efficient therapy (about 60%) in SMMC-7721 hepatocellular carcinoma cells through fluorescence resonance energy transfer (FRET) process, which demonstrates the firefly BLS has already functioned in some extent, but not perfect. CDs-PIX is an excellent PS for PDT applications, but its corresponding excitation inner light source needs further studies.
TL;DR: A widefield fluorescence lifetime imaging device with 250 mm working distance, working under similar conditions such as surgical microscopes based on a time‐of‐flight dual tap CMOS camera, that is invariant to light scattering and absorption while being sensitive to the molecular composition of the tissue.
Abstract: Achieving a maximal safe extent of resection during brain tumor surgery is the goal for improved patient prognosis. Fluorescence-guided neurosurgery using 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX has thereby become a valuable tool enabling a high frequency of complete resections and a prolonged progression-free survival in glioblastoma patients. We present a widefield fluorescence lifetime imaging device with 250 mm working distance, working under similar conditions such as surgical microscopes based on a time-of-flight dual tap CMOS camera. In contrast to intensity-based fluorescence imaging, our method is invariant to light scattering and absorption while being sensitive to the molecular composition of the tissue. We evaluate the feasibility of lifetime imaging of protoporphyrin IX using our system to analyze brain tumor phantoms and fresh 5-ALA-labeled human tissue samples. The results demonstrate the potential of our lifetime sensing device to go beyond the limitation of current intensity-based fluorescence-guided neurosurgery.
TL;DR: It is demonstrated that ZnPP and PPIX are formed by two independent mechanisms in porcine skeletal muscles whose optimal pH values are 5.5 and 4.75.
Abstract: This study investigated the effects of pH, muscle fiber type, and precursor levels on zinc protoporphyrin IX (ZnPP) formation in porcine skeletal muscles. ZnPP formation could be classified into three distinct groups with pH optima of 4.75, 5.5, or both. The effects of temperature and incubation time on ZnPP formation at the new optimal pH 4.75 differed significantly from those at pH 5.5 reported in previous studies. Protoporphyrin IX (PPIX) formation at pH 4.75 nearly coincided with that of ZnPP, suggesting that the latter strongly affects the former, as observed at pH 5.5. The amount of ZnPP formed at pH 4.75 was related to the ratio of type I muscle fibers. Although myoglobin degradation occurred at pH 4.75, no decrease in heme content corresponded to the formation of ZnPP and PPIX. These results demonstrate that ZnPP and PPIX are formed by two independent mechanisms in porcine skeletal muscles whose optimal pH values are 5.5 and 4.75.
03 May 2019
TL;DR: It is shown that the lack of oxidised PQ impairs PPX function, leading to accumulation and subsequently uncontrolled oxidation of Protogen to non-metabolised Proto, demonstrating existence of a link between chlorophyll biosynthesis and photosynthetic electron transport in Chlamydomonas reinhardtii.
Abstract: In the last common enzymatic step of tetrapyrrole biosynthesis, prior to the branching point leading to the biosynthesis of heme and chlorophyll, protoporphyrinogen IX (Protogen) is oxidised to protoporphyrin IX (Proto) by protoporphyrinogen IX oxidase (PPX). The absence of thylakoid-localised plastid terminal oxidase 2 (PTOX2) and cytochrome b6f complex in the ptox2 petB mutant, results in almost complete reduction of the plastoquinone pool (PQ pool) in light. Here we show that the lack of oxidised PQ impairs PPX function, leading to accumulation and subsequently uncontrolled oxidation of Protogen to non-metabolised Proto. Addition of 3(3,4-Dichlorophenyl)-1,1-dimethylurea (DCMU) prevents the over-reduction of the PQ pool in ptox2 petB and decreases Proto accumulation. This observation strongly indicates the need of oxidised PQ as the electron acceptor for the PPX reaction in Chlamydomonas reinhardtii. The PPX-PQ pool interaction is proposed to function as a feedback loop between photosynthetic electron transport and chlorophyll biosynthesis. Pawel Brzezowski et al. demonstrated existence of a link between chlorophyll biosynthesis and photosynthetic electron transport in Chlamydomonas reinhardtii. The lack of oxidised plastoquinone pool impairs function of PROTOPORPHYRINOGEN IX OXIDASE, leading to accumulation of non-metabolised protoporphyrin IX.
