作为一种植物来源的药物，胡椒碱在许多疾病的治疗中具有疗效，但其天然的低溶解度和生物利用度极大地限制了其临床应用。在这里，我们从黑胡椒中提取胡椒碱，优化了胡椒碱的结构以制备各种衍生物，然后探索了这些衍生物的抗癌活性。胡椒碱及其衍生物对4T1细胞具有高度的抗癌选择性，在低浓度100μg/mL下显示明显的抗癌特性。此外，我们使用密度泛函理论研究了胡椒碱及其衍生物的物理化学性质，证明了它们具有显著的生物活性。此外，我们制备了壳聚糖基微凝胶，以高81.7%的装载效率包封了亲水胡椒碱衍生物，以克服胡椒碱衍生物的低水溶解度。值得注意的是，肿瘤细胞中过多的谷胱甘肽会引发微凝胶的降解，并实现高达72.3%的可控药物释放。由于其出色的特性，壳聚糖基微凝胶载药胡椒碱衍生物对4T1细胞具有约13.14%的良好抗癌效果。因此，壳聚糖基微凝胶通过包封克服了胡椒碱衍生物的低水溶解度，进一步增强了其传递效率和细胞内摄取能力，实现了优异的抗癌活性。这项研究通过优化胡椒碱的结构和壳聚糖基微凝胶来展示了亲水植物来源药物的增强抗癌效果，并提高了药物输送能力。版权所有©2023年Elsevier B.V.发表。

As a plant-derived drug, piperine possesses therapeutic efficacy for many diseases, but its inherent low solubility and bioavailability have greatly limited its clinical use. Herein, we extracted piperine from black pepper, optimized the structure of piperine to prepare various derivatives, and then explored the anticancer activity of these derivatives. Piperine and its derivatives have high anticancer selectivity against 4T1 cells, exhibiting obvious anticancer properties even at a low concentration of 100 μg/mL. Furthermore, the physicochemical properties of piperine and its derivatives were investigated using density functional theory, demonstrating their considerable biological activity. Moreover, the chitosan-based microgels were prepared to encapsulate the hydrophobic piperine derivative with a high loading efficiency of 81.7 % to overcome the low water solubility of the piperine derivative. It is worth noting that excessive glutathione in tumor cells triggers the degradation of microgels and realizes controllable drug release of up to 72.3 %. Due to its excellent properties, chitosan-based microgels loaded with the piperine derivative can obtain good anticancer behavior of approximately 13.14 % cell viability against 4T1 cells. Therefore, the chitosan-based microgels overcome the low water solubility of the piperine derivative through encapsulation and thus further augment their delivery efficiency and cell internalization capability to realize excellent anticancer activity. This work demonstrates the enhanced anticancer efficacy of the hydrophobic plant-derived drug by means of structural optimization of piperine and chitosan-based microgels with boosted drug delivery.Copyright © 2023. Published by Elsevier B.V.