新型肠道OCTN2靶向的程序化生物激活的吉西他滨亲脂化载体前药的研究

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.

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。

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。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。体内药动学结果显示L-肉毒碱修饰的前药可以显著提高吉西他滨的口服生物利用度（4.9倍），说明OCTN2是一个有前景的口服药物靶点。进一步研究发现肉碱/有机阳离子转运蛋白2（OCTN2）和单羧酸转运蛋白1（MCT1）在肠道具有高的转运能力和互补的肠道分布。设计同时靶向肠道OCTN2和MCT1的环化激活吉西他滨前药可能会有更好的口服吸收。因此，我们进一步探究了靶向肠道MCT1的分子内环化激活的吉西他滨前药，进而实现更高效的吉西他滨口服递送。截止到目前，本课题已发表SCI论文11篇，申请专利5项，获授权专利4项，超过了我们初始定的目标。

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