Preparation of ethylene glycol chitosan-diethylenetriamine pentaacetic acid and assessment for its relative safety

Feng ZENG; Weilin FU; Rong LI; Tao LI; Yao XIAO; Yi ZHANG; Xiangyu CHEN; Minghua LIU

doi:10.16016/j.2097-0927.202201123

您当前的位置：

首页 >

文章列表页 >

Preparation of ethylene glycol chitosan-diethylenetriamine pentaacetic acid and assessment for its relative safety

Pharmacy | 更新时间：2026-01-09

- Preparation of ethylene glycol chitosan-diethylenetriamine pentaacetic acid and assessment for its relative safety
- Journal of Army Medical University Vol. 44, Issue 9, Pages: 967-974(2022)
- 作者机构：
  
  1.400038 重庆，陆军军医大学(第三军医大学)第一附属医院：急诊科
  2.400038 重庆，陆军军医大学(第三军医大学)军事预防医学系复合伤研究所，创伤、烧伤与复合伤国家重点实验室
  3.400038 重庆，陆军军医大学(第三军医大学)第一附属医院：关节科
- 作者简介：
- 基金信息：
  
  the Key Project of Military Logistics Scientific Research(BLJ20J005)
- DOI：10.16016/j.2097-0927.202201123
  CLC： R818.03; R818.052
- Received：14 January 2022，
  
  Revised：2022-03-07，
  
  Published：15 May 2022
- 稿件说明：
移动端阅览
Feng ZENG, Weilin FU, Rong LI, et al. Preparation of ethylene glycol chitosan-diethylenetriamine pentaacetic acid and assessment for its relative safety[J]. Journal of Army Medical University, 2022, 44(9): 967-974.
DOI：

Feng ZENG, Weilin FU, Rong LI, et al. Preparation of ethylene glycol chitosan-diethylenetriamine pentaacetic acid and assessment for its relative safety[J]. Journal of Army Medical University, 2022, 44(9): 967-974. DOI： 10.16016/j.2097-0927.202201123.

摘要

目的

合成乙二醇壳聚糖-二乙烯三胺五乙酸(glycol chitosan-diethylenetriamine pentaacetic acid，GC-DTPA)并验证其细胞相容性及常规使用剂量范围内全身毒性。

方法

通过有机合成、化学交联方法等将二乙烯三胺五乙酸(diethylenetriamine pentaacetic acid，DTPA)接枝到乙二醇壳聚糖(Glycol Chitosan，GC)上，核磁共振氢谱(proton nuclear magnetic resonance

H NMR)及傅立叶变换红外光谱(Fourier transform infrared，FT-IR)对GC-DTPA进行表征。CCK8法检测不同浓度GC-DTPA对ICE-6细胞增殖的影响。6~8周龄健康SPF级SD大鼠80只，雌雄不拘，体质量180~220 g。随机分为GC-DTPA 60、90、120 mg/kg实验组与对照组(给予同等剂量生理盐水)，每组20只。观察各组大鼠体质量变化及存活率，全自动血液体液分析仪及全自动生化免疫分析仪检测14 d血常规、血生化；HE染色系统显微镜观察各器官病理学变化。

结果

经FT-IR、

H NMR表征，DTPA成功接枝到GC上。不同浓度GC-DTPA组的细胞相对存活率均在90%以上；给药14 d后各剂量组大鼠血常规、血生化等指标差异无临床意义，各器官组织病理未见损伤性改变。

结论

有机合成、化学交联方法合成的GC-DTPA未见明显细胞毒性；口服给药至120 mg/kg时未见明显全身毒性。

Abstract

Objective

To synthesize ethylene glycol chitosan-diethylenetriamine pentaacetic acid (GC-DTPA)

and evaluate its cytocompatibility and systemic toxicity within the dose range of routine use.

Methods

DTPA was grafted onto ethylene glycol chitosan (GC) by organic synthesis and chemical cross-linking method

and was subsequently characterized with proton nuclear magnetic reso

nance (

H NMR) and Fourier transform infrared (FT-IR) spectroscopy. CCK-8 assay was used to detect the effects of different concentrations of GC-DTPA on the proliferation of ICE-6 cells. In addition

80 healthy SPF SD rats (aged 6~8 weeks

body weight 180~220 g) were randomly divided into 4 groups (

=20): control group (given normal saline)

and experimental groups (60

90 and 120 mg/kg GC-DTPA

respectively by intragastric gavage). The change of body weight and survival rate of rats in each group were observed. Blood routine test and blood biochemical examination were performed in the rats on the 14th day after gavage with aid of automatic blood humoral and biochemical immunoassay analyzers respectively. Then

the rats were sacrificed and the pathological changes of organs were observed after HE staining.

