Improving contrast enhancement in magnetic resonance imaging using 5-aminolevulinic acid-induced protoporphyrin IX for high-grade gliomas

Yamamoto, Junkoh; Kakeda, Shingo; Yoneda, Tetsuya; Ogura, Shun‐ichiro; Shimajiri, Shohei; Tanaka, Tohru; Korogi, Yukunori; Nishizawa, Shigeru

doi:10.3892/ol.2016.5539

Cited by 5 publications

(11 citation statements)

References 51 publications

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“…For multi-dose (fractionated) IR, the PpIX concentration within tumour cells may be altered with each fraction. In addition, we previously confirmed 5-ALA-induced PpIX as a potential biomarker for malignant gliomas via MRI in a prospective clinical case study (64). Therefore, we suggest that modulation of the intensity and field of the radiation beam based on 5-ALA-induced PpIX tumour concentrations evaluated by MRI for each patient and for each fraction can increase the therapeutic effect in tumours and decrease the side effects of IR, such as radiation necrosis, brain oedema, and leukoencephalopathy, on normal surrounding tissue by avoiding excessive IR exposure.…”

Section: -Ala Enhances Mitochondrial Stress By Ir and Leads To Increased Cell Death With Mitochondrial Changes In Glioma Cellsmentioning

confidence: 58%

5-Aminolevulinic acid enhances mitochondrial stress upon ionizing irradiation exposure and increases delayed production of reactive oxygen species and cell death in glioma cells

Ueta

Yamamoto

Tanaka

et al. 2016

International Journal of Molecular Medicine

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5-Aminolevulinic acid (5-ALA) can accumulate protoporphyrin IX (PpIX) in tumour cell mitochondria and is well known for its utility in fluorescence-guided resection of malignant gliomas as a live molecular marker. Previously, we and other authors demonstrated that 5-ALA has a radiosensitizing effect for tumours. In the present study, we aimed to investigate the mechanism underlying the radiosensitizing effect of 5-ALA by focusing on glioma cell mitochondria. Using an enhancer (ciprofloxacin) of 5-ALA-induced PpIX accumulation, we evaluated the influence of ionizing irradiation (IR) and delayed reactive oxygen species (ROS) production 12 h after IR by colony-forming assay and flow cytometry (FCM) with different amounts of PpIX accumulation. The mitochondrial mass and mitochondrial electron transport chain (mtETC) activity were evaluated by FCM and western blot analysis. Cell death and delayed ROS production after IR in glioma cells were increased in proportion to 5-ALA-induced PpIX accumulation. Delayed ROS production enhanced by 5-ALA localized to the glioma cell mitochondria. Mitochondrial mass and mitochondrial complex III activity, among mtETC factors, were also increased 12 h after IR in glioma cells in proportion to 5-ALA-induced PpIX accumulation with some variation. These results suggest that 5-ALA enhances IR-induced mitochondrial oxidative stress and leads to increased cell death with mitochondrial changes, thereby acting as a targeting mitochondrial drug, and so‑called radiosensitizer in glioma cells.

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Section: -Ala Enhances Mitochondrial Stress By Ir and Leads To Increased Cell Death With Mitochondrial Changes In Glioma Cellsmentioning

confidence: 58%

5-Aminolevulinic acid enhances mitochondrial stress upon ionizing irradiation exposure and increases delayed production of reactive oxygen species and cell death in glioma cells

Ueta

Yamamoto

Tanaka

et al. 2016

International Journal of Molecular Medicine

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“…Cleavage of the Boc-protected group provided dendron 8. The structure of dendron 8 was confirmed by 1 H and 13 C NMR and LC-MS/MS. Dendron 8 was coupled to 9 using the standard amide coupling reagents DCC and HOBt to provide 10 in a reasonable yield (48%).…”

Section: ■ Results and Discussionmentioning

confidence: 92%

“…Alkaline hydrolysis of 11 afforded core 12. Coupling of Fmoc-β-alanine and aminomethane tris(3-tert-butoxycarbonyl propionate) (13) in the presence of HOBt and DCC provided 14 in excellent yield (92%). Tri-acid 15 was obtained in quantitative yield by the treatment of 14 with formic acid.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Design of Bifunctional Dendritic 5-Aminolevulinic Acid and Hydroxypyridinone Conjugates for Photodynamic Therapy

