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. 2011 Jan;14(1):1-6.
doi: 10.3779/j.issn.1009-3419.2011.01.01.

[Experimental study of CT guided ³²P-CP-PLLA microparticle implantation in the treatment of rabbit VX2 lung tumor]

[Article in Chinese]
Donghui Pan  1 , Min Yang, Yuping Xu, Lizhen Wang, Lu Liu, Peilin Huang
Affiliations

[Experimental study of CT guided ³²P-CP-PLLA microparticle implantation in the treatment of rabbit VX2 lung tumor]

[Article in Chinese]
Donghui Pan et al. Zhongguo Fei Ai Za Zhi. 2011 Jan.

Abstract
in English, Chinese

Background and objective: ³²P-chromic phosphate-poly (L-lactic) acid (³²P-CP-PLLA) microparticle is a novel potent brachytherapy implant, which has good biocompatibility and biodegradability. The aim of this study is to investigate the changes of pathology and PET/CT images in VX2 rabbit tumor after treatment with intratumorol administration of ³²P-CP-PLLA microparticles, and to explore the effects and influence of tumor growth and apoptosis related proteins in VX2 lung tumor treatment with ³²P-CP-PLLA microparticles.

Methods: Twenty-four tumor bearing rabbits were randomly divided into 4 groups (6 in each group). Group 1, 2 and 3 were treated groups; group 4 was the control. Under CT guidance, ³²P-CPPLLA microparticles were implanted into tumors. Low, medium and high treatment doses were 93 MBq (group 1), 185 MBq (group 2) and 370 MBq (group 3), respectively. ¹⁸F-FDG PET/CT was performed at d0, d3, d7 and d14 after intratumoral administration. In the control group, ¹⁸F-FDG PET/CT images were acquired at the same time points but without treatment. The standardized uptake value (SUV) of tumor regions were calculated. After last PET/CT imaging, the rabbits were euthanized and the tumors were removed for histological and immunohistochemical examination. The pathology and the expression of apoptosis related proteins (bcl-2, bax) were compared.

Results: No significant difference of SUVmax was observed between the treatment groups and the control group at d0. At d14, the SUVmax values for group 1, 2 and 3 were 0.80±0.10, 1.1±0.19 and 2.85±0.15, respectively, and were significantly lower than that of the control group (5.61±0.50)(P < 0.05). Significant dose-response relationship was observed in SUVmax between group 1 and group 2, and the SUV values gradually decreased from d7 to d14 after treatment. In group 3, SUVmax gradually increased and reached a peak at d7 then significantly decreased. The SUVmax values of group 3 were significantly lower than those of the control at the same time point (P < 0.05). HE staining found degenerative necrosis at the site was nearby the microparticle. Necrosis became serious increasing with the radioactivity. Inflammatory cell infiltration was rarely seen in tumors treated with 93 MBq or 185 MBq ³²P-CP-PLLA microparticles. In contrast, the necrotic area was surrounded by marked inflammatory cell infiltration in group 3. IHC analysis showed that the expression of bcl-2 in treated groups were lower than those in the control group, and the expression of bax in treated group was higher than those in the control group (P < 0.05). The ratio of bcl-2/bax protein significantly decreased in the treated group (P < 0.05). Dose dependence was seen in the expression of apoptosis related proteins.

Conclusions: The sustained irradiation of ³²P-CP-PLLA microparticles can direct kill the VX2 tumor cell, thus the glycolysis of which were suppressed. Although the alive tumor cells still presented faraway from the microparticle, the expression of apoptosis related proteins in which were significantly different from the control. Bcl-2 and bax gene were induced to participate in regulation for the apoptosis of VX2 tumor cell by ionizing radiation from ³²P-CP-PLLA microparticles, so that the tumor growth was inhibited.

