In vivo production of fluorine-18 in a chicken egg tumor model of breast cancer for proton therapy range verification.
In vivo production of fluorine-18 in a chicken egg tumor model of breast cancer for proton therapy range verification.
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DOI：
10.1038/s41598-022-11037-7
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发表时间：
2022-04-30
影响因子：
4.6
通讯作者：
Fraile, Luis M.
中科院分区：
文献类型：
--
作者：
Espana, Samuel;Sanchez-Parcerisa, Daniel;Bragado, Paloma;Gutierrez-Uzquiza, Alvaro;Porras, Almudena;Gutierrez-Neira, Carolina;Espinosa, Andrea;Onecha, Victor V.;Ibanez, Paula;Sanchez-Tembleque, Victor;Udias, Jose M.;Fraile, Luis M.
通过正电子发射断层扫描（PET）的临床质子治疗系统的范围验证不是一种成熟的技术，有两个主要问题：布拉格峰区域的低能质子信号不足和PET发射器的生物洗脱。已经提出使用造影剂（包括18 O、68 Zn或63 Cu，在产生PET发射体的核反应中对于低能质子具有高截面的同位素）来增强质子路径的最后毫米中的PET信号。在这里，我们调查的可能性18 O-富集水（18-W），一种潜在的造影剂，可以在大比例纳入活组织中，通过取代常规水。我们假设18-W也可以缓解生物洗脱的问题，因为活细胞内产生的PET（18 F）同位素将以氟阴离子（F-）的形式被捕获，即使在照射后数小时也可以检测到其信号。为了验证我们的假设，我们设计了一个有两个主要目标的实验：首先，证明18-W可以将足够的18 O掺入到活的有机体中，以在质子照射后从18 F产生可检测的信号，其次，确定仍然被困在细胞内的活性量。实验在头颈癌的鸡胚绒毛尿囊膜肿瘤模型上进行。七个鸡蛋与可见的肿瘤注入18-W和8-MeV的质子（范围在水中：0.74毫米），相当于临床质子在粒子范围的结束照射。在小动物PET-CT扫描仪中检测和定量照射后产生的活性，并通过将离体肿瘤置于γ辐射检测器中进一步研究。在所获得的图像中，可以在照射后长达9小时的活鸡胚的肿瘤区域中检测到18 F（源自18-W）的比活度，这证实了如果采用合适的造影剂，则低能质子确实可以产生可检测的PET信号。此外，在两个鸡蛋中的动态PET研究证明了生物洗脱的最小影响，在照射后8小时，68%保留了特定的18F活性。此外，4个辐照肿瘤的离体分析表明，目标中高达3%的氧原子被来自注入的18-W的18 O取代，并且证明在洗涤后18F的比活性的截留率为59%，支持我们的假设，即F-离子仍然被截留在细胞内。注入18-W可以通过取代细胞内的常规水将18 O掺入动物组织中，当用低能质子照射时产生PET信号，该信号可用于质子治疗的范围验证。细胞内产生的18F仍然被捕获，并且遭受最小的生物洗脱，从而允许更长时间的PET采集更清晰的定位。进一步的研究必须评估该技术在更接近临床实践的剂量测定条件下的可行性，以确定其在患者中使用的潜在方案。
Range verification of clinical protontherapy systems via positron-emission tomography (PET) is not a mature technology, suffering from two major issues: insufficient signal from low-energy protons in the Bragg peak area and biological washout of PET emitters. The use of contrast agents including 18O, 68Zn or 63Cu, isotopes with a high cross section for low-energy protons in nuclear reactions producing PET emitters, has been proposed to enhance the PET signal in the last millimeters of the proton path. However, it remains a challenge to achieve sufficient concentrations of these isotopes in the target volume. Here we investigate the possibilities of 18O-enriched water (18-W), a potential contrast agent that could be incorporated in large proportions in live tissues by replacing regular water. We hypothesize that 18-W could also mitigate the problem of biological washout, as PET (18F) isotopes created inside live cells would remain trapped in the form of fluoride anions (F-), allowing its signal to be detected even hours after irradiation. To test our hypothesis, we designed an experiment with two main goals: first, prove that 18-W can incorporate enough 18O into a living organism to produce a detectable signal from 18F after proton irradiation, and second, determine the amount of activity that remains trapped inside the cells. The experiment was performed on a chicken embryo chorioallantoic membrane tumor model of head and neck cancer. Seven eggs with visible tumors were infused with 18-W and irradiated with 8-MeV protons (range in water: 0.74 mm), equivalent to clinical protons at the end of particle range. The activity produced after irradiation was detected and quantified in a small-animal PET-CT scanner, and further studied by placing ex-vivo tumours in a gamma radiation detector. In the acquired images, specific activity of 18F (originating from 18-W) could be detected in the tumour area of the alive chicken embryo up to 9 h after irradiation, which confirms that low-energy protons can indeed produce a detectable PET signal if a suitable contrast agent is employed. Moreover, dynamic PET studies in two of the eggs evidenced a minimal effect of biological washout, with 68% retained specific 18F activity at 8 h after irradiation. Furthermore, ex-vivo analysis of 4 irradiated tumours showed that up to 3% of oxygen atoms in the targets were replaced by 18O from infused 18-W, and evidenced an entrapment of 59% for specific activity of 18F after washing, supporting our hypothesis that F- ions remain trapped within the cells. An infusion of 18-W can incorporate 18O in animal tissues by replacing regular water inside cells, producing a PET signal when irradiated with low-energy protons that could be used for range verification in protontherapy. 18F produced inside cells remains entrapped and suffers from minimal biological washout, allowing for a sharper localization with longer PET acquisitions. Further studies must evaluate the feasibility of this technique in dosimetric conditions closer to clinical practice, in order to define potential protocols for its use in patients.
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影响因子：
3.5
作者：
Hueso-González F;Rabe M;Ruggieri TA;Bortfeld T;Verburg JM
通讯作者：
Verburg JM
影响因子：
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作者：
Cho J;Grogg K;Min CH;Zhu X;Paganetti H;Lee HC;El Fakhri G
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影响因子：
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作者：
Herraiz, J. L.;Espana, S.;Udias, J. M.
通讯作者：
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影响因子：
4.7
作者：
Jacobson, Orit;Kiesewetter, Dale O.;Chen, Xiaoyuan
通讯作者：
Chen, Xiaoyuan
DOI：
10.1016/j.nima.2012.11.009
发表时间：
2013-02-11
影响因子：
1.4
作者：
Fraile, L. M.;Mach, H.;Udias, J. M.
通讯作者：
Udias, J. M.