Automated radiosynthesis and in vivo evaluation of [18F]ADPM06 as a photosensitizer for photodynamic therapy
Kazunori KawamuraTomoteru YamasakiMasayuki FujinagaKokufuta TomomiYiding ZhangWakana MoriYusuke KuriharaMasanao OgawaKaito TsukagoeNobuki NengakiMing‐Rong Zhang
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Abstract Background A family of BF 2 -chelated tetraaryl-azadipyrromethenes was developed as non-porphyrin photosensitizers for photodynamic therapy. Among the developed photosensitizers, ADPM06 exhibited excellent photochemical and photophysical properties. Molecular imaging is a useful tool for photodynamic therapy planning and monitoring. Radiolabeled photosensitizers can efficiently address photosensitizer biodistribution, providing helpful information for photodynamic therapy planning. To evaluate the biodistribution of ADPM06 and predict its pharmacokinetics on photodynamic therapy, we synthesized [ 18 F]ADPM06 and evaluated its in vivo properties. Results [ 18 F]ADPM06 was automatically synthesized by Lewis acid-assisted isotopic 18 F- 19 F exchange using ADPM06 and tin (IV) chloride at room temperature for 10 min. Radiolabeling was carried out using 0.4 µmol of ADPM06 and 200 µmol of tin (IV) chloride. The radiosynthesis time was approximately 60 min, and the radiochemical purity was > 95% at the end of the synthesis. The decay-corrected radiochemical yield from [ 18 F]F - at the end of irradiation was 13 ± 2.7% ( n = 5). In the biodistribution study, radioactivity levels in the heart, lungs, liver, pancreas, spleen, kidney, small intestine, muscle, and brain gradually decreased over 120 min after the initial uptake. The mean radioactivity level in the bone was the highest among all organs investigated and increased for 120 min after injection. Upon co-injection with ADPM06, the radioactivity levels in the blood, heart, and brain significantly increased, whereas those in the lung, liver, pancreas, kidney, small intestine, muscle, and bone were not affected. In the metabolite study of the plasma in mice, the percentage of radioactivity corresponding to [ 18 F]ADPM06 was 76.3 ± 1.6% ( n = 3). In a positron emission tomography study using MDA-MB-231-HTB-26 tumor-bearing mice, radioactivity accumulated in the bone at a relatively high level and in the tumor at a moderate level for 60 min after injection. Conclusions We synthesized [ 18 F]ADPM06 using an automated 18 F-labeling synthesizer and evaluated the biodistribution of [ 18 F]ADPM06 in mice, which may be useful for predicting the pharmacokinetics of ADPM06 in photodynamic therapy.Keywords:
Biodistribution
Radiosynthesis
Photodynamic Therapy(PDT) was a new technology for disease diagnosis and treatment with photosensitizer conducting photodynamic reaction.Photosensitizer was gradually matured through the first-generation photosensitizers-porphyrin and its derivatives,second-generation photosensitizer-phthalocyanine compounds,as well as third-generation photo-sensitizer.The property and synthesis of the three generations of photosensitizers were described.
First generation
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Photodynamic therapy (PDT) is highly effective in treating tumors located near body surface, offering strong tumor suppression and low damage to normal tissue nearby. PDT is also effective for treating a number of other conditions. PDT not only provide a precise and selective method for the treatment of various diseases by itself, it can also be used in combination with other traditional therapies. Because PDT uses light as the unique targeting mechanism, it has simpler and more direct targeting capability than traditional therapies. The core material of a PDT system is the photosensitizer which converts light energy to therapeutic factors/substances. Different photosensitizers have their distinct characteristics, leading to different advantages and disadvantages. These could be enhanced or compensated by using proper PDT system. Therefore, the selected type of photosensitizer would heavily influence the overall design of a PDT system. In this article, we evaluated major types of inorganic and organic PDT photosensitizers, and discussed future research directions in the field.
Light energy
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Photodynamic therapy (PDT) requires a photosensitizer, light, and oxygen to induce cell death. The majority of efforts to advance PDT focus only on the first two components. Here, we employ perfluorocarbon nanoemulsions to simultaneously deliver oxygen and a photosensitizer. We find that the implementation of fluorous soluble photosensitizers enhances the efficacy of PDT.