Results

FT-IR spectroscopy and 1H-NMR suggested that DTPA was successfully grafted onto GC

and GC-DTPA exhibited excellent cytocompatibility

with cell viability all above 90% after its treatment at different concentrations. In 14 d after administration

no significant differences were seen in the results of blood routine and blood biochemical tests

or in pathological changes of organs and tissues in each group.

Conclusion

The GC-DTPA synthesized by chemical synthesis and cross-linking method shows no obvious cytotoxicity

and no systemic toxicity is seen even after oral administration dose up to 120 mg/kg.

关键词

Keywords

references

RANTAVAARA A. Ingestion doses in Finland due to (90)Sr, (134)Cs, and (137)Cs from nuclear weapons testing and the Chernobyl accident[J]. Appl Radiat Isot, 2008, 66(11): 1768-1774. DOI: 10.1016/j.apradiso.2007.12.018.

BRUMFIEL G, FUYUNO I. Fukushima's legacy of fear[J]. Nature, 2012, 483: 138-40. DOI: 10.1038/483138a.

MINENKO V F, ULANOVSKY A V, DROZDOVITCH V V, et al . Individual thyroid dose estimates for a case-control study of Chernobyl-related thyroid cancer among children of Belarus: part Ⅱ. Contributions from long-lived radionuclides and external radiation[J ] . Health Phys, 2006, 90(4): 312-327. DOI: 10.1097/01.HP.0000183761.30158.c1.

APOSTOAEI A I. Absorption of strontium from the gastrointestinal tract into plasma in healthy human adults[J]. Health Phys, 2002, 83(1): 56-65. DOI: 10.1097/00004032-200207000-00006.

BJORNERSTEDT R, HAGGROTH S. Determination of strontium-90 distribution in human bone[J]. Nature, 1960, 185: 366-367. DOI: 10.1038/185366a0.

RAABE O G, PARKS N J. Skeletal uptake and lifetime retention of 90Sr and 226Ra in beagles[J]. Radiat Res, 1993, 133(2): 204-218.

ARTS J, BADE S, BADRINAS M, et al . Should DTPA, an Aminocarboxylic acid (ethylenediamine-based) chelating agent, be considered a developmental toxicant?[J ] . Regul Toxicol Pharmacol, 2018, 97: 197-208. DOI: 10.1016/j.yrtph.2018.06.019.

荆晓光, 刘舒云, 郭维民, 等. 可注射性乙二醇壳聚糖/双醛功能化聚乙二醇水凝胶的细胞相容性[J]. 中国组织工程研究, 2019, 23(2): 196-203. DOI: 10.3969/j.issn.2095-4344.1507.

JING X G, LIU S Y, GUO W M, et al . Cytocompatibility of injectable glycol chitosan/dibenzaldehyde-terminated poly-ethyleneglycol hydrogel[J ] . Chin J Tissue Eng Res, 2019, 23(2): 196-203. DOI: 10.3969/j.issn.2095-4344.1507.

王爱勤, 李洪启, 俞贤达. 不同介质中乙二醇壳聚糖的合成及性能研究[J]. 天然产物研究与开发, 1997, 9(2): 28-31. DOI: 10.16333/j.1001-6880.1997.02.008.

WANG A Q, LI H Q, YU X D. Studies on synthesis and preperties of glycolchitosan in the different solvents[J]. Nat Prod Res Dev, 1997, 9(2): 28-31. DOI: 10.16333/j.1001-6880.1997.02.008.

余敬谋, 李永杰, 王成润, 等. 乙二醇壳聚糖-胆固醇接枝物载多柔比星自聚集纳米粒的制备及其大鼠体内药动学研究[J]. 中国药学杂志, 2010, 45(4): 277-282.

YU J M, LI Y J, WANG C R, et al . Preparation of doxorubicin loaded self-aggregated nanoparticles based on cholesterol-modified glycol chitosan conjugate and its pharmacokinetics in rats[J ] . Chin Pharm J, 2010, 45(4): 277-282.

WANG W J, XUE C H, MAO X Z. Chitosan: Structural modification, biological activity and application[J]. Int J Biol Macromol, 2020, 164: 4532-4546. DOI: 10.1016/j.ijbiomac.2020.09.042.

