纳米制剂及纳米材料在放射性核素促排中的应用

放射性突发事件造成的放射性核素内污染,严重危害人体健康,促排剂的研发和及新技术的应用可减少核素产生的内照射的损伤。纳米制剂较传统制剂具有提高药物溶出度、靶向和定位释药、易穿过生物膜屏障等优点。近年来很多学者针对不同促排药物,采用不同的纳米制剂形式,包括纳米微粒、纳米脂质体、纳米乳等进行相关研究,以期达到更好的临床应用效果。性能优异的纳米材料具有高效快速吸附、高生物相容性等优点,在放射性核素促排中的应用越来越广泛。本文结合国内外相关文献,将核素内污染按核素沉积的不同部位和组织器官进行分类,介绍了相关纳米制剂及纳米材料在放射性核素促排中的应用,为后续进一步研究提供参考。     

邻苯二酚氨羧酸螯合剂对钍内污染早期给药效果

目的 研究邻苯二酚氨羧酸螯合剂的促排^234Th的效果和抗自由基作用在防护核素内照射损伤中的作用关系。方法 首先确定小鼠ip中毒^234Th致内照射损伤的剂量和时间，选择0.6MBq／鼠的中毒剂量ip后，立即im螯合剂，连续3d，并以DTPA和VitE作促排效果和抗自由基作用的阳性对照，第4天处死动物，观察整体和肝、骨中^234Th蓄积量，骨髓有核细胞数(BMNC)，骨髓、肝脏和血清脂质过氧化产物丙二醛(MDA)含量及骨髓和肝脏的病理变化。结果 小鼠ip^234Th0.6MBq／鼠第4～8天，骨髓和肝脏出现明显的内照射损伤。给予螯合剂9501、7601和DTPA后，均有明显的促排作用，使整体中^234Th蓄积量比中毒组分别下降81％、86％和72％，以第一次用药效果最为明显；肝、骨中总的^234Th蓄积量分别仅为中毒组的22％、21％和58％，其中9501、7601的效果明显优于DT—PA，骨中蓄积量仅为DTPA的1／3～1／5。9501和7601立即给药未观察到^234Th急性中毒后的内照射损伤，BMNC数、骨髓MDA含量正常，骨髓、肝脏未见明显的病理改变。DTPA组可见骨髓组织轻度受损。给予VitE未能减轻骨髓、肝组织的内照射损伤，可能由于在短时间内核素大量蓄积于组织中所致。VitE和DTPA合并用药，显示DTPA的促排活性和VitE的抗氧化作用。结论 9501和7601立即给药对核素内照射损伤有明显的防护作用，主要是由于其显著的促排作用。     

壳聚糖衍生物纳米粒子的制备及对体内放射性锶的促排作用

目的制备壳聚糖-乙二胺四乙酸(CTS-EDTA)纳米粒,通过动物实验观察壳聚糖-乙二胺四乙酸纳米粒(CEC-Nano)对放射性锶的促排效果尤其是预防性给药的促排效果。方法通过N-酰化反应连接壳聚糖与乙二胺四乙酸纳,并将反应产物与TPP利用离子凝胶法制成纳米粒。通过染毒前与染毒后给药,比较其治疗性与预防性促排效果。结果 CTS-EDTA纳米粒通过透射电镜观察显示可得到粒度较为均一的球形纳米粒子。体内实验表明,小鼠骨头尤其是颅骨的放射性锶含量在预防给药治疗组比对照组和即刻给药治疗组明显低(P<0.05),小鼠体内整体放射性锶残留量也比其他组明显低(P<0.05)。结论 CEC-Nano对体内放射性锶具有良好的促排效果尤其是预防性给药治疗促排效果更好。     

Solid dispersions of the penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA): formulation design and optimization studies

Abstract

The penta-ethyl ester prodrug of diethylenetriaminepentaacetic acid (DTPA), which exists as an oily liquid, was incorporated into a solid dispersion for oral administration by the solvent evaporation method using blends of polyvinylpyrrolidone (PVP), Eudragit® RL PO and α-tocopherol. D-optimal mixture design was used to optimize the formulation. Formulations that had a high concentration of both Eudragit® RL PO and α-tocopherol exhibited low water absorption and enhanced stability of the DTPA prodrug. Physicochemical properties of the optimal formulation were evaluated using Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). In vitro release of the prodrug was evaluated using the USP Type II apparatus dissolution method. DSC studies indicated that the matrix had an amorphous structure, while FTIR spectrometry showed that DTPA penta-ethyl ester and excipients did not react with each other during formation of the solid dispersion. Dissolution testing showed that the optimized solid dispersion exhibited a prolonged release profile, which could potentially result in a sustained delivery of DTPA penta-ethyl to enhance bioavailability. In conclusion, DTPA penta-ethyl ester was successfully incorporated into a solid matrix with high drug loading and improved stability compared to prodrug alone.     