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Photodynamic sensitizers are drugs activated by light of a specific wavelength and are used in the photodynamic therapy (PDT) of certain diseases. Second‐ and third‐generation photosensitizers with improved PDT properties are now under investigation. In this issue of the British Journal of Pharmacology , Leung et al . have described the synthesis and investigation of a second‐generation photosensitizer (BAM‐SiPc) targeted towards the cells of HepG2 and HT29 tumours. BAM‐SiPc is selectively functionalized with bis‐amino groups and has demonstrated potent PDT activity in a small animal model. However, it also exhibited non‐selective distribution and accumulation in multiple animal (small mouse) organs and tissue. These issues highlight the importance and need for good biodistribution and localization properties for an efficacious photosensitizer. The lack of tumour specificity may have a significant impact on the potential BAM‐SiPc has in clinical PDT.
Biodistribution
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Photodynamic therapy (PDT) kills cancer cells by converting tumour oxygen into reactive singlet oxygen ((1)O2) using a photosensitizer. However, pre-existing hypoxia in tumours and oxygen consumption during PDT can result in an inadequate oxygen supply, which in turn hampers photodynamic efficacy. Here to overcome this problem, we create oxygen self-enriching photodynamic therapy (Oxy-PDT) by loading a photosensitizer into perfluorocarbon nanodroplets. Because of the higher oxygen capacity and longer (1)O2 lifetime of perfluorocarbon, the photodynamic effect of the loaded photosensitizer is significantly enhanced, as demonstrated by the accelerated generation of (1)O2 and elevated cytotoxicity. Following direct injection into tumours, in vivo studies reveal tumour growth inhibition in the Oxy-PDT-treated mice. In addition, a single-dose intravenous injection of Oxy-PDT into tumour-bearing mice significantly inhibits tumour growth, whereas traditional PDT has no effect. Oxy-PDT may enable the enhancement of existing clinical PDT and future PDT design.
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Photodynamic therapy (PDT) is a noninvasive technique for diagnosis and therapy of diseases by using the photodynamic effects. Clinically, PDT has been used in the treatments of various tumors in head and neck, pancreas, lung, prostate and skin. Compared to the traditional treatments of tumors, PDT exhibits many advantages such as less damage, low toxicity, good selectivity, wide applicability and less drug resistance, which draw more attention in the field of tumor therapy. The action mechanisms of PDT against tumors are very complicated and photosensitizer is one of the key factors that influence the photodynamic effects of PDT. To enhance the tumor-targeted delivery of photosensitizer and improve their oxygen-carrying ability are believed as the important ways to increase the photodynamic effects. In this paper, review is given on the research advances in action mechanisms of photodynamic therapy and photosensitizer in recent years.
Key words:
Photodynamic therapy; Photosensitizer; Action mechanism
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Photodynamic therapy (PDT) requires photosensitizer, light, and oxygen to induce cell death. The majority of efforts to advance PDT focus only on the first two components. Here, we employ perfluorocarbon nanoemulsions to simultaneously deliver oxygen and photosensitizer. We find that the implementation of fluorous soluble photosensitizers enhances the efficacy of PDT.
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Photodynamic therapy (PDT) is a treatment applied by a laser system in combination with a photosensitive drug (photosensitizer) that is excited by laser light. Accumulation of the photosensitizer at the disease site and local excitation by laser irradiation make it possible to selectively treat the diseased region, preserving the functionality and appearance of the treated area. Photodynamic Diagnosis (PDD) enables the identification of a specific disease site through the capturing of fluorescence generated by the photosensitizer. It is expected PDD will prove useful in identifying the disease site for Glioblastoma, amalignant brain tumor for which clear boundaries cannot be easily detected.
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<p>Photodynamic therapy (PDT) requires photosensitizer, light, and oxygen to induce cell death. The majority of efforts to advance PDT focus only on the first two components. Here, we employ perfluorocarbon nanoemulsions to simultaneously deliver oxygen and photosensitizer. We find that the implementation of fluorous soluble photosensitizers enhances the efficacy of PDT. </p>
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Photodynamic Therapy (PDT) is a new method developed from last century to treat series of malignant tumor,superficial or intracavitary benign lesion by injection of photosensitiser systemic or local application,then a special wave-length light is used to treat the lesion.As an influential factor,Photosensitiser plays an important role in PDT.This article summarized the mechanism of PDT,characteristic and photochemistry of photosensitizer,focus on the uptake,distribution and effect in PDT of photosensitiser.
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