YOON S P, HAN M S, KIM J W, et al . Protective effects of chitosan oligosaccharide on paraquat-induced nephrotoxicity in rats[J ] . Food Chem Toxicol, 2011, 49(8): 1828-1833. DOI: 10.1016/j.fct.2011.04.036.

GULIK E S, KOSTESHA N I A. Radioprotective efficacy of chitosan, dissolved in aqueous extract of Abies Sibirica[J]. Radiats Biol Radioecol, 2004, 44(5): 563-565.

ZHAI X C, YANG X, ZOU P, et al . Protective effect of chitosan oligosaccharides against cyclophosphamide-induced immunosuppression and irradiation injury in mice[J ] . J Food Sci, 2018, 83(2): 535-542. DOI: 10.1111/1750-3841.14048.

BHATT R, SREEDHAR B, PADMAJA P. Adsorption of chromium from aqueous solutions using crosslinked chitosan-diethylenetriaminepentaacetic acid[J]. Int J Biol Macromol, 2015, 74: 458-466. DOI: 10.1016/j.ijbiomac.2014.12.041.

REPO E, MALINEN L, KOIVULA R, et al . Capture of co(Ⅱ) from its aqueous EDTA-chelate by DTPA-modified silica gel and chitosan[J ] . J Hazard Mater, 2011, 187(1/2/3): 122-132. DOI: 10.1016/j.jhazmat.2010.12.113.

KOSTIAL K, KARGACIN B, LANDEKA M. Oral Zn-DTPA treatment reduces cadmium absorption and retention in rats[J]. Toxicol Lett, 1987, 39(1): 71-75. DOI: 10.1016/0378-4274(87)90258-x.

MICCOLI L, MÉNÉTRIER F, LAROCHE P, et al . Chelation treatment by early inhalation of liquid aerosol DTPA for removing Plutonium after rat lung contamination[J ] . Radiat Res, 2019, 192(6): 630-639. DOI: 10.1667/RR15451.1.

SU EDA K, SADGROVE M P, HUCKLE J E, et al . Orally administered DTPA penta-ethyl ester for the decorporation of inhaled (241)Am[J ] . J Pharm Sci, 2014, 103(5): 1563-1571. DOI: 10.1002/jps.23932.

WILSON J P, COBB R R, DUNGAN N W, et al . Decorporation of systemically distributed americium by a novel orally administered diethylenetriaminepentaacetic acid (DTPA) formulation in beagle dogs[J ] . Health Phys, 2015, 108(3): 308-318. DOI: 10.1097/HP.0000000000000199.

胡丹飞. 新型促排剂WSC-DTPA纳米粒对内污染铀促排和防护作用的研究[D]. 苏州: 苏州大学, 2013.

HU D F. Decorporation and radiation protection effects of WSC-DTPA nanoparticles on internal uranium exposure[D]. Suzhou: Soochow University, 2013.

芦娟娟. O-羧甲基壳聚糖枝接偶氮色素的制备及抗还原能力的研究[D]. 天津: 天津大学, 2016.

LU J J. Research on O-carboxymethyl chitosan grafted azo pigment: preparation and anti-reductive ability[D]. Tianjin: Tianjin University, 2016.

GULAKOV A V. Accumulation and distribution of (137)Cs and (90)Sr in the body of the wild boar (Sus scrofa) found on the territory with radioactive contamination[J]. J Environ Radioact, 2014, 127: 171-175. DOI: 10.1016/j.jenvrad.2013.06.008.

付维林, 陈翔宇, 李蓉, 等. 支气管喷入高剂量贫铀染毒犬模型早期损伤特点研究[J]. 第三军医大学学报, 2021, 43(1): 52-58. DOI: 10.16016/j.1000-5404.202007210.

FU W L, CHEN X Y, LI R, et al . Features of early injuries in canine model of high dose depleted uranium exposure through bronchial spraying[J ] . J Third Mil Med Univ, 2021, 43(1): 52-58. DOI: 10.16016/j.1000-5404.202007210.

郭剑平, 杨仲田, 张华屏. 低聚壳聚糖的辐射防护作用小鼠试验研究[J]. 辐射防护通讯, 2010, 30(2): 23-25.

GUO J P, YANG Z T, ZHANG H P. Study on radiation protection effect of oligo-chitosan for mice[J]. Radiat Prot Bull, 2010, 30(2): 23-25.

