Abstract：
This study aimed to develop an innovative dosage form for 10-hydroxycamptothecin (HCPT), a chemotherapeutic agent with limited aqueous solubility and stability, to enhance its parenteral delivery and targeting to hepatic cancer. We formulated HCPT into a nanoemulsion using tributyrin, a dietary component with histone deacetylase inhibitor activity. The resulting HCPT-loaded tributyrin nanoemulsion (Tri-HCPT-E) underwent extensive evaluations. Tri-HCPT-E significantly improved the aqueous solubility, stability, and anti-cancer activities in HepG2 cells. Pharmacokinetic studies confirmed the increased stability and hepatic targeting, with Tri-HCPT-E leading to a 120-fold increase in plasma exposure of intact HCPT and a 10-fold increase in hepatic exposure compared to the commercial free solution. Co-administration of 17α-ethynylestradiol, an up-regulator of low-density lipoprotein (LDL) receptor, further enhanced the distribution and metabolism of HCPT, demonstrating an association between the LDL receptor pathway and hepatic targeting. Most importantly, Tri-HCPT-E exhibited superior in vivo anti-cancer efficacy in a mouse xenograft model compared to the commercial formulation, without causing escalated hepatic or renal toxicity. In conclusion, formulating HCPT into a nanoemulsion with tributyrin has proven to be an innovative and effective strategy for targeted hepatic cancer chemotherapy while tributyrin, a pharmacologically active dietary component, has emerged as a promising functional excipient for drug delivery.
摘要：
本研究旨在开发10-羟基喜树碱（HCPT）的创新剂型，具有有限的水溶性和稳定性的化学治疗剂，以增强其胃肠外递送和靶向肝癌。我们使用三丁酸甘油酯将HCPT配制成纳米乳液，具有组蛋白脱乙酰酶抑制剂活性的饮食成分。得到的负载HCPT的三丁酸甘油酯纳米乳液(Tri-HCPT-E)进行了广泛的评价。Tri-HCPT-E显著提高了水溶性,稳定性,和在HepG2细胞中的抗癌活性。药代动力学研究证实了增加的稳定性和肝靶向，与商业免费溶液相比，Tri-HCPT-E导致完整HCPT的血浆暴露增加120倍，肝脏暴露增加10倍。17α-乙炔雌二醇的共同给药，低密度脂蛋白（LDL）受体的上调，进一步增强了HCPT的分布和代谢，显示LDL受体途径与肝靶向之间的关联。最重要的是,与商业制剂相比，Tri-HCPT-E在小鼠异种移植模型中表现出优异的体内抗癌功效。不会导致肝或肾毒性升级。总之,将HCPT与三丁酸甘油酯配制成纳米乳液已被证明是靶向肝癌化疗的创新和有效策略，而三丁酸甘油酯，具有药理活性的饮食成分，已经成为一种有前途的功能性赋形剂用于药物递送。
