吸入上转换纳米颗粒对小鼠的体内毒性研究

发布时间：2018-10-13 08:41

【摘要】：上转换纳米颗粒（upconversion nanoparticles，UCNPs）是由数种稀土元素掺杂于某些固体晶格中构成的纳米颗粒。它能够吸收低能级光子而发出高能级光子，是新兴的最富前景的纳米材料之一。 由于独特的原子结构，上转换纳米颗粒是由低能级长波长的近红外线激发，相对于传统的发光物质，避免了短波长激发光（通常是紫外线）产生自体荧光的干扰，且因为波长长，对生物组织的穿透能力强而损伤小，可实现深部组织非侵入式探测和治疗。上转换纳米颗粒具有优越的光学特性还包括：发射光稳定性好、无光闪烁、无光漂白，可以实现长期激发以便观察检测；最大吸收峰与最大发射峰之间波长差大，避免激发光对发射光检测的干扰；激发光谱窄，检测灵敏度高；通过掺杂不同的稀土元素产生不同的发射光，可实现多色同时检测。目前，上转换纳米颗粒主要应用于生物分子检测、细胞显像、肝细胞移植示踪、光动力治疗等生物医学领域。 然而，要实现在临床医学领域更广阔的应用，上转换纳米颗粒需要具备生物相容性好、毒性低等条件。这需要我们从生物材料安全性角度对其毒性进行研究。然而目前关于上转换纳米颗粒的毒理学研究大多是体外毒性研究，体内毒性研究任重而道远。本课题在整体动物水平，采用经气道滴注剂量25mg/kg.bw的方式，研究上转换纳米颗粒对小鼠整体状态及重要脏器的形态和功能的影响，得到以下 结果： 1.经气道滴注上转换纳米颗粒后动物表现出进食减少、活动减少、毛色发暗体重减轻，这些现象在15天后得到恢复。 2.经气道滴注上转换纳米颗粒后动物肺部出现明显的炎症反应和增生表现，超微结构显示颗粒主要存在于Ⅱ型肺泡上皮细胞中，且该细胞嗜锇性板层小体有空虚的表现。肺湿干重比结果显示，，染毒后第2天肺水明显增多；静态肺顺应性压力-体积曲线右移；动脉血偏酸性，PO2降低。 3.肝脏细胞肿胀，无法分辨细胞界限，细胞核增大松散，细胞胞浆疏松，出现严重的空泡变性。这种病变在第1天最明显，此后逐渐恢复，到第9天时肝脏形态基本恢复正常状态。血清生化结果发现谷丙转氨酶（ALT）第1天和第2天明显升高，总胆红素（TBIL）没有明显变化。 4.肾脏病理检查未见明显改变，血清学检查发现第1天血尿素氮（BUN）升高，肌酐（CREA）和对照组相比没有明显异常。 5.脾脏病理可见淋巴小结面积逐渐增大，帽部朝向红髓，边缘区不清晰，红髓中分布大量淋巴细胞，15天时恢复正常形态。 6.心脏病理检查未见明显改变。 综上所述，可以初步认为：25mg/kg.bw上转换纳米颗粒通过气道单次进入小鼠体内后，机体有一过性的毒性反应；其主要靶器官为肺脏和肝脏，能引起相应器官形态和功能的损害；能引发脾脏的体液免疫反应；引起肾小球滤过功能短暂下降；对心脏形态没有影响。
[Abstract]:Upconversion nanoparticles (upconversion nanoparticles,UCNPs) are nanoparticles doped with several rare earth elements in some solid lattices. It can absorb low-level photons and emit high-energy photons. It is one of the most promising nanomaterials. Due to its unique atomic structure, the up-conversion nanoparticles are excited by low energy level and long wavelength near infrared ray. Compared with traditional luminescent materials, it avoids the interference of short wavelength excited light (usually UV) from autofluorescence. Because of the long wavelength and the strong penetrating ability to biological tissue, it can be used to detect and treat deep tissues in a non-invasive manner. The up-conversion nanoparticles also have excellent optical properties, such as good emission stability, no light scintillation, no light bleaching, can be excited for a long time for observation and detection, and the wavelength difference between the maximum absorption peak and the maximum emission peak is large. Avoid the interference of excitation light to emission detection; narrow excitation spectrum and high detection sensitivity; by doping different rare earth elements to produce different emission light, multi-color simultaneous detection can be realized. At present, upconversion nanoparticles are mainly used in biomedical fields such as biomolecules detection, cell imaging, hepatocyte transplantation tracer, photodynamic therapy and so on. However, in order to be more widely used in clinical medicine, up-conversion nanoparticles need good biocompatibility and low toxicity. This requires us to study the toxicity of biomaterials from the point of view of their safety. However, most of the toxicological studies on upconversion nanoparticles are in vitro toxicity studies. At the whole animal level, the effects of up-conversion nanoparticles on the whole state of mice and the morphology and function of important organs were studied by the way of transairway infusion dose of 25mg/kg.bw. The results were as follows: 1. The animals showed a decrease in food intake, decreased activity and loss of dark weight of hair color after instillation of nanoparticles through the airway. These phenomena recovered after 15 days. 2. There were obvious inflammatory reaction and proliferation in the lungs of the animals after instillation of the nanoparticles in the airway. The ultrastructure showed that the granules mainly existed in type 鈪

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