TL;DR: It is demonstrated that PpIX is a dual inhibitor of p53/MDM2 and p53-downstream apoptotic targets and activates apoptosis in B-cell chronic lymphocytic leukemia cells without illumination and without affecting normal cells.
Abstract: p53 is a tumor suppressor, which belongs to the p53 family of proteins. The family consists of p53, p63 and p73 proteins, which share similar structure and function. Activation of wild-type p53 or TAp73 in tumors leads to tumor regression, and small molecules restoring the p53 pathway are in clinical development. Protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid, is a clinically approved drug applied in photodynamic diagnosis and therapy. PpIX induces p53-dependent and TAp73-dependent apoptosis and inhibits TAp73/MDM2 and TAp73/MDM4 interactions. Here we demonstrate that PpIX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and activates apoptosis in B-cell chronic lymphocytic leukemia cells without illumination and without affecting normal cells. PpIX stabilizes p53 and TAp73 proteins, induces p53-downstream apoptotic targets and provokes cancer cell death at doses non-toxic to normal cells. Our findings open up new opportunities for repurposing PpIX for treating lymphoblastic leukemia with wild-type TP53.
TL;DR: ALA triggered GST activity encoded by GSTU43, and increased tomato tolerance to low temperature-induced oxidative stress, perhaps with the assistance of ascorbate- and/or a glutathione-regenerating cycles, and actively regulated the plant redox homeostasis.
Abstract: Exogenous 5-aminolevulinic acid (ALA) positively regulates plants chlorophyll synthesis and protects them against environmental stresses, although the protection mechanism is not fully clear Here, we explored the effects of ALA on chlorophyll synthesis in tomato plants, which are sensitive to low temperature We also examined the roles of the glutathione S-transferase (GSTU43) gene, which is involved in ALA-induced tolerance to oxidation stress and regulation of chlorophyll synthesis under low temperature Exogenous ALA alleviated low temperature caused chlorophyll synthesis obstacle of uroporphyrinogen III (UROIII) conversion to protoporphyrin IX (Proto IX), and enhanced the production of chlorophyll and its precursors, including endogenous ALA, Proto IX, Mg-protoporphyrin IX (Mg-proto IX), and protochlorophyll (Pchl), under low temperature in tomato leaves However, ALA did not regulate chlorophyll synthesis at the level of transcription Notably, ALA up-regulated the GSTU43 gene and protein expression and increased GST activity Silencing of GSTU43 with virus-induced gene silencing reduced the activities of GST, superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase, and increased the membrane lipid peroxidation; while fed with ALA significant increased all these antioxidase activities and antioxidant contents, and alleviated the membrane damage ALA triggered GST activity encoded by GSTU43, and increased tomato tolerance to low temperature-induced oxidative stress, perhaps with the assistance of ascorbate- and/or a glutathione-regenerating cycles, and actively regulated the plant redox homeostasis This latter effect reduced the degree of membrane lipid peroxidation, which was essential for the coordinated synthesis of chlorophyll
TL;DR: In vivo studies showed that the P p IX-loaded HLDM micelles could induce remarkable anti-tumor effect, and a promising laminarin-based nanomedicine platform acts as a new drug delivery system to enhance the uptake, accumulation, and PDT efficacy of Pp IX in vitro and in vivo.
Abstract: Laminarin conjugate-based nano-scaled particles were in this study proposed as a delivery system for protoporphyrin IX (Pp IX) in photodynamic therapy (PDT) of human breast cancer cells (MCF-7). Hematin-Laminarin-Dithiodipropionic Acid-MGK, named as HLDM, was an amphiphilic carrier material with dual pH/redox sensitive that could be used to load hydrophobic drug to improve their solubility and enhance biocompatibility. Therefore, we combined photosensitizer (Pp IX) with HLDM to fabricate a novel nano-micelles, herein called Pp IX-loaded HLDM micelles. The Pp IX-loaded HLDM micelles were 149.3 ± 35 nm sized in neutral water. Phototoxicity, in vitro PDT effect, and dual sensibility to pH and redox microenvironment of Pp IX-loaded HLDM micelles were examined at different concentrations by using MCF-7 human breast cancer cells. The experiments on phototoxicity and reactive oxygen species (ROS) production proved that the micelles could produce PDT to kill the cancer cells with a certain wavelength light. The apoptosis experiment indicated that the micelles could cause nuclear damage. In vivo PDT effect of the micelles was studied by constructing the tumor-bearing nude mouse model of MCF-7 cells. In vivo studies showed that the Pp IX-loaded HLDM micelles could induce remarkable anti-tumor effect. A promising laminarin-based nanomedicine platform acts as a new drug delivery system to enhance the uptake, accumulation, and PDT efficacy of Pp IX in vitro and in vivo.
