Magnetic nanoparticles for drug targeting: from design to insights into systemic toxicity. Preclinical evaluation of hematological, vascular and neurobehavioral toxicology
Magnetic nanoparticles for drug targeting: from design to insights into systemic toxicity. Preclinical evaluation of hematological, vascular and neurobehavioral toxicology
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DOI：
10.1039/c6bm00954a
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发表时间：
2017-04-01
影响因子：
6.6
通讯作者：
Lassalle, Veronica L.
中科院分区：
文献类型：
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作者：
Agotegaray, Mariela A.;Campelo, Adrian E.;Lassalle, Veronica L.
为了获得具有生物相容性的磁性纳米药物载体，开发了一种简单的两步药物包封方法，用于多种疾病的靶向治疗。该纳米器械由包被有壳聚糖（Chit@ MNP）的磁铁矿核心组成，作为双氯芬酸（Dic）负载的平台，作为模型药物（Dic-Chit@ MNP）。与药物掺入和定量有关的机制和实验条件得到进一步解决。这项多学科研究旨在阐明MNP在血液学、血管、神经和行为水平上的毒理学影响。血液相容性试验表明，MNP在评价剂量（1，10和100 μ g mL（-1））下不影响血沉或红细胞完整性。血液涂片的显微镜评价表明，MNP不会诱导血细胞的形态学变化。血小板聚集也不受MNP的影响，仅观察到Dic-Chit@ MNP轻微减少，这可能是双氯芬酸所致。所研究的制剂没有对大鼠主动脉内皮细胞产生细胞毒性，并且没有观察到细胞活力或其合成NO的能力的变化。在用Chit@ MNP亚急性处理小鼠后，评估功能观察组合中的行为和功能神经系统参数。接触组尿池减少。在组织病理学研究中观察到肾炎和脾脏中巨核细胞数量增加。亚急性暴露于Chit@ MNP不会导致用于评估神经行为毒性的参数发生显著变化。本手稿中关注的方面与临床前水平相关，提供了有关磁性纳米器件生物相容性的新知识，用于生物医学应用。
A simple two-step drug encapsulation method was developed to obtain biocompatible magnetic nano-carriers for the potential targeted treatment of diverse diseases. The nanodevice consists of a magnetite core coated with chitosan (Chit@MNPs) as a platform for diclofenac (Dic) loading as a model drug (Dic-Chit@MNPs). Mechanistic and experimental conditions related to drug incorporation and quantification are further addressed. This multi-disciplinary study aims to elucidate the toxicological impact of the MNPs at hematological, vascular, neurological and behavioral levels. Blood compatibility assays revealed that MNPs did not affect either erythrosedimentation rates or erythrocyte integrity at the evaluated doses (1, 10 and 100 mu g mL(-1)). A microscopic evaluation of blood smears indicated that MNPs did not induce morphological changes in blood cells. Platelet aggregation was not affected by MNPs either and just a slight diminution was observed with Dic-Chit@MNPs, an effect possibly due to diclofenac. The examined formulations did not exert cytotoxicity on rat aortic endothelial cells and no changes in cell viability or their capacity to synthesize NO were observed. Behavioral and functional nervous system parameters in a functional observational battery were assessed after a subacute treatment of mice with Chit@MNPs. The urine pools of the exposed group were decreased. Nephritis and an increased number of megakaryocytes in the spleen were observed in the histopathological studies. Sub-acute exposure to Chit@MNPs did not produce significant changes in the parameters used to evaluate neurobehavioral toxicity. The aspects focused on within this manuscript are relevant at the pre-clinical level providing new and novel knowledge concerning the biocompatibility of magnetic nanodevices for biomedical applications.