背景与目的: 新型放射性植入剂32P-磷酸铬-聚-L-乳酸（32P-CP-PLLA）粒子具有良好的生物相容性和降解性，适用于实体肿瘤的近距离放射治疗。本研究旨在探讨兔VX2肺肿瘤经32P-CP-PLLA粒子瘤体间植入近距离治疗前后PET/CT显像及病理学的变化，分析32P-CP-PLLA粒子植入对荷VX2肺癌兔肿瘤生长及凋亡相关蛋白的影响。

方法: 24只荷瘤兔随机分成4组。每组6只。1组-3组为治疗组；4组为对照组。在CT导引下经皮穿刺将总放射性活度为93 MBq、185 MBq和370 MBq的32P-CP-PLLA粒子分别植入1组、2组和3组肿瘤组织内。对照组不做任何干预。分别在治疗后第0天、第3天、第7天和第14天进行18F-FDG PET/CT显像，观察标准摄取值（standardized uptake value, SUV）的变化。最后1次PET/CT显像后处死荷瘤兔，取出肿瘤组织，进行病理学检查和免疫组织化学分析，比较肿瘤细胞形态和凋亡基因（bcl-2, bax）表达的变化。

结果: 第0天时，治疗组和对照组之间SUVmax无明显差异。治疗后第14天，1组、2组和3组SUVmax值分别为1.1±0.19、0.80±0.10和2.85±0.15，均较对照组（5.61±0.50）明显下降。第7天-第14天时，1组和2组SUVmax较第3天呈现持续下降趋势，且呈剂量效应关系（P < 0.05）。治疗后第3天-第14天，3组SUVmax较第0天显著上升，并在第7天达到峰值，后明显下降。同期3组SUVmax明显低于对照组SUVmax。HE染色显示近粒子处的肿瘤细胞变性坏死，坏死程度随剂量的增加而严重。3组可见坏死组织周围有大量炎性细胞浸润，而1组-2组炎性细胞浸润不明显。免疫组化显示治疗组bcl-2表达强度低于对照组，bax表达强度高于对照组（P < 0.05）。治疗组bcl-2/bax比值明显下调（P < 0.05）。凋亡基因的表达呈剂量效应关系。

结论: 32P-CP-PLLA粒子持续照射可直接杀伤VX2肿瘤细胞从而抑制其葡萄糖代谢功能。远离粒子处虽可见存活肿瘤细胞，但凋亡基因表达明显异于对照组。32P-CP-PLLA粒子可通过电离辐射诱导bcl-2和bax基因参与VX2移植瘤细胞凋亡过程的调控，从而抑制肿瘤生长。

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Figures

1
1
兔VX2肺癌PET/CT显像图。A、B、C和D分别为对照组、1组、2组和3组治疗第0天时PET/CT显像图。E、F、G和H分别为对照组、1组、2组和3组治疗第14天时PET/CT显像图。 PET/CT images of rabbit VX2 lung tumor. A, B, C and D are the PET/CT images of rabbit VX2 lung tumor of the control, group 1, group 2 and group 3 at d0. E, F, G and H are the PET/CT images of rabbit VX2 lung tumor of the control, group 1, group 2 and group 3 at d14 after treatment respectively.
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32P-CP-PLLA粒子植入后兔VX2肺癌最大标准摄取值（SUVmax）变化图 Changes in the SUVmax of rabbit VX2 lung tumor after implanted with 32P-CP-PLLA microparticle
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瘤体植入粒子后第14天肿瘤病理切片图。A：第14天后，1组、2组、3组和4组HE染色图及bcl-2和bax的免疫组化图片；B：bcl-2和bax定量分析图。*：与对照组比较，P < 0.05；+各治疗组之间比较，P < 0.05。 Histology and immunohistochemistry. A: Tumor stained with HE, bcl-2 and bax of the control, group 1, group 2 and group 3 on d14 after treatment respectively; B: Quantitative assessment of bcl-2 and bax expression. *: P < 0.05, bcl-2 and bax expressions of treated group was significantly different than that of the control group; +: P < 0.05. Significant differences were seen in bcl-2 and bax expression between each treated groups.
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