Ong Yong Sze, Saiful Yazan Latifah, Ng Wei Keat, Noordin Mustapha M, Sapuan Sarah, Foo Jhi Biau, Tor Yin Sim
Laboratory of Molecular Biomedicine, Institute of Bioscience.
Laboratory of Molecular Biomedicine, Institute of Bioscience; Department of Biomedical Science, Faculty of Medicine and Health Sciences.
Int J Nanomedicine. 2016 Nov 9;11:5905-5915. doi: 10.2147/IJN.S114205. eCollection 2016.
Thymoquinone (TQ), the predominant active lipophilic component in seed oil, has a variety of pharmacological properties such as anticancer activities. However, translation of TQ to clinical phase is still not possible due to its hydrophobic properties. This problem can be solved by encapsulating it in nanoformulations to enhance its pharmacological properties. In our previous study, TQ has been successfully encapsulated in a nanostructured lipid carrier (hereinafter referred to as TQNLC) with excellent physiochemical properties such as high encapsulation efficiency, high drug-loading capacity, particle diameter less than 100 nm, and stability up to 2 years. In vitro studies also proved that TQNLC exhibited antiproliferative activity toward breast and cervical cancer cell lines. However, no toxicity profile related to this formulation has been reported. In this study, we determine and compare the in vivo toxicity of both TQNLC and TQ.
The in vivo toxicity (acute and subacute toxicity) study was carried out by oral administration of TQNLC and TQ to BALB/c mice. Animal survival, body weight, organ weight-to-body weight ratio, hematological profile, biochemistry profile, and histopathological changes were analyzed.
In acute toxicity, TQ that is loaded in nanostructured lipid carrier (NLC) was found to be less toxic than pure TQ. It can be concluded that encapsulation of TQ in lipid carrier minimizes the toxicity of the compound. In the subacute toxicity study, oral administration of 100 mg/kg of TQNLC and TQ did not cause mortality to either male or female but resulted in toxicity to the liver. It is postulated that long-term consumption of TQNLC and TQ may cause toxicity to the liver but not to the extent of altering the functions of the organ. For both treatments, the no observed adverse effect level (NOAEL) was found to be 10 mg/kg/d for mice in both sexes.
For long-term oral consumption, TQ and TQNLC at a dose of 10 mg/kg is safe in mice and does not exert any toxic effect. The results provide safety information of TQNLC, which would further help researchers in clinical use.
百里醌（TQ）是种子油中的主要活性亲脂性成分，具有多种药理特性，如抗癌活性。然而，由于其疏水性，TQ仍无法进入临床阶段。通过将其封装在纳米制剂中以增强其药理特性，可以解决这个问题。在我们之前的研究中，TQ已成功封装在纳米结构脂质载体（以下简称TQNLC）中，该载体具有优异的理化性质，如高包封率、高载药量、粒径小于100nm以及长达2年的稳定性。体外研究也证明，TQNLC对乳腺癌和宫颈癌细胞系具有抗增殖活性。然而，尚未有关于该制剂毒性特征的报道。在本研究中，我们测定并比较了TQNLC和TQ的体内毒性。
通过对BALB/c小鼠口服TQNLC和TQ进行体内毒性（急性和亚急性毒性）研究。分析动物存活率、体重、器官重量与体重比、血液学指标、生化指标以及组织病理学变化。
在急性毒性实验中，发现负载于纳米结构脂质载体（NLC）中的TQ比纯TQ毒性更小。可以得出结论，将TQ封装在脂质载体中可使该化合物的毒性降至最低。在亚急性毒性研究中，口服100mg/kg的TQNLC和TQ对雄性或雌性小鼠均未导致死亡，但对肝脏产生了毒性。据推测，长期食用TQNLC和TQ可能会对肝脏造成毒性，但不会达到改变器官功能的程度。对于两种处理方式，两性小鼠的未观察到不良反应水平（NOAEL）均为10mg/kg/d。
对于长期口服，剂量为10mg/kg的TQ和TQNLC对小鼠是安全的，且不会产生任何毒性作用。这些结果提供了TQNLC的安全性信息，这将进一步帮助研究人员在临床应用中参考。
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