TL;DR: Reducing FECH level by silencing FECH in SkBr3 breast cancer cells completely abrogated the enhancement effect of DFO, and demonstrates that FECH activity is an important determinant of tumor response to DFO treatment.
Abstract: Aminolevulinic acid (ALA) is a prodrug that is metabolized in the heme biosynthesis pathway to produce protoporphyrin IX (PpIX) for tumor fluorescence detection and photodynamic therapy (PDT). The iron chelator deferoxamine (DFO) has been widely used to enhance PpIX accumulation by inhibiting the iron-dependent bioconversion of PpIX to heme, a reaction catalyzed by ferrochelatase (FECH). Tumor response to DFO treatment is known to be highly variable, and some tumors even show no response. Given the fact that tumors often exhibit reduced FECH expression/enzymatic activity, we examined how reducing FECH level affected the DFO enhancement effect. Our results showed that reducing FECH level by silencing FECH in SkBr3 breast cancer cells completely abrogated the enhancement effect of DFO. Although DFO enhanced ALA-PpIX fluorescence and PDT response in SkBr3 vector control cells, it caused a similar increase in MCF10A breast epithelial cells, resulting in no net gain in the selectivity toward tumor cells. We also found that DFO treatment induced less increase in ALA-PpIX fluorescence in tumor cells with lower FECH activity (MDA-MB-231, Hs 578T) than in tumor cells with higher FECH activity (MDA-MB-453). Our study demonstrates that FECH activity is an important determinant of tumor response to DFO treatment.
TL;DR: This study indicates that modification of the amino group in 5-ALA derivatives with a self-immolative disulfide linker is an effective strategy to improve their chemical stability and pharmacological activities, and SA is a potential photosensitizer for photodiagnosis and PDT of tumors.
TL;DR: Clinical clearance was reduced in lesions located on the limbs, hands and feet with lower Ppix accumulation and subsequent photobleaching adversely affecting the outcome achieved, and if air cooling pain relief was employed during light irradiation, PpIX photOBleaching was lower and this resulted in an approximate three-fold reduction in the likelihood of achieving clinical clearance.
Abstract: Photodynamic therapy (PDT) is a light activated drug therapy that can be used to treat a number of dermatological cancers and precancers. Improvement of efficacy is required to widen its application. Clinical protoporphyrin IX (PpIX) fluorescence data were obtained using a pre-validated, non-invasive imaging system during routine methyl aminolevulinate (MAL)-PDT treatment of 172 patients with licensed dermatological indications (37.2% actinic keratosis, 27.3% superficial basal cell carcinoma and 35.5% Bowen's disease). Linear and logistic regressions were employed to model any relationships between variables that may have affected PpIX accumulation and/or PpIX photobleaching during irradiation and thus clinical outcome at three months. Patient age was found to be associated with lower PpIX accumulation/photobleaching, however only a reduction in PpIX photobleaching appeared to consistently adversely affect treatment efficacy. Clinical clearance was reduced in lesions located on the limbs, hands and feet with lower PpIX accumulation and subsequent photobleaching adversely affecting the outcome achieved. If air cooling pain relief was employed during light irradiation, PpIX photobleaching was lower and this resulted in an approximate three-fold reduction in the likelihood of achieving clinical clearance. PpIX photobleaching during the first treatment was concluded to be an excellent predictor of clinical outcome across all lesion types.
TL;DR: PpIX and BPD target cancer cells’ vulnerabilities namely activate TAp73 tumor suppressor and inhibit oncogenic Trx1, and may contribute to faster repurposing of Ppix and B PD to treat pancreatic tumors.
Abstract: Aim: TAp73 is a tumor suppressor, which compensates for p53 loss and induces apoptosis in tumors in response to genotoxic stress or small-molecule treatments. Pancreatic ductal adenocarcinoma has a...
