title: Neuropeptide Y3-36incorporated into PVAX nanoparticle improves functional blood flow in a murine model of hind limb ischemia.
abstract: We generated a novel nanoparticle called PVAX, which has intrinsic antiapoptotic and anti-inflammatory properties. This nanoparticle was loaded with neuropeptide Y3-36(NPY3-36), an angiogenic neurohormone that plays a central role in angiogenesis. Subsequently, we investigated whether PVAX-NPY3-36could act as a therapeutic agent and induce angiogenesis and vascular remodeling in a murine model of hind limb ischemia. Adult C57BL/J6 mice (n= 40) were assigned to treatment groups: control, ischemia PBS, ischemia PVAX, ischemia NPY3-36, and Ischemia PVAX-NPY3-36Ischemia was induced by ligation of the femoral artery in all groups except control and given relevant treatments (PBS, PVAX, NPY3-36, and PVAX-NPY3-36). Blood flow was quantified using laser Doppler imaging. Ondays 3and14posttreatment, mice were euthanized to harvest gastrocnemius muscle for immunohistochemistry and immunoblotting. Blood flow was significantly improved in the PVAX-NPY3-36group after 14 days. Western blot showed an increase in angiogenic factors VEGF-R2 and PDGF-β (P= 0.0035 andP= 0.031, respectively) and antiapoptotic marker Bcl-2 in the PVAX-NPY3-36group compared with ischemia PBS group (P= 0.023). Proapoptotic marker Smad5 was significantly decreased in the PVAX-NPY3-36group as compared with the ischemia PBS group (P= 0.028). Furthermore, Y2receptors were visualized in endothelial cells of newly formed arteries in the PVAX-NPY3-36group. In conclusion, we were able to show that PVAX-NPY3-36can induce angiogenesis and arteriogenesis as well as improve functional blood flow in a murine model of hind limb ischemia.NEW & NOTEWORTHYOur research project proposes a novel method for drug delivery. Our patented PVAX nanoparticle can detect areas of ischemia and oxidative stress. Although there have been studies about delivering angiogenic molecules to areas of ischemic injury, there are drawbacks of nonspecific delivery as well as short half-lives. Our study is unique because it can specifically deliver NPY3-36to ischemic tissue and appears to extend the amount of time therapy is available, despite NPY3-36's short half-life.
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Derek
authors.initials: D
authors.lastname: Eshun
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Rabya
authors.initials: R
authors.lastname: Saraf
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Soochan
authors.initials: S
authors.lastname: Bae
authors.affiliation: Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and.
authors.forename: Jelliffe
authors.initials: J
authors.lastname: Jeganathan
authors.affiliation: Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and.
authors.forename: Feroze
authors.initials: F
authors.lastname: Mahmood
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Serkan
authors.initials: S
authors.lastname: Dilmen
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Qingen
authors.initials: Q
authors.lastname: Ke
authors.affiliation: Department of Polymer⋅Nano Science and Technology, Chonbuk National University, Jeonju, South Korea.
authors.forename: Dongwon
authors.initials: D
authors.lastname: Lee
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kang
authors.affiliation: Department of Anesthesia, Critical Care & Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and rmatyal1@bidmc.harvard.edu.
authors.forename: Robina
authors.initials: R
authors.lastname: Matyal
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism; D006614:Hindlimb / Q000187:drug effects* / Q000378:metabolism; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009479:Neuropeptides / Q000008:administration & dosage*; D012039:Regional Blood Flow / Q000187:drug effects*
chemical_list: D043925:Angiogenesis Inducing Agents; D015415:Biomarkers; D009479:Neuropeptides
keywords: NPY3–36; PVAX; angiogenesis; functional blood flow; hind limb ischemia