海藻酸锌纳米凝胶超声雾化吸入安全性评价

Safety evaluation of ultrasonic atomization inhalation of Zinc alginate hydrogel nanoparticles

[目的]制备一种纳米凝胶以期作为药物输送的理想载体,并观察其超声雾化吸入后对小鼠气管和肺组织的影响,初步探讨该给药方式的安全性和可行性。[方法]采用反相微乳法制备海藻酸锌纳米凝胶(ALG-NPs),并通过粒径与Zeta电位,透射电子显微镜(TEM),差示扫描量热(DSC)以及傅里叶变换红外光谱(FT-IR)对其进行表征分析。将48只BALB/c小鼠随机分为4组,分别为空白对照组、ALG-NPs低、中、高(100、150、200 mg/kg)剂量组,每组分为7 d、14 d 2个亚组。超声雾化吸入给药,每日1次,20 min/次,于末次雾化1 h后进行血清、肺组织匀浆检测及组织病理学分析。[结果] ALG-NPs平均粒径为(71.24±2.12)nm,Zeta电位为(-19.4±0.64)mV,表征分析结果表明纳米凝胶体系构建成功。与空白对照组相比,ALG-NPs低、中剂量组肺组织和气管的组织切片病理分析未见异常且血清及肺组织匀浆中炎症因子水平正常。ALG-NPs高剂量组(14 d)肺组织偶有炎症细胞浸润且血清及肺组织匀浆中白介素-6(IL-6)水平显著升高。[结论] ALG-NPs作为药物载体,中低剂量给药是安全的,但长期大剂量地吸入对呼吸系统有一定的刺激性,应合理控制给药剂量与时间。

[Objective] A hydrogel nanoparticle preparation was developed as an ideal carrier for drug delivery,and the effects of nanoparticles via inhalation on the trachea and lung tissue were observed. The safety and feasibility of the inhalation drug delivery were preliminarily investigated.[Methods] The Zinc alginate hydrogel nanoparticles(ALG-NPs) were prepared by reverse microemulsion method,and characterized by determination of particle size and Zeta potential,transmission electron microscopy(TEM),differential scanning calorimetry(DSC) and fourier transform infrared spectroscopy(FT-IR). Forty-eight BALB/c mice were randomly divided into four groups,including the control,the ALG-NPs low,middle,and high dose(100,150,200 mg/kg) groups,and each group was also divided into 2 subgroups for 7 days and 14 days administration separately. Each group was administrated by inhaling ALG-NPs,once a day,20 min/time. After the last inhalation 1 h,the serum,lung tissue homogenate and pathology were determined.[Results] The average particle size of ALG-NPs was(71.24 ± 2.12) nm,and the Zeta potential was(-19.4 ± 0.64) m V. The results of characterization analysis indicated that the ALG-NPs system was successfully constructed. Compared with the control group,the lung tissue and trachea of the low and middle dose groups of ALG-NPs showed no abnormal lesions and the levels of inflammatory cytokines in serum and lung tissue homogenate were normal. Inflammatory cells infiltrated occasionally in the lung tissue,and IL-6 levels in serum and lung tissue homogenate were significantly increased in the ALG-NPs high dose group(14 days).[Conclusion] As a drug carrier,medium and low doses of ALG-NPs were safe,but long-term high dose of ALG-NPs inhalation had a certain irritating effect on the respiratory system,and the dose and inhalation time of ALG-NPs should be properly controlled.