Ultrasound imaging and on-demand therapy of peripheral arterial diseases using H2O2-Activated bubble generating anti-inflammatory polymer particles

Eunkyeong Jung; Joungyoun Noh; Changsun Kang; Donghyuck Yoo; Chulgyu Song; Dongwon Lee

doi:10.1016/j.biomaterials.2018.07.003

Ultrasound imaging and on-demand therapy of peripheral arterial diseases using H₂O₂-Activated bubble generating anti-inflammatory polymer particles

Biomaterials. 2018 Oct:179:175-185. doi: 10.1016/j.biomaterials.2018.07.003. Epub 2018 Jul 2.

Authors

Eunkyeong Jung¹, Joungyoun Noh², Changsun Kang¹, Donghyuck Yoo¹, Chulgyu Song³, Dongwon Lee⁴

Affiliations

¹ Department of BIN Convergence Technology, Chonbuk National University, Baekjedaero 567, Jeonju, Chonbuk, 54896, Republic of Korea.
² Department of Polymer⋅Nano Science and Technology, Chonbuk National University, Baekjedaero 567, Jeonju, Chonbuk, 54896, Republic of Korea.
³ Department of Electronics Engineering, Chonbuk National University, Baekjedaero 567, Jeonju, Chonbuk, 54896, Republic of Korea.
⁴ Department of BIN Convergence Technology, Chonbuk National University, Baekjedaero 567, Jeonju, Chonbuk, 54896, Republic of Korea; Department of Polymer⋅Nano Science and Technology, Chonbuk National University, Baekjedaero 567, Jeonju, Chonbuk, 54896, Republic of Korea. Electronic address: dlee@chonbuk.ac.kr.

PMID: 29990676
DOI: 10.1016/j.biomaterials.2018.07.003

Abstract

Muscles of peripheral artery disease (PAD) patients are under oxidative stress associated with a significantly elevated level of reactive oxygen species (ROS) including hydrogen peroxide (H₂O₂). Curcumin is a major active constituent of turmeric and is well known for its highly potent antioxidant, anti-inflammatory and angiogenic effects. We previously reported antioxidant vanillyl alcohol-incorporated copolyoxalate (PVAX) which is designed to rapidly scavenge H₂O₂ and release bioactive vanillyl alcohol and CO₂ in a H₂O₂-triggered manner. In this work, we developed curcumin-loaded PVAX (CUR-PVAX) nanoparticles as contrast-enhanced ultrasound imaging agents as well as on-demand therapeutic agents for ischemic injuries based on the hypothesis that PVAX nanoparticles generate echogenic CO₂ bubbles through H₂O₂-triggered oxidation of peroxalate esters and the merger of curcumin and PVAX exerts H₂O₂-activatable synergistic therapeutic actions. CUR-PVAX nanoparticles also displayed the drastic ultrasound signal in ischemic areas by generating CO₂ bubbles. CUR-PVAX nanoparticles exhibited significantly higher antioxidant and anti-inflammatory activities than empty PVAX nanoparticles and equivalent curcumin in vascular endothelial cells. A mouse model of ischemic injury was used to evaluate the potential of CUR-PVAX nanoparticles as ultrasound imaging agents and on-demand therapeutic agents. CUR-PVAX nanoparticles significantly suppressed the expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). Moreover, CUR-PVAX nanoparticles significantly enhanced the level of vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule-1 (PECAM-1, also known as CD31), leading to blood perfusion into ischemic tissues. We, therefore, believe that CUR-PVAX nanoparticles hold great translational potential as novel theranostic agents for ischemic diseases such as PAD.

Keywords: Curcumin; Hydrogen peroxide; Ischemia; Peripheral arterial disease; Ultrasound imaging.

Publication types

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

MeSH terms

Animals
Anti-Inflammatory Agents / therapeutic use
Antioxidants / chemistry
Antioxidants / metabolism
Apoptosis / drug effects
Curcumin / therapeutic use
Hydrogen Peroxide / chemistry*
Hydrogen Peroxide / metabolism
Mice
Nanoparticles / chemistry
Oxidative Stress / drug effects
Peripheral Arterial Disease / diagnostic imaging*
Peripheral Arterial Disease / drug therapy
Peripheral Arterial Disease / metabolism*
Polymers / chemistry*
Reactive Oxygen Species / metabolism

Substances

Anti-Inflammatory Agents
Antioxidants
Polymers
Reactive Oxygen Species
Hydrogen Peroxide
Curcumin