针对急性胰腺炎的胰腺和肺双器官靶向递药系统研究

The incidence of Acute Pancreatitis (AP) is increasing yearl. H2 receptor blockers, anti-infection antibiotics or anti-inflammatory drugs are mainly clinical treatment drugs, however, all of these show poor therapeutic effects. One reason is the presence of blood- pancreas barrier (BPB) between blood and pancreatic tissue, which make the majority of drug distribution in the pancreas rarely. And another one is that the inflammatory cytokines released from AP can cause Multiple Organ Dysfunction Syndrome(MODS), even Multiple Organ Failure(MOF), of which the incidence of acute pancreatitis associated lung injury(APALI) is as high as 60%-70% and about 50% of AP deaths combined with Acute Respiratory Distress Syndrome. Therefore, achieving the drugs targeted delivery to pancreas and lung double-organ means a lot for the treatment of acute pancreatitis. The applicant find that HIPDM(N,N'-trimethyl-N'[2-hydroxy-3-methyl-5- iodobenzyl] -1,3- propylene diamine ) is a good tracer for pancreas and lung tissue when analyzing the imaging agents for clinical use. It is envisaged that we can employ the small molecule propylene diamines (HPDM) which is structurally similar with HIPDM as a guide molecule to modify drugs, expecting achieve the drugs targeted delivery to pancreas and lung double-organ. This study uses rhubarb acid, the effective ingredient, from the rhubarb which is an important drug for clinical treatment of AP as a model drug, connecting with HPDM derivatives by ester bond, amino-methyl ester bond to construct the prodrug targeted to pancreas and lung. The relationship between the structure of HPDM derivatives and targeting effects to pancreas and lung, metabolism regularity and targeting mechanisms are also clarified in this study. All of these provide the new ideas for the treatment of acute pancreatitis and set a foundation for study on novel drugs which targeted to pancreas and lung double- organ.

急性胰腺炎（AP）的发病率正逐年增高，临床以H2受体阻断剂、抗感染抗生素或抗炎药物治疗为主，但疗效都不佳。原因之一是胰腺组织与血液之间存在血胰屏障（BPB），使绝大多数药物在胰腺分布极少；二是AP释放的炎症因子可导致多器官功能不全甚至衰竭，其中肺损伤发生率高达 60%-70%，约50%的AP死亡病例合并急性呼吸窘迫综合征。因此，实现药物的胰腺和肺双器官靶向递送对于AP的治疗意义重大。 申请者分析临床使用的显像剂发现HIPDM是良好的胰腺、肺组织示踪剂。故设想以与HIPDM结构类似的HPDM类小分子为导向分子修饰药物，有望实现药物的胰腺和肺双器官靶向递药。经预试证明了这一设想。因此，本课题以临床治疗AP的重要药物大黄的有效成分大黄酸等为模型药物，与HPDM类衍生物通过酯键、氨甲酯键等相连，构建胰腺和肺双器官靶向前体药物，并阐明HPDM类衍生物结构与肺、胰腺靶向性之间的关系、代谢规律、靶向机制

本课题在国内外首次提出进行双器官靶向（源靶器官胰腺、次级靶器官肺）治疗SAP的设想。设计利用临床使用多年疗效确切的大黄的有效成分大黄酸为模型药物，选择适当的小分子化合物为导向分子，构建具有穿过BPB达到胰腺和肺双器官靶向作用的前体药物，使其在源靶器官—胰腺发挥治疗作用的同时，还将在肺部起到抗炎作用，从而降低APALI的发生率和SAP病人的死亡率。.为了开发出可用于临床的胰腺和肺靶向载体，我们对文献进行了综合分析，发现胰腺、肺组织可以摄取示踪剂——放射性碘标记的HIPDM（N,N,N’-三甲基-N’[2-羟基-3甲基-5-碘苄基]-1,3丙二胺），因此我们设想选择与HIPDM结构类似的小分子丙二胺类作为导向分子修饰药物，制成的前体药物有望高效地通过BPB导入胰腺，并增加其在肺部的分布。. 基于以上基础，设计并合成了小分子HIPDM衍生物。考察了HR在血浆、胰腺、肺组织匀浆以及不同pH值缓冲液中的稳定性。采用MTT法对HPDM、Rhein及HR的体外细胞毒性进行研究，结果表明，4h内，HPDM的引入没有增加药物的细胞毒性；体外细胞摄取实验结果表明，HPDM的引入能增加胰腺细胞AR42J对HR的摄取；通过竞争性抑制实验表明，这种AR42J细胞的摄取可能是由胰腺腺泡细胞AR42J上的有机阳离子转运体受体介导的。采用LC-MS/MS法进行了Rhein和HR在大鼠体内的药物动力学研究，Rhein制成前体药物HR后，在胰腺和肺组织中分布显著增加，靶向性极其显著，达到了本课题组双靶向——胰腺和肺——药物给药系统设计的目的。对HR的药效学性质进行了研究，分别建立了大鼠重症急性胰腺炎相关肺损伤模型和大鼠哮喘模型，实验结果表明，在重症急性胰腺炎模型中，HR与Rhein相比，能明显减轻SAP过程中胰腺和肺的损伤。. 综上本课题成功合成了双靶向给药系统的载体HPDM及前体药物HR，HPDM的引入改变了药物的体内分布，大大提高了药物在胰腺和肺的蓄积。这表明HPDM可以作为高效、低毒的胰腺和肺靶向给药的小分子载体。