Abstract
Atherosclerotic plaque remains the leading contributor to cardiovascular disease and requires invasive surgical procedures for its removal. Nanomedicine offers a minimally invasive approach to alleviate plaque burden by targeted therapeutic delivery. However, nanocarriers are limited without the ability to sense and respond to the diseased microenvironment. In this study, targeted self-assembled peptide amphiphile (PA) nanofibers are developed that cleave in response to biochemical cues expressed in atherosclerotic lesions—reactive oxygen species (ROS) and intracellular glutathione—to deliver a liver X receptor agonist (LXR) to enhance macrophage cholesterol efflux. The PAs release LXR in response to physiological levels of ROS and reducing agents and can be co-assembled with plaque-targeting PAs to form nanofibers. The resulting LXR PA nanofibers promoted cholesterol efflux from macrophages in vitro as well as LXR alone and with lower cytotoxicity. Further, the ApoA1-LXR PA nanofibers target plaque within an atherosclerotic mouse model in vivo and activate ATP-binding cassette A1 (ABCA1) expression as well as LXR alone with reduced liver toxicity. Taken together, these results demonstrate the potential of self-assembled PA nanofibers for controlled therapeutic delivery to the atherosclerotic niche.
| Original language | English (US) |
|---|---|
| Article number | 2100103 |
| Journal | Advanced Therapeutics |
| Volume | 4 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2021 |
Funding
This study was supported in part by funding from the National Institutes of Health (1R01HL116577‐01) and the University of North Carolina's School of Medicine. E.B.P. was supported by the American Heart Association Postdoctoral Fellowship 18POST33960499 and the Burroughs Wellcome Fund Collaborative Research Training Grant. T.D.C. and S.I.S. acknowledge funding support from the Center for Regenerative Nanomedicine at the Simpson Querrey Institute at Northwestern. The authors gratefully acknowledge Mark Seniw for the PA molecular graphics illustrations. The HPLC‐MS analysis used equipment supported by the National Science Foundation under Grant No. CHE‐1726291. Peptide amphiphile synthesis was performed in the Peptide Synthesis Core Facility of the Simpson Querrey Institute at Northwestern University. The U.S. Army Research Office, the U.S. Army Medical Research and Materiel Command, and Northwestern University provided funding to develop this facility and ongoing support is being received from the Soft and Hybrid Nanotechnology Experimental (SHyNE). This work made use of the BioCryo facility of Northwestern University's NUANCE Center, which received support from the SHyNE Resource (NSF ECCS‐1542205); the MRSEC program (NSF DMR‐1720139) at the Materials Research Center; the International Institute for Nanotechnology (IIN); and the State of Illinois, through the IIN. Portions of this work were performed at the DuPont‐Northwestern‐Dow Collaborative Access Team (DND‐CAT) located at Sector 5 of the Advanced Photon Source. DND‐CAT was supported by Northwestern University, The Dow Chemical Company, and DuPont de Nemours, Inc. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE‐AC02‐06CH11357. This study was supported in part by funding from the National Institutes of Health (1R01HL116577-01) and the University of North Carolina's School of Medicine. E.B.P. was supported by the American Heart Association Postdoctoral Fellowship 18POST33960499 and the Burroughs Wellcome Fund Collaborative Research Training Grant. T.D.C. and S.I.S. acknowledge funding support from the Center for Regenerative Nanomedicine at the Simpson Querrey Institute at Northwestern. The authors gratefully acknowledge Mark Seniw for the PA molecular graphics illustrations. The HPLC-MS analysis used equipment supported by the National Science Foundation under Grant No. CHE-1726291. Peptide amphiphile synthesis was performed in the Peptide Synthesis Core Facility of the Simpson Querrey Institute at Northwestern University. The U.S. Army Research Office, the U.S. Army Medical Research and Materiel Command, and Northwestern University provided funding to develop this facility and ongoing support is being received from the Soft and Hybrid Nanotechnology Experimental (SHyNE). This work made use of the BioCryo facility of Northwestern University's NUANCE Center, which received support from the SHyNE Resource (NSF ECCS-1542205); the MRSEC program (NSF DMR-1720139) at the Materials Research Center; the International Institute for Nanotechnology (IIN); and the State of Illinois, through the IIN. Portions of this work were performed at the DuPont-Northwestern-Dow Collaborative Access Team (DND-CAT) located at Sector 5 of the Advanced Photon Source. DND-CAT was supported by Northwestern University, The Dow Chemical Company, and DuPont de Nemours, Inc. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.
Keywords
- cardiovascular disease
- drug delivery
- nanomedicine
- nanotechnology
- peptide amphiphiles
ASJC Scopus subject areas
- Medicine (miscellaneous)
- Pharmacology
- Pharmaceutical Science
- Genetics(clinical)
- Biochemistry, medical
- Pharmacology (medical)
