Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University (Parkville Campus), 399 Royal Parade, Parkville, Victoria 3052, Australia.
Mol Pharm. 2019 Dec 2;16(12):4987-4999. doi: 10.1021/acs.molpharmaceut.9b00855. Epub 2019 Nov 1.
Drugs are commonly administered via the intraperitoneal (IP) route to treat localized infections and cancers in patients and to test drug efficacy and toxicity in preclinical studies. Despite this, there remain large gaps in our understanding of drug absorption routes (lymph vs blood) and pharmacokinetics following IP administration. This is particularly true when drugs are administered in complex delivery systems such as liposomes which are the main marketed formulation for several drugs that are administered intraperitoneally. This study investigated the impact of liposome surface properties (charge and PEGylation) on absorption into lymph and blood, and lymphatic disposition patterns, following IP administration. To achieve this, stable H-dipalmitoyl-phosphatidylcholine (DPPC) and C-sucrose-radiolabeled liposomes of 100-150 nm diameter with negative, neutral, or positive surface charge, or a PEGylated surface, were prepared and administered intraperitoneally to rats. Radiolabel concentrations were measured in lymph, blood, and lymph nodes (LNs). Lymph was collected from the thoracic lymph duct at either the abdomen (ABD) or the jugular-subclavian junction (JSJ). The lymphatic recovery of the radiolabels was substantially lower after administration in positively charged compared to the neutral, negative, or PEGylated liposomes. Radiolabel recovery was substantially greater (up to 18-fold) in the thoracic lymph collected at the JSJ when compared to that at the ABD, suggesting that liposomes entered the lymphatics at the diaphragm. Consistent with this, the concentration of the liposome labels was substantially higher (up to seven-fold) in mediastinal than in mesenteric LNs. Overall, this study shows how the peritoneal absorption and lymphatic disposition of drugs administered intraperitoneally can be manipulated through a careful selection of the drug delivery system and may thus be optimized to treat localized conditions such as cancers, infections, inflammatory diseases, and acute and critical illness.
药物通常通过腹腔内（IP）途径给药，以治疗患者的局部感染和癌症，并在临床前研究中测试药物的疗效和毒性。尽管如此，我们对药物吸收途径（淋巴与血液）以及 IP 给药后的药代动力学仍存在很大的理解差距。当药物以复杂的给药系统（如脂质体）给药时，这种情况尤其如此，脂质体是几种腹腔内给药药物的主要市售制剂。本研究调查了脂质体表面性质（电荷和聚乙二醇化）对 IP 给药后吸收进入淋巴和血液以及淋巴分布模式的影响。为了实现这一目标，制备了具有负、中或正表面电荷或聚乙二醇化表面的稳定 H-二棕榈酰磷脂酰胆碱（DPPC）和 C-蔗糖放射性标记的 100-150nm 直径的脂质体，并将其腹腔内给药给大鼠。测量了淋巴、血液和淋巴结（LN）中的放射性标记浓度。从胸导管在腹部（ABD）或颈静脉锁骨下交界处（JSJ）收集淋巴。与中性、负电荷或聚乙二醇化脂质体相比，正电荷脂质体给药后放射性标记物的淋巴回收率明显较低。与 ABD 相比，JSJ 处收集的胸淋巴中放射性标记物的回收率明显更高（高达 18 倍），这表明脂质体在膈膜处进入了淋巴管。与此一致的是，纵隔淋巴结中脂质体标记物的浓度明显更高（高达 7 倍）。总的来说，这项研究表明，通过仔细选择药物递送系统，可以操纵腹腔内给药的药物腹膜吸收和淋巴分布，从而可以优化治疗局部疾病，如癌症、感染、炎症性疾病以及急性和危重病。
