32P-磷酸铬-聚L乳酸粒子组织间植入对犬长期毒性研究

目的 探讨³²P-磷酸铬-聚L乳酸粒子(³²P-CP-PLLA)间质植入比格犬的安全性和毒性。方法 30只比格犬,随机分成不同药物(³²P-CP-PLLA和胶体³²P-CP)、剂量(185、370和740 MBq)和部位(肝脏和臀大肌)10组(n=3)。术后定期称体重,检测实验室指标,测量血液、排泄物放射性计数率值,动态γ显像和组织形态学观察。结果 γ显像示胶体肝脏组全肝显影,放射性不均匀分布,余组局部放射性持续浓聚,肝脏未见显影。肝内注射胶体³²P-CP 471.67 MBq/m²,全肝吸收剂量为31 Gy,无肝功能损伤;注射794.28 MBq/m²,全肝吸收剂量为56 Gy,有较强的肝毒性及全身毒副作用。肝内植入1588.89 MBq/m²的³²P-CP-PLLA粒子,植入区肝组织的吸收剂量为89.83~178.68 Gy,未见肝功能受损。肝脏胶体370 MBq组分别于23、29和45 d死亡肝纤维化5项全程均值明显高于其他各组。有效半减期:³²P-CP-PLLA平均为11.78 d;³²P-CP肝脏组为6.82 d,肌肉组为8.73 d。组织学表现:肝脏胶体370 MBq组4周内见肝细胞中、重度肝细胞损伤,4~6周出现肝细胞坏死及增生;其余各组4周内见轻~中度肝细胞水肿,8周后未见异常。肌肉给药各组主要表现为横纹肌细胞一过性水肿变性。 血液中放射性计数率值粒子组随时间呈现锯齿状缓慢递减,胶体组呈指数下降。结论 ³²P-CP-PLLA粒子具有在植入部位不迁移,可体内降解,无明显毒副作用等优良特性,适治于不同血供的实体肿瘤。比格犬肝脏能接受³²P-CP致死剂量2倍活度的放射性粒子的辐射。

Long-term toxicity studies on 32P-chromic phosphate-poly-L lactic acid seeds interstitial delivery of beagle dogs

Objective To explore the toxicity and safety of 32P-CP-PLLA seeds interstitial implantation. Methods 30 beagle dogs were randomly divided into 10 groups according to different drugs (32P-CP-PLLA and 32P-CP),different doses (185, 370 and 740 MBq) and different sites (gluteus and liver). At different time-points after surgery, the weights of dogs were measured. The blood routine and blood biochemical indexes,PC Ⅲ ,HA,CG,PCⅣ and LN were examined. ECT imaging was performed and histology was observed dynamically. Blood, urine and faeces were measured continuously for 12 weeks and 30 days, respectively. Results ECT imaging demonstrated in seed groups and 32P-CP muscle groups radioactivity concentrated continuously in the area of implantation, without liver imaging. 471.67 MBq/m2 of 32 P-CP was injected in liver,while the absorbed dose was 31 Gy,without significant liver damage. When the dose was 794. 28 MBq/m2 , the absorbed dose was 56 Gy,with strong liver and systemic toxicity. But implanting seeds at the same or higher dose, the absorbed dose was 89.83-178.68 Gy in the area of implantation, and the rest liver was 1.09-2. 18 Gy,without liver damage. Dogs in liver group died at 23, 29 and 45 d, respectively, and the inspections of liver fibrosis were higher than the means of the other groups.Blood routine and blood biochemistry indexes between the other groups showed no significant differences.Effective half-life of 32P-CP-PLLA was 11.78 d, while that of 32P-CP was 6. 82 d in liver, and 8. 73 d in gluteus. Mild to moderate injury were found in liver group at 4 weeks. Moderate to serious injury were found. Liver cell necrosis and proliferation were found at 4-6 weeks in other liver groups. In muscle groups,only cellular edema was found in muscle groups at 2 week. The radioactivity count rate in blood for seed groups showed slowly jagged decreasing over time, and decreased exponentially for 32PCP groups. The radioactivity count rate in urine and faeces were multi-peak descending in seed groups. Conclusions 32P-CP-PLLA seeds have the advantages of suitable target location, degradable, non-migration and easy to protection, and it could be used in treatment for different blood supply types of solid tumors. Liver of beagle dog could endure the dose from 32 P-CP-PLLA seed twice as 32P-CP lethal dose.