螯合剂BPCBG对急性铀中毒大鼠的促排效果及肾损伤的保护作用

目的 探讨螯合剂BPCBG对急性铀中毒大鼠促排作用的量-效和时,效关系以及对铀致肾损伤的保护作用.方法 Sprague-Dawley( SD)雄性大鼠按随机数字表法分为正常对照组、铀中毒组、不同剂量BPCBG组和DTPA-CaNa3组.给药组大鼠于腹腔注射醋酸铀酰(100μg/只)后,立即分别肌肉注射60、120和600μmol/kg BPCBG及120和600μmol/kg DTPA-CaNa3,或于注射醋酸铀酰前0.5和2h、铀中毒后0、0.5、1及2h肌肉注射120 μmol/kg BPCBG,铀中毒组于注射醋酸铀酰后立即注射等体积生理盐水,正常对照组仅注射生理盐水.采用ICP-MS方法检测24 h尿铀排出量和肾、骨中铀蓄积量.大鼠注射醋酸铀酰(500 μg/只)后立即注射600 μmol/kg BPCBG和1200 μmol/kg DTPA-CaNa3,48 h后检测血清肌酐(SCR)与尿素氮(BUN)含量,取一侧肾脏做肾组织病理切片观察.结果 铀中毒后立即注射不同剂量BPCBG(60、120和600 μmoL/kg)使24h尿铀排出量比铀中毒组增加(t =2.22、4.43、5,80,P＜0.05),肾和骨铀蓄积量下降(t.3.33、5.59、4.53,P＜0.01和t=2.15、8.70、9.10,P＜0.05),随给药剂量增加促排效果明显提高.提前0.5h或延迟0.5和1h给予BPCBG,仍有较好的排铀效果(与铀中毒组比较,尿铀排出量:提前0.5 h t=4.34,延迟0.5 ht=3.35,P＜0.05;肾铀蓄积量:t=5.75、7.74、5.87,P＜005:骨铀蓄积量:t=6.43、5.22、2.60,P＜0.05),但随铀中毒和给药间隔时间的延长而下降.BPCBG立即给药能明显减轻铀中毒致肾脏的病理损伤,使SCR及BUN含量降低至正常对照组水平,对铀致肾功能损伤具有保护作用.DTPA-CaNa3虽然能明显降低大鼠肾铀蓄积量(与铀中毒组相比,120和600-μmol/kg,t =2.28、3.35,P＜0.05),但未能显著增加尿铀排出量,骨铀蓄积量还有增加趋势,并且对铀致大鼠肾损伤无保护作用.结论 BPCBG对急性铀中毒大鼠有良好的促排效果与肾脏保护作用,有可能成为一种新型铀促排螯合剂.     

双分子取代苯酚类螯合剂的合成及对放射性钍的促排效果研究

目的本文旨在寻找新的治疗用螯合剂，以加速排除沉积在体内的放射性钍，达到放射防护的目的。方法首先通过Ｍａｎｎｉｃｈ反应合成双分子取代苯酚类螯合剂，然后经动物实验：ＳＤ大鼠静脉中毒２３４Ｔｈ后立即肌注药物，２天后解剖动物测定２３４Ｔｈ量，计算排出量和蓄积量，研究其促排效果。结果所报道的螯合剂不仅能增加大鼠在尿、粪中２３４Ｔｈ的排除，同时能降低在肝、骨中的蓄积，呈现较好的促排效果。其中以化合物Ⅷ促排效果最好，２天后可排除６８％的２３４Ｔｈ；在肝、骨中的沉积仅为１１．７％，而对照组则是８７．６％。结论螯合剂Ⅷ值得进一步研究探讨。     

Preparing for a "dirty bomb" attack:The optimum mix of medical countermeasure resources

