Toxicity of Multiwalled Carbon Nanotubes with End Defects Critically Depends on Their Functionalization Density
Toxicity of Multiwalled Carbon Nanotubes with End Defects Critically Depends on Their Functionalization Density
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DOI：
10.1021/tx2003728
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发表时间：
2011-11-01
影响因子：
4.1
通讯作者：
Mishra, Anil K.
中科院分区：
文献类型：
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作者：
Jain, Sanyog;Thakare, Vivek S.;Mishra, Anil K.
由于羧化碳纳米管易于与治疗药物、蛋白质和寡核苷酸等折衷功能分子共价结合，因此被认为是最有前途的生物医学和制药应用纳米载体。在本研究中，我们试图研究如何通过改变酸氧化多壁碳纳米管的官能化程度来调整其毒性，并将毒性趋势与其生物分布特征相关联。根据这一原理，小鼠被暴露于10毫克/公斤的普利斯汀(P)和酸氧化(F)多壁碳纳米管，通过单次静脉注射不同程度的羧化。此后，进行了广泛的毒性研究，以了解p-MWCNT和各种f-MWCNT制剂对健康小鼠生理的短期(7天)和长期(28天)影响。具有高纵横比、表面疏水性和金属杂质的原始多壁碳纳米管被发现在小鼠体内引起显著的肝毒性和氧化损伤，尽管损伤在28天后恢复。相反，酸氧化的羧化碳纳米管具有更短的长度、亲水性和高分散性，比原始的碳纳米管毒性更小、生物相容性更好。通过对多壁碳纳米管的各项生化指标、炎症指标和肝脏组织病理学检查的研究表明，随着功能化密度的增加，多壁碳纳米管的毒性逐渐降低。将p-MWCNTs与强无机酸回流4h所获得的缩短和功能化程度足以使CNTs具有完全的亲水性和生物相容性，同时引起最小的肝脏蓄积和炎症。静脉注射99m标记的多壁碳纳米管在小鼠体内的定量生物分布研究清楚地表明，碳纳米管从肝、脾和肺等网状内皮系统(RES)器官中的清除严重依赖于功能化密度。较短长度的多壁碳纳米管(MWCNTs)在所有脏器中均未被保留，并通过肾脏排泄途径迅速从体循环中排出，未见明显的肾毒性。由于p-MWCNT和f-MWCNT处理组均无明显的肾毒性，因此较大尺寸和较低功能化程度的CNT不能通过肾脏排泄途径从体内排出，被认为是通过胆道在粪便中排泄。
Carboxylated carbon nanotubes stand as the most promising nanovectors for biomedical and pharmaceutical applications due to their ease of covalent conjugation with eclectic functional molecules including therapeutic drugs, proteins, and oligonucleotides. In the present study, we attempt to investigate how the toxicity of acid-oxidized multiwalled carbon nanotubes (MWCNTs) can be tweaked by altering their degree of functionalization and correlate the toxicity trend with their biodistribution profile. In line with that rationale, mice were exposed to 10 mg/kg of pristine (p) and acid-oxidized (f) MWCNTs with varying degrees of carboxylation through a single dose of intravenous injection. Thereafter, extensive toxicity studies were carried out to comprehend the short-term (7 day) and long-term (28 day) impact of p- and various f-MWCNT preparations on the physiology of healthy mice. Pristine MWCNTs with a high aspect ratio, surface hydrophobicity, and metallic impurities were found to induce significant hepatotoxicity and oxidative damage in mice, albeit the damage was recovered after 28 days of treatment. Conversely, acid-oxidized carboxylated CNTs with shorter lengths, hydrophilic surfaces, and high aqueous dispersibility proved to be less toxic and more biocompatible than their pristine counterparts. A thorough scrutiny of various biochemical parameters, inflammation indexes, and histopathological examination of liver indicated that toxicity of MWCNTs systematically decreased with the increased functionalization density. The degree of shortening and functionalization achieved by refluxing p-MWCNTs with strong mineral acids for 4 h were sufficient to render the CNTs completely hydrophilic and biocompatible, while inducing minimal hepatic accumulation and inflammation. Quantitative biodistribution studies in mice, intravenously injected with Tc-99m labeled MWCNTs, clearly designated that clearance of CNTs from reticuloendothelial system (RES) organs such as liver, spleen, and lungs was critically functionalization density dependent. Well-individualized MWCNTs with shorter lengths (3 mu mol/mg) were not retained in any of the RES organs and rapidly cleared out from the systematic circulation through renal excretion route without inducing any obvious nephrotoxicity. As both p- and f-MWCNT-treated groups were devoid of any obvious nephrotoxicity, CNTs with larger dimensions and lower degrees of functionalization, which fail to dear out from the body via renal excretion route, were thought to be excreted via biliary pathway in faeces.