Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Oct:143:93-108.
doi: 10.1016/j.biomaterials.2017.07.035. Epub 2017 Jul 29.

Non-proinflammatory and responsive nanoplatforms for targeted treatment of atherosclerosis

Affiliations

Non-proinflammatory and responsive nanoplatforms for targeted treatment of atherosclerosis

Yin Dou et al. Biomaterials. 2017 Oct.

Abstract

Atherosclerosis is the leading cause of many fatal cardiovascular and cerebrovascular diseases. Whereas nanomedicines are promising for targeted therapy of atherosclerosis, great challenges remain in development of effective, safe, and translational nanotherapies for its treatment. Herein we hypothesize that non-proinflammatory nanomaterials sensitive to low pH or high reactive oxygen species (ROS) may serve as effective platforms for triggerable delivery of anti-atherosclerotic therapeutics in cellular and tissue microenvironments of inflammation. To demonstrate this hypothesis, an acid-labile material of acetalated β-cyclodextrin (β-CD) (Ac-bCD) and a ROS-sensitive β-CD material (Ox-bCD) were separately synthesized by chemical modification of β-CD, which were formed into responsive nanoparticles (NPs). Ac-bCD NP was rapidly hydrolyzed in mildly acidic buffers, while hydrolysis of Ox-bCD NP was selectively accelerated by H2O2. Using an anti-atherosclerotic drug rapamycin (RAP), we found stimuli-responsive release of therapeutic molecules from Ac-bCD and Ox-bCD nanotherapies. Compared with non-responsive poly(lactide-co-glycolide) (PLGA)-based NP, Ac-bCD and Ox-bCD NPs showed negligible inflammatory responses in vitro and in vivo. By endocytosis in cells and intracellularly releasing cargo molecules in macrophages, responsive nanotherapies effectively inhibited macrophage proliferation and suppressed foam cell formation. After intraperitoneal (i.p.) delivery in apolipoprotein E-deficient (ApoE-/-) mice, fluorescence imaging showed accumulation of NPs in atherosclerotic plaques. Flow cytometry analysis indicated that the lymphatic translocation mediated by neutrophils and monocytes/macrophages may contribute to atherosclerosis targeting of i.p. administered NPs, in addition to targeting via the leaky blood vessels. Correspondingly, i.p. treatment with different nanotherapies afforded desirable efficacies. Particularly, both pH and ROS-responsive nanomedicines more remarkably delayed progression of atherosclerosis and significantly enhanced stability of atheromatous lesions, in comparison to non-responsive PLGA nanotherapy. Furthermore, responsive nanovehicles displayed good safety performance after long-term administration in mice. Consequently, for the first time our findings demonstrated the therapeutic advantages of nanomedicines responsive to mildly acidic or abnormally high ROS microenvironments for the treatment of atherosclerosis.

Keywords: Atherosclerosis; Cyclodextrin materials; Inflammation; Reactive oxygen species; Responsive nanotherapy; Targeting.

PubMed Disclaimer

Similar articles

Cited by

MeSH terms