Gao Yan, Yang Xue, Wang Ziyi, Zhong Zhangfeng, Hu Yuanjia, Wang Yitao
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
Front Chem. 2020 Feb 28;8:134. doi: 10.3389/fchem.2020.00134. eCollection 2020.
Anabasine (ANA), a major piperidine alkaloid originally isolated from wild tobacco trees (), has been known to induce serious developmental toxicities such as skeletal deformities in livestock and humans. In this study, we thoroughly investigated the supramolecular nano-encapsulations of ANA by an artificial nanocontainer, cucurbit[7] uril (CB[7]), and examined the influences of the nano-encapsulation on ANA's inherent developmental toxicities on a zebrafish model. We have shown that CB[7] formed 1:1 host-guest inclusion complexes with ANA via a relatively high binding strength [ of (7.45 ± 0.31) × 10 M] in an aqueous solution, via UV-vis and H nuclear magnetic resonance spectroscopic titrations, as well as isothermal titration calorimetry titration. As a consequence, CB[7] significantly attenuated the developmental toxicity of ANA on zebrafish . In contrast, for a comparative purpose, β-CD didn't exert any influence on the toxicity of ANA due to its weak binding with ANA, which was not even measurable via either spectroscopic methods or ITC titration. This is the first head-to-head comparison of this pair of nanocontainers, CB[7] and β-CD, on their potential roles in influencing the toxicity of guest molecules and the results suggested that CB[7] could become a more promising functional excipient for reducing the inherent toxicities of active pharmaceutical ingredients, particularly alkaloids that may form relatively strong host-guest binding species with the host.
新烟草碱（ANA）是一种最初从野生烟草树中分离出的主要哌啶生物碱，已知会在牲畜和人类中引发严重的发育毒性，如骨骼畸形。在本研究中，我们深入研究了人工纳米容器葫芦[7]脲（CB[7]）对ANA的超分子纳米封装，并在斑马鱼模型上研究了纳米封装对ANA固有发育毒性的影响。我们通过紫外可见光谱和氢核磁共振光谱滴定以及等温滴定量热法滴定表明，在水溶液中，CB[7]与ANA通过相对较高的结合强度[（7.45±0.31）×10⁶ M]形成了1:1的主客体包合物。结果，CB[7]显著减弱了ANA对斑马鱼的发育毒性。相比之下，作为对照，β-环糊精（β-CD）由于与ANA的结合较弱，对ANA的毒性没有任何影响，甚至通过光谱方法或等温滴定量热法滴定都无法测量。这是对这一对纳米容器CB[7]和β-CD在影响客体分子毒性方面的潜在作用的首次直接比较，结果表明CB[7]可能成为一种更有前景的功能性辅料，用于降低活性药物成分的固有毒性，特别是那些可能与主体形成相对较强主客体结合物种的生物碱。