Background:In radiological emergencies with radionuclide incorporation,decorporation treatment is particularly effective if started early.Treating all people potentially contaminated ("urgent treatment") may require large antidote stockpiles.An efficacious way to reduce antidote requirements is by using radioactivity screening equipment.We analyzed the suitability of such equipment for triage purposes and determined the most efficient mix of screening units and antidote daily doses.Methods:The committed effective doses corresponding to activities within the detection limits of monitoring portals and mobile whole-body counters were used to assess their usefulness as triage tools.To determine the optimal resource mix,we departed from a large-scale scenario (60,000 victims) and based on purchase prices of antidotes and screening equipment in Germany,we calculated efficiencies of different combinations of medical countermeasure resources by data envelopment analysis.Cost-effectiveness was expressed as the costs per life year saved and compared to risk reduction opportunities in other sectors of society as well as the values of a statistical life.Results:Monitoring portals are adequate instruments for a sensitive triage after cesium-137 exposure with a high screening throughput.For the detection of americium-241 whole-body counters with a lower daily screening capacity per unit are needed.Assuming that 1％ of the potentially contaminated patients actually need decorporation treatment,an efficient resource mix includes 6 monitoring portals and 25 mobile whole-body counters.The optimum mix depends on price discounts and in particular the fraction of victims actually needing treatment.The cost-effectiveness of preparedness for a "dirty bomb" attack is less than for common health care,but costs for a life year saved are less than for many risk-reduction interventions in the environmental sector.Conclusion:To achieve economic efficiency a high daily screening capacity is of major importance to substantially decrease the required amount of antidote doses.Among the determinants of the number of equipment units needed,the fraction of the potentially contaminated victims that actually needs treatment is the most difficult to assess.Judging cost-effectiveness of the preparedness for "dirty bomb" attacks is an issue of principle that must be dealt with by political leaders.     

邻苯二酚氨羧酸螯合剂对钍内污染延缓给药的效果

目的 进一步确证邻苯二酚氨羧酸螯合剂在体内的抗自由基作用，增进对核素内照射损伤的防护效果，及与促排效果之间的关系。方法 小鼠ip^234Th0．6MBq／鼠3d后im螯合剂，连续3d，并以DTPA和VitE作促排效果和抗自由基作用的阳性对照，第8天处死动物检测整体和肝、骨中^234Th蓄积量，骨髓有核细胞计数，骨髓、血清、肝匀浆MDA含量，观察骨髓、肝脏组织的病理变化。结果 9501、7601、DTPA延缓给药均仍有明显的促排效果，使整体^234蓄积量比中毒组下降15％～16％，肝、骨蓄积量下降分别为中毒组的77％-79％和72％～75％，三者的效果相比差异无显著性，但明显低于即刻用药的效果。9501和7601能明显减轻^234Th内污染小鼠的辐射损伤，骨髓有核细胞数，骨髓、肝脏MDA含量正常，未见明显的骨髓、肝脏的病理改变。而DTPA组的防护效果较差．出现较明显的骨髓组织损伤。VitE给药后第8天对减轻^234Th所致骨髓、肝脏内照射损伤有一定的效果。结论 9501和7601对核素内照射损伤有明显的防护效果，具有促排和抗自由基作用的双重功能，是2个较理想的螯合剂，值得进一步研究。     

L5178Y sublines: a look back from 40 years. Part 2: Response to ionizing radiation

The aim was to review and summarize the results of 40 years of study concerning the response to ionizing radiation of the pair of L5178Y (LY) sublines, LY-R and LY-S, that differ in sensitivity to various DNA-damaging agents, among them X- and γ-rays. The reviewed data indicate the key importance of DNA damage repair and fixation for the ultimate fate of the irradiated LY cell. The cause of slow double-strand break (DSB) repair in LY-S cells is not identified, but a defect in non-homologous end-joining (NHEJ) would explain most features of the cellular response of LY-S cells to irradiation, as compared with repair-competent LY-R cells. The most prominent features are the very high radiosensitivity of G1 cells, extensive poly(ADP-ribose)-dependent damage fixation, long G2 arrest, considerable chromosomal damage seen as premature chromatin condensation (PCC) fragments and aberrations in metaphase cells. The main cause of radiosensitivity difference between LY sublines is in DNA repair/damage fixation ability. At the level of damage corresponding to a comparable lethal effect, the type of death differs between LY sublines; LY-S cells die in considerably greater proportion by apoptosis than LY-R cells, whereas the latter die in greater proportion by necrosis. This observation is consistent with differential expression of proteins that are pro- or anti-apoptotic. The prominent role of poly(ADP-ribosylation) in the response of LY-S cells apparently is connected with damage fixation, but is in contrast to other cell lines hypersensitive to X- or γ-radiation with DSB repair defects.     

锕系元素的螯合药物——Ⅹ.新型镅促排药物的研究

设计、合成了14个多氨基多羧基酚类螯合剂,其中10个是未见文献报告的新化合物。对10个螯合剂进行~(241)Am促排药效的研究,动物实验表明,在50μmol/kg剂量下有7个对肝镅有明显促排效果,整合剂Va对肝镅、骨镅和肾镅均有明显促排作用。