A Targeting Nanotherapy for Abdominal Aortic Aneurysms

Juan Cheng; Runjun Zhang; Chenwen Li; Hui Tao; Yin Dou; Yuquan Wang; Houyuan Hu; Jianxiang Zhang

doi:10.1016/j.jacc.2018.08.2188

A Targeting Nanotherapy for Abdominal Aortic Aneurysms

J Am Coll Cardiol. 2018 Nov 27;72(21):2591-2605. doi: 10.1016/j.jacc.2018.08.2188.

Authors

Juan Cheng¹, Runjun Zhang², Chenwen Li¹, Hui Tao¹, Yin Dou¹, Yuquan Wang², Houyuan Hu³, Jianxiang Zhang⁴

Affiliations

¹ Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing, China.
² Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing, China; Department of Cardiology, Southwest Hospital, Third Military Medical University, Chongqing, China.
³ Department of Cardiology, Southwest Hospital, Third Military Medical University, Chongqing, China. Electronic address: houyuanhu@hotmail.com.
⁴ Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing, China. Electronic address: jxzhang@tmmu.edu.cn.

PMID: 30466517
DOI: 10.1016/j.jacc.2018.08.2188

Abstract

Background: Abdominal aortic aneurysm (AAA) is a leading cause of mortality and morbidity in the elderly. Currently, there remain no effective drugs that can prevent the growth of aneurysms and delay aneurysm rupture in the clinical setting.

Objectives: The aim of this study was to develop a nanotherapy that can target aneurysms and release drug molecules in response to the inflammatory microenvironment.

Methods: Using a reactive oxygen species (ROS)-responsive nanoparticle and a candidate drug rapamycin, in combination with a peptide ligand for integrin and biomimetic cloaking with macrophage cell membrane, a nanotherapy was developed. Its effectiveness was demonstrated by in vitro and in vivo studies.

Results: Based on a facile and translational method, a rapamycin-loaded responsive nanotherapy was successfully prepared, which could release drug molecules upon triggering by the high level of ROS. In cells associated with the development of AAAs, the nanotherapy significantly inhibited calcification and attenuated ROS-mediated oxidative stress and apoptosis. By passively targeting aneurysms and releasing drug molecules in response to the inflammatory microenvironment, the intravenously injected ROS-responsive nanotherapy more effectively prevented aneurysm expansion in AAA rats than a nonresponsive control nanotherapy. After decoration with a peptide ligand cRGDfK and macrophage cell membrane, the aneurysmal targeting capability and therapeutic effects of a ROS-responsive nanotherapy with a mean diameter of 190 nm were further enhanced. Moreover, the nanotherapy showed a good safety profile in a preliminary safety test.

Conclusions: The multifunctional nanotherapy can be further studied as a promising targeted drug for treatment of aneurysms. The underlying design principles enable the development of a broad range of nanomedicines for targeted therapy of other vascular diseases.

Keywords: aneurysm; inflammation; nanotherapy; reactive oxygen species; targeting.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aortic Aneurysm, Abdominal / drug therapy*
Aortic Aneurysm, Abdominal / metabolism*
Aortic Aneurysm, Abdominal / pathology
Cells, Cultured
Drug Delivery Systems / methods*
Immunosuppressive Agents / administration & dosage*
Male
Mice
Muscle, Smooth, Vascular / drug effects
Muscle, Smooth, Vascular / metabolism
Muscle, Smooth, Vascular / pathology
Myocytes, Smooth Muscle / drug effects
Myocytes, Smooth Muscle / metabolism
Myocytes, Smooth Muscle / pathology
Nanoparticles / administration & dosage*
RAW 264.7 Cells
Random Allocation
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species / antagonists & inhibitors
Reactive Oxygen Species / metabolism
Sirolimus / administration & dosage*

Substances

Immunosuppressive Agents
Reactive Oxygen Species
Sirolimus