目前，针对低膜渗透性药物口服吸收差的难题，通常采取亲脂化前药和载体前药两种策略。然而，它们存在着水溶性差和转运能力有限的问题。此外，大多数前药的生物激活是基于非特异性酶，活化效率低且部位不可控。为此，我们提出“程序化生物激活的亲脂化载体前药”的设计理念。该思路一方面通过脂质连接桥来调节前药脂溶性及其与转运体的亲和性，利用载体介导和被动转运的双驱动机制来提高药物膜渗透性；另一方面通过控制连接桥的有序断裂和变换功能性基团来调控前药的激活部位和速度。本课题以肠道新型有机阳离子转运体2(OCTN2)为靶点，在前药结构中同时引入环化激活、低氧激活和亲脂性的连接桥制备程序化生物激活的吉西他滨口服载体前药；以膜渗透性、稳定性、亲和性、激活速度为指标进行前药性质考察，建立定量结构-亲和性/稳定性/激活效率的关系，解析影响前药吸收、激活、分布和疗效的关键因素。课题成果将为口服载体前药开发提供新的设计思路。

For low permeability drugs, there are two kinds of strategies to improve oral absorption, including lipophilicifized prodrugs and carrier prodrugs, but there are still some problems, such as poor water solubility and limited transport capacity. In addition, low efficiency of metabolic enzymes in activating produgs has greatly restricted its oral application. So we put forward a “programmed bioactivation of lipophilicifized carrier prodrug” design concept, utilizing the lipid bridge to adjust prodrug lipophilicity and affinity with the transporter, and adopting the self-immolative bridge to control drug release in a predtermined manner. Transporter-mediated and passive transport co-driven permeation is used to overcome the poor membrane permeation. Importantly, programmed-activable self-immolative bridge is used to overcome the low efficiency of prodrug activation by changing the activation site and controlling the speed and extent of activation. In this study, intestinal OCTN2 was used as a target to prepare programmed-activable lipophilicifized carrier prodrugs and L-carnitine was conjugated to gemcitabine through lipid bridge, cyclization-activated bridge and hypoxically activated bridge. Membrane permeability, stability, affinity, activation rate were used to screen prodrugs, and quantitative structure-affinity/stability/permeability/activation efficiency relationship was established to elucidate the key biopharmaceutical factors on the oral absorption, activation, distribution and efficacy. The findings of this study provide new design modality for the oral prodrugs design.