et al. 2018

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Iron chelators have recently attracted interest in the field of photodynamic therapy (PDT) owing to their role in enhancement of intracellular protoporphyrin IX (PpIX) generation induced by 5-aminolevulinic acid (ALA) via the biosynthetic heme cycle. Although ALA is widely used in PDT, cellular uptake of ALA is limited by its hydrophilicity. In order to improve ALA delivery and enhance the PpIX production, several dendrimers incorporating both ALA and 3-hydroxy-4-pyridinone (HPO) were synthesized. The ability of the dendrimers to enter cells and be metabolized to the PpIX photosensitizer was studied in several human cancer cell lines. The dendrimers were found to be significantly more efficient than ALA alone in PpIX production. The higher intracellular PpIX levels showed a clear correlation with enhanced cellular phototoxicity following light exposure. Dendritic derivatives are therefore capable of efficiently delivering both ALA and HPO, which act synergistically to amplify in vitro PpIX levels and enhance PDT efficacy.

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“…In these reactions, the photoactive substance 5‐aminobutyric acid (ALA) should be used, as ALA can generate strongly photoactive PpIX in the living body, which can easily accumulate in malignant tumors and can release red fluorescence under excitation . Thus, ALA can be widely applied in the early diagnosis and positioning of malignant tumors . Red fluorescence is dependent on ALA dosage, but ALA is a heme precursor that accumulates in the human body, leading to acute intermittent porphyria, high‐dose ALA is associated with several symptoms, such as abdominal pain attacks, neuromuscular weaknesses, neuropsychiatric alterations, and increased hepatocellular carcinoma incidence, and the use of exogenous ALA to elevate porphyrin levels in photodynamic therapy adds further significance to ALA toxicology .…”

Section: Introductionmentioning

confidence: 99%

Comparative Study of the Effects of Ferrochelatase‐siRNA Transfection Mediated by Ultrasound Microbubbles and Polyethyleneimine in Combination with Low‐dose ALA to Enhance PpIX Accumulation in Human Endometrial Cancer Xenograft Nude Mice Models

Zhang

Gao

et al. 2019

Photochem & Photobiology

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Comparison of the fluorescence intensity caused by the accumulation of PpIX in endometrial cancer xenografts in nude mice after low-dose 5-Aminolevulinic acid (ALA) injection combined with siRNA transfection was mediated by ultrasound microbubbles and polyethyleneimine (PEI) to explore the feasibility of the ultrasound microbubble technique as transfection agents. Knockdown of ferrochelatase (FECH) in human endometrial cancer xenografts in nude mice was performed by transfection with FECH-siRNA mediated by PEI and ultrasound microbubbles alone or in combination; then, low-dose ALA was injected. Subsequently, an in vivo animal imaging system was employed to detect the fluorescence intensity in xenografts. Red fluorescence was observed in xenografts given more than 6.25 mg kg À1 of ALA. When the dose of ALA was greater than 50 mg kg À1 , there was a significant difference in the fluorescence between tumor and other tissues. After the nude mice were transfected with siRNA and treated with low-dose ALA (1.0 mg kg À1 ), apparent PpIX fluorescence of the xenografts was observed, and the fluorescence intensity was PEI+ ultrasound microbubbles > PEI > ultrasound microbubbles. Ultrasound microbubbles in combination with PEI could generate a higher fluorescence intensity of PpIX than that obtained with ultrasound microbubbles or PEI alone, and ultrasound microbubbles could wholly or partially replace PEI under certain conditions. *Corresponding authors' e-mails: twxy163@163.com (Xiaoyu Wang); shaotsiang@ 163.com (Shaoqiang Lin) † Co-first authors.

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Improving contrast enhancement in magnetic resonance imaging using 5-aminolevulinic acid-induced protoporphyrin IX for high-grade gliomas

Cited by 5 publications

References 51 publications

5-Aminolevulinic acid enhances mitochondrial stress upon ionizing irradiation exposure and increases delayed production of reactive oxygen species and cell death in glioma cells

5-Aminolevulinic acid enhances mitochondrial stress upon ionizing irradiation exposure and increases delayed production of reactive oxygen species and cell death in glioma cells

Design of Bifunctional Dendritic 5-Aminolevulinic Acid and Hydroxypyridinone Conjugates for Photodynamic Therapy

Comparative Study of the Effects of Ferrochelatase‐siRNA Transfection Mediated by Ultrasound Microbubbles and Polyethyleneimine in Combination with Low‐dose ALA to Enhance PpIX Accumulation in Human Endometrial Cancer Xenograft Nude Mice Models

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