Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia

Abstract

Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360 ng rapamycin per patch without detectable rapamycin in serum; nanoparticles were detectable in the liver, kidney and spleen but no other sites within 24 hours. In a rat venous patch angioplasty model, control patches developed robust neointimal hyperplasia on the patch luminal surface characterized by Eph-B4-positive endothelium and underlying SMC and infiltrating cells such as macrophages and leukocytes. Patches delivering rapamycin developed less neointimal hyperplasia, less smooth muscle cell proliferation, and had fewer infiltrating cells but retained endothelialization. NP covalently linked to pericardial patches are a novel composite delivery system that allows sustained site-specific delivery of therapeutics; NP delivering rapamycin inhibit patch neointimal hyperplasia. NP linked to patches may represent a next generation of tissue engineered cardiovascular implants.

Inhibition of programmed death‐1 decreases neointimal hyperplasia after patch angioplasty

“…There was also a significant thinner adventitial layer of the IP injection and coating patches (Figure 3a,c). These results are similar to our previous data showing that rapamycin decreases neointimal hyperplasia that forms on patches 17 …”

Transforming Growth Factor-β1 Inhibits Pseudoaneurysm Formation After Aortic Patch Angioplasty

“…We previously showed that nanoparticles covalently bonded to pericardial patches can deliver therapeutic agents to the adjacent vena cava. 18 We confirmed that this strategy could similarly deliver drugs to the aorta after aortic patch angioplasty. Nanoparticles containing rhodamine were bonded to patches and used for aortic patch angioplasty; as expected, rhodamine was delivered to the aortic wall, with increased delivery over 24 hours (Supplementary figure 4).…”

Nanoparticles administered intrapericardially enhance payload myocardial distribution and retention

“…Combined with nanoparticles engineered to exhibit slow drug release kinetics, the pericardium can function as a sustained release drug-eluting depot for prolonged drug delivery to the heart. Recently, Hualong and coworkers demonstrated neointimal hyperplasia inhibition through sustained rapamycin delivery from a pericardial patch [51], successfully limiting smooth muscle cell migration and hyperplasia.…”