TL;DR: An ester between aminolaevulinic acid (ALA) and CP94 was synthesized (AP2-18) and experimentally evaluated to determine whether protoporphyrin IX (PpIX)-induced PDT effectiveness could be improved as discussed by the authors.
TL;DR: It is suggested that frataxin could be the iron donor in the final step of heme synthesis in plant mitochondria, and this work constitutes an important advance in the elucidation of the mechanisms of he me synthesis in plants.
TL;DR: It is demonstrated that presence of serum in cell culture medium and differences in cellular confluence can negatively influence Ppix accumulation in U87 cell lines and the efficacy of a precisely tuned pharmacological treatment in increasing PpIX accumulation and consequently fluorescence in glioblastoma cells is shown.
Abstract: Fluorescence image guided surgical resection (FIGR) of high grade gliomas (HGGs) takes advantage of the accumulation of the tracer protoporphyrin IX (PpIX) in glioma cells following administration of 5-aminolevulinic acid (5-ALA). Occasionally, PpIX fluorescence intensity may be insufficient, thus compromising the efficacy and precision of the surgical intervention. The cause for the signal variation is unclear and strategies to improve the intensity of PpIX fluorescence are considered necessary. We have previously shown that differential expression of the epidermal growth factor receptor in glioblastoma cells affects PpIX fluorescence. Herein, we investigated other factors impairing PpIX accumulation and pharmacological treatments able to enhance PpIX fluorescence in glioblastoma cells displaying lower signal. In the present study we demonstrate that presence of serum in cell culture medium and differences in cellular confluence can negatively influence PpIX accumulation in U87 cell lines. We hypothesized that PpIX fluorescence intensity results from the interplay between the metabolic clearance of PpIX mediated by ferrochelatase and heme oxygenase-1 and the cellular efflux of PpIX through the ATP-binding cassette subfamily G member 2 (ABCG2). Based on the availability of compounds targeting these proteins and inhibiting them, in this study we used modulators such as genistein, an isoflavone able to inhibit ABCG2; deferoxamine, which chelate iron ions impairing FECH activity and tin protoporphyrin IX (SnPP), the specific HO-1 inhibitor. Finally, we showed the efficacy of a precisely tuned pharmacological treatment in increasing PpIX accumulation and consequently fluorescence in glioblastoma cells. This strategy may translate in more sensitive tracing of tumor cells in-vivo and improved FIGR of HGGs and possibly low grade gliomas (LGGs).
TL;DR: It is demonstrated that, the probes can be effectively photosensitized to produce reactive oxygen species (ROS) under the excitation of 980 nm NIR light and present an outstanding ability in targeting tumor cells and high efficiency in inducing cell death through the photoactivation by 980‽nm laser.
Abstract: Photodynamic therapy that involves the photosensitizer transferring the absorbed energy to surrounding tissue oxygen has been used in clinical treatment of cancer. However, the clinically used porphyrin derivatives as PDT photosensitizers usually need high energy excitation light, which generally gives rise to limited tissue penetration depth and thereby limited photoactivation efficiency. Herein, protoporphyrin IX was chemically modified by jeffamines for improving the hydrophilicity and biocompatibility, and the resulting water-soluble porphyrin-jeffamine (PJ) was further covalently conjugated to the PEGylated upconversion nanoparticles (UCNPs) via “click” reaction, which is an efficient way to precisely control the resonance energy transfer from UCNPs to PJs. Our work demonstrates that, the probes can be effectively photosensitized to produce reactive oxygen species (ROS) under the excitation of 980 nm NIR light. When compared with the clinically used photosensitizer molecules, the probes exhibit a comparable capability for producing ROS. Besides, the probes present an outstanding ability in targeting tumor cells and high efficiency in inducing cell death through the photoactivation by 980 nm laser.
TL;DR: The presented device is the first quantitative wide-field fluorescence imaging system for PDT dosimetry designed for clinical skin use and for maximal ease of translation into clinical workflow.
