Sustained release of multiple growth factors from injectable polymeric system as a novel therapeutic approach towards angiogenesis.
OBJECTIVE
The aim was to investigate that a bio-degradable alginate and poly lactide-co-glycolide (PLG) system capable of delivering growth factors sequentially would be superior to single growth factor delivery in promoting neovascularization and improving perfusion.


METHODS
Three groups of apoE null mice underwent unilateral hindlimb ischemia surgery and received ischemic limb intramuscular injections of alginate (Blank), alginate containing VEGF(165) (VEGF), or alginate containing VEGF(165) combined with PLG microspheres containing PDGF-BB (VEGF/PDGF). Vascularity in the ischemic hindlimb was assessed by morphologic and immunohistochemical end-points, while changes in blood flow were assessed by Laser Doppler Perfusion Index. Muscle VEGF and PDGF content was assessed at multiple time points.


RESULTS
In the VEGF/PDGF group, local tissue VEGF and PDGF levels peaked at week 2 and 4, respectively, with detectable PDGF levels at week 6. At week 6, mean vessel mean diameter was significantly greater in the VEGF/PDGF group compared to the VEGF or Blank groups with evidence of well-formed smooth muscle-lined arterioles.


CONCLUSIONS
Sequential delivery of VEGF and PDGF using an injectable, biodegradable platform resulted in stable and sustained improvements in perfusion. This sustained, control-released, injectable alginate polymer system is a promising approach for multiple growth factor delivery in clinical application.
Sun
Qinghua
Q
Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio 43210-1252, USA. sun.224@osu.edu
Silva
Eduardo A
EA
Wang
Aixia
A
Fritton
James C
JC
Mooney
David J
DJ
Schaffler
Mitchell B
MB
Grossman
Paul M
PM
Rajagopalan
Sanjay
S
D000464:Alginates / Q000008:administration & dosage / Q000493:pharmacokinetics; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D020723:Glucuronic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics; D006603:Hexuronic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007511:Ischemia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D011091:Polyesters / Q000008:administration & dosage / Q000493:pharmacokinetics; D011108:Polymers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011897:Random Allocation
D000464:Alginates; D020533:Angiogenesis Inhibitors; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006603:Hexuronic Acids; D036341:Intercellular Signaling Peptides and Proteins; D011091:Polyesters; D011108:Polymers; C033616:poly(lactide); D020723:Glucuronic Acid