title: Peptide-loaded nanoparticles and radionuclide imaging for individualized treatment of myocardial ischemia.
abstract: OBJECTIVE
  To determine whether chitosan hydrogel nanoparticles loaded with vascular endothelial growth factor (VEGF) peptides (81-91 fragments) capable of targeting the ischemic myocardium enhance angiogenesis and promote therapeutic effects and whether radionuclide image-guided dosage control is feasible.
  
  
  METHODS
  Experimental procedures and protocols were approved by the Institutional Animal Care and Use Committee. Rats (n = 32, eight per group) were subjected to myocardial ischemia (control group) and received chitosan hydrogel nanoparticles with VEGF165 proteins (chitosan VEGF) or VEGF81-91 peptides (chitosan peptides) via apical puncture. Ischemic hearts receiving chitosan without angiogenic factors served as the chitosan control. Myocardial perfusion was examined 7 days after surgery by using technetium 99m ((99m)Tc) tetrofosmin (37 MBq) autoradiography, and changes in vascular density with immunohistochemical staining were reviewed. Kruskal-Wallis test and Bonferroni corrected Mann-Whitney U test were used for multiple comparisons. Wilcoxon signed rank test was used to compare myocardial retention of (99m)Tc chitosan.
  
  
  RESULTS
  Thirty minutes of myocardial ischemia resulted in perfusion defects (median, 54%; interquartile range [IQR], 41%-62%). Chitosan VEGF decreased perfusion defect extent (median, 68%; IQR, 63%-73%; P = .006 vs control) and increased vascular density (median, 81 vessels per high-power field; IQR, 72-100; P = .009 vs control). Administration of chitosan peptides reduced the degree of perfusion defects (median, 66%; IQR, 62%-73%; P = .006 vs control) and increased vascular density (median, 82 vessels; IQR, 78-92; P = .006 vs control). The effects of chitosan peptides on perfusion and vascular density were comparable to those seen with chitosan VEGF proteins (P = .713 and P = .833, respectively). Chitosan radiolabeled with (99m)Tc was administered twice at reperfusion with a 1-hour interval to determine whether image-guided dosage control is feasible. The hearts initially retained 4.6% (IQR, 4.1%-5.0%) of (99m)Tc chitosan administered and 9.2% (IQR, 6.6%-12.7%; P = .068) with subsequent injection.
  
  
  CONCLUSIONS
  VEGF peptides have angiogenic potential and resulted in therapeutic effectiveness. Adjunct use of single photon emission computed tomography was also demonstrated for individualized treatment of myocardial ischemia by further tailoring the therapeutic dosing. Online supplemental material is available for this article.
authors.affiliation: From the Department of Nuclear Medicine, Molecular Imaging and Therapeutic Medicine Research Center, Cyclotron Research Center, Institute for Medical Sciences, and Biomedical Research Institute, Chonbuk National University Medical School and Hospital, 634-18 GeumAm-dong Duckjin-gu Jeonju-si, Jeollabuk-do 561-803, South Korea (H.H., J.K., P.S.O., T.K.L., K.S.N., H.S.J., S.T.L., M.H.S., H.J.J.); and Department of Biomedical Engineering, Chonnam National University, Yeosu, South Korea (C.M.L.).
authors.forename: Hyosook
authors.initials: H
authors.lastname: Hwang
authors.forename: Jeongll
authors.initials: J
authors.lastname: Kwon
authors.forename: Phil-Sun
authors.initials: PS
authors.lastname: Oh
authors.forename: Tai-Kyoung
authors.initials: TK
authors.lastname: Lee
authors.forename: Kyung-Suk
authors.initials: KS
authors.lastname: Na
authors.forename: Chang-Moon
authors.initials: CM
authors.lastname: Lee
authors.forename: Hwan-Seok
authors.initials: HS
authors.lastname: Jeong
authors.forename: Seok Tae
authors.initials: ST
authors.lastname: Lim
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Sohn
authors.forename: Hwan-Jeong
authors.initials: HJ
authors.lastname: Jeong
mesh_terms: D000818:Animals; D001345:Autoradiography; D048271:Chitosan / Q000494:pharmacology; D020100:Hydrogels / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D057054:Molecular Imaging / Q000379:methods; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D015425:Myocardial Reperfusion; D053758:Nanoparticles; D009943:Organophosphorus Compounds; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D020100:Hydrogels; D009943:Organophosphorus Compounds; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D042461:Vascular Endothelial Growth Factor A; C078700:technetium tc-99m tetrofosmin; D048271:Chitosan