Platelet-like proteoliposomes enable active drug delivery to infarcted heart tissue

摘要

Introduction: To date, ischemic heart disease (IHD) continues to be the major cause of death in many countries. It is well established that the recruitment of monocytes to the infarcted area is a significant contributor to pathophysiology of the disease. Once these circulating monocytes cross the endothelium they becomes macrophages, which then causes more damages to the infarct heart through their profound inflammatory activity. Unfortunately, drugs that target these macrophages or other drug targets, often have undesired off-targeting effects as most of them rely on the enhanced permeability retention (EPR) effect in getting to the target area. Since platelets are known to bind to the circulating monocytes in patients with IHD, it is hypothesized that active drug targeting to infarcted heart can be achieved through the interaction of platelet-like proteoliposomes (PLPs) with the circulating monocytes. In this study, cobalt protoporphyrin (CoPP), a small molecule that inhibits cardiac macrophages' inflammatory activity while inducing toxicity at other organs was used as the drug example. Materials and Methods: The fabrication of PLPs involved mixing platelet membrane proteins with Dil-labelled DOPC/cholesterol. Bioactivity of PLPs was characterized by in vitro immunofiuorescence assay. Biodistribution of control liposomes and PLPs in murine model of I/R (ischemia-reperfusion) injury was analyzed by high performance liquid chromatography (HPLC). Histological stainings were performed to analyze the size of infarct area in the murine model after i.v. injected with PLPs-encapsulated CoPP. Likewise, echocardiography and blood tests were used to access cardiac functions of murine model of myocardial infarction (MI) after i.v. injection of PLPs-encapsulated CoPP. Results and Discussion: Fluorescence images revealed that control liposomes were phagocytized by murine endothelial cells, monocytes and macrophages. In contrast, PLPs only showed positive interactions with monocytes and macrophages, suggesting that PLPs would not induce undesired thrombosis through the interactions with endothelium. ～72 hours of reperfusion, which is the time that the amount of the recruited monocytes peaks at. Moreover, the mice treated with PLPs-encapsulated CoPP showed significant encapsulated CoPP. Unlike free CoPP or liposome-encapsulated CoPP, the mice treated with PLPs-encapsulated CoPP showed significant improvement in cardiac functions, while minimizing the known side-effects of CoPP such as liver and kidney toxicity. Conclusions: Using the circulating monocytes in murine model of either I/R or Ml as 'shuttle bus', PLPs minized the need of relying on EPR effect in reaching the heart. Thus PLPs were demonstrated to be an effective delivery system in carrying CoPP to the infarct area, while minimizing the potential side-effects of the drug.