GITERU S G, CRIDGE B, OEY I, et al . In-vitro degradation and toxicological assessment of pulsed electric fields crosslinked zein-chitosan-poly(vinyl alcohol) biopolymeric films[J ] . Food Chem Toxicol, 2020, 135: 111048. DOI: 10.1016/j.fct.2019.111048.

LUU T T, DINH V P, NGUYEN Q H, et al . Pb(Ⅱ) adsorption mechanism and capability from aqueous solution using red mud modified by chitosan[J ] . Chemosphere, 2022, 287: 132279. DOI: 10.1016/j.chemosphere.2021.132279.

ZHANG Y Z, ZHA O M W, CHENG Q, et al . Research progress of adsorption and removal of heavy metals by chitosan and its derivatives: a review[J ] . Chemosphere, 2021, 279: 130927. DOI: 10.1016/j.chemosphere.2021.130927.

高旭, 李鹏, 王学刚, 等. EDTA螯合-电絮凝处理低浓度含铀废水[J]. 环境工程, 2018, 36(7): 27-32. DOI: 10.13205/j.hjgc.201807006.

GAO X, LI P, WANG X G, et al . Treatment of low concentration uranium-containing wastewater by edta chelating-electrocoagulation[J ] . Environ Eng, 2018, 36(7): 27-32. DOI: 10.13205/j.hjgc.201807006.

张刘珍. 新型内污染纳米型促排药物的研制[D]. 苏州: 苏州大学, 2009.

ZHANG L Z. A new nano-chelating agent to 89Sr[D]. Suzhou: Soochow University, 2009.

陆正清. 糖醇类营养型合成甜味剂的开发与应用[J]. 食品工业科技, 2004, 25(10): 115-7.

LU Z Q. Development and application of sugar alcohol nutritional synthetic sweeteners[J]. Sci Technol Food Ind, 2004 2004, 25(10): 115-117.

张英杰. 甘露醇在临床应用中的新进展[J]. 临床荟萃, 1996, 11(15): 695.

ZHANG Y J. New progress in clinical application of mannitol[J]. Clin Focus, 1996, 11(15): 695.

邓雯, 陈莉莉, 刘晶, 等. SPF级SD大鼠血液学及血清生化指标正常值探讨[J]. 毒理学杂志, 2010, 24(2): 174-175. DOI: 10.16421/j.cnki.1002-3127.2010.02.004.

DENG W, CHEN L L, LIU J, et al . Study on normal values of hematology and serum biochemical indexes in SPF SD rats[J ] . J Toxicol, 2010, 24(2): 174-175. DOI: 10.16421/j.cnki.1002-3127.2010.02.004.

张薇, 唐彬, 付新录, 等. 不同月龄SPF级SD大鼠临床生理生化背景数据分析[J]. 热带医学杂志, 2018, 18(1): 5-10. DOI: 10.3969/j.issn.1672-3619.2018.01.002.

ZHANG W, TANG B, FU X L, et al . Analysis of the background data of hemocytology and biochemistry in the blood of SPF Sprague Dawley rats at different ages[J ] . J Trop Med, 2018, 18(1): 5-10. DOI: 10.3969/j.issn.1672-3619.2018.01.002.

赵毓梅, 郑定仙, 黄业宇, et al . SD大鼠血常规、血液生化指标、脏体比正常参考值范围研究[J ] . 中国卫生检验杂志, 2002, 12(2): 165-7.

ZHAO Y M, ZHENG DI X, HUANG Y Y, Study on normal reference range of blood routine, blood biochemical indexes and organ-body ratio in etal. SD rats[J]. Chin J Heal Lab Technol, 2002, 12(2): 165-7.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Preparation and performance of PEGylated chitosan nanoparticles for ocular drug delivery by eye drops

Preparation of endostatin-loaded chitosan nanoparticles and antitumor effect of the nanoparticles combined with cisplatin in Lewis lung cancer mice

Effect of microgroove surface on surface properties and cytocompatibility of silicone rubber

Preparation and characterization of fluorescent chitosan nanoprobe

Preparation of controlled-released three-dimensional chitosan scaffold loading with TGF-β3 microspheres

Related Author

Shichun LIU

Chunhua CAI

Wenjun ZHOU

Ji XU

丁瑞麟

谢芳

胡月

何汶峰

Related Institution

Department of Ophthalmology, Yongchuan Hospital of Chongqing Medical University

Central Laboratory, Yongchuan Hospital of Chongqing Medical University

⁰