Abstract: Significance: While clinical treatment of actinic keratosis by photodynamic therapy (PDT) is widely practiced, there is a well-known variability in response, primarily caused by heterogeneous accumulation of the photosensitizer protoporphyrin IX (PpIX) between patients and between lesions, but measurement of this is rarely done. Aim: Develop a smartphone-based fluorescence imager for simple quantitative photography of the lesions and their PpIX levels that can be used in a new clinical workflow to guide the reliability of aminolevulinic acid (ALA) application for improved lesion clearance. Approach: The smartphone fluorescence imager uses an iPhone and a custom iOS application for image acquisition, a 3D-printed base for measurement standardization, an emission filter for PpIX fluorescence isolation, and a 405-nm LED ring for optical excitation. System performance was tested to ensure measurement reproducibility and the ability to capture photosensitizer accumulation and photobleaching in pre-clinical and clinical settings. Results: PpIX fluorescence signal from tissue-simulating phantoms showed linear sensitivity in the 0.01 to 2.0 μ M range. Murine studies with Ameluz® aminolevulinic acid (ALA) gel and initial human testing with Levulan® ALA cream verified that in-vivo imaging was feasible, including that PpIX production over 1 h is easily captured and that photobleaching from the light treatment could be quantified. Conclusions: The presented device is the first quantitative wide-field fluorescence imaging system for PDT dosimetry designed for clinical skin use and for maximal ease of translation into clinical workflow. The results lay the foundation for using the system in clinical studies to establish treatment thresholds for the individualization of PDT treatment.
07 Aug 2019
TL;DR: It is demonstrated that cancer cells exhibited dormancy in a cell density-dependent manner not only in spheroids but also in 2D culture, and ALA-PDT would be an effective approach for dormant cancer cells and can be enhanced by combining with a cell-growth inhibitor.
Abstract: Photodynamic therapy (PDT) and diagnosis (PDD) using 5-aminolevulinic acid (ALA) to drive the production of an intracellular photosensitizer, protoporphyrin IX (PpIX), are in common clinical use. However, the tendency to accumulate PpIX is not well understood. Patients with cancer can develop recurrent metastatic disease with latency periods. This pause can be explained by cancer dormancy. Here we created uniformly sized PC-3 prostate cancer spheroids using a 3D culture plate (EZSPHERE). We demonstrated that cancer cells exhibited dormancy in a cell density-dependent manner not only in spheroids but also in 2D culture. Dormant cancer cells accumulated high PpIX levels and were sensitive to ALA-PDT. In dormant cancer cells, transporter expressions of PEPT1, ALA importer, and ABCB6, an intermediate porphyrin transporter, were upregulated and that of ABCG2, a PpIX exporter, was downregulated. PpIX accumulation and ALA-PDT cytotoxicity were enhanced by G0/G1-phase arrestors in nondormant cancer cells. Our results demonstrate that ALA-PDT would be an effective approach for dormant cancer cells and can be enhanced by combining with a cell-growth inhibitor.
TL;DR: In this article, a platform for biosynthesis of porphyrins in Escherichia coli was developed with the aim of producing a variety of Porphyrin derivatives for examining their photocatalytic properties within a porous material.
Abstract: Porphyrins absorb light to initiate photocatalytic activity. The complex, asymmetric structures of natural porphyrins such as heme, chlorophyll, and their derivatives hold unique interest. A platform for biosynthesis of porphyrins in Escherichia coli is developed with the aim of producing a variety of porphyrins for examining their photocatalytic properties within a porous material. Bioderived protoporphyrin IX is tethered inside the highly porous metal-organic framework (MOF) NU-1000 via solvent-assisted ligand incorporation. This MOF catalyzes the photocatalytic oxidation of 2-chloroethyl ethyl sulfide with improved performance over an expanded range of the visible spectrum when compared to unmodified NU-1000.
01 Jan 2019
TL;DR: The reaction mechanisms, enzymology and structure function relationships of the enzymes involved in synthesizing chlorophyll a from protoporphyrin IX have been reviewed extensively over the last 20 years.
Abstract: Chlorophyll biosynthesis and specific enzymes with the chlorophyll biosynthetic pathway have been reviewed extensively over the last 20 years. This chapter is intended to both summarize and update on previous reviews but it will primarily concentrate on the reaction mechanisms, enzymology and structure function relationships of the enzymes involved in synthesizing chlorophyll a from protoporphyrin IX.
TL;DR: Photo-bactericidal activity of modified fibers against 2 gram-positive bacteria strains, including Staphylococcus aureus and Bacillus subtilis, were investigated and compared to those of unmodified and azido-modified Lyocell fibers.
Abstract: Here, we report the preparation of porphyrin-functionalized Lyocell fibers according to an azide-alkyne click concept. First, azido-modified Lyocell fibers and alkynylated protoporphyrin building b...