Rescue of SCID murine ischemic hindlimbs with pH-modified rhbFGF/poly(DL-lactic-co-glycolic acid) implants.
Site-specific controlled release of biologically active angiogenic growth factors such as recombinant human basic fibroblast growth factor (rhbFGF) is a promising approach to improve collateral circulation in patients suffering from ischemic heart disease or peripheral vascular disease. Previously, we demonstrated stabilization of rhbFGF encapsulated in injectable poly(DL-lactic-co-glycolic acid) (PLGA) millicylindrical implants upon co-incorporation of Mg(OH)2 to raise the microclimate pH in the polymer. The purpose of this study was to compare stabilized (S; +Mg(OH)2+other stabilizers), partially stabilized (PS; -Mg(OH)2+other stabilizers), unstabilized (US; no stabilizers), and blank (B) PLGA-encapsulated rhFGF formulations to promote angiogenesis in SCID mice. Following 4 weeks subcutaneous implantation at a 0.1 microg dose in healthy animals, the S group exhibited significantly higher blood vessel density (62+/-17 vessels/mm2) compared with PS, US, and B groups (11+/-2*, 17+/-7*, and 3+/-1** respectively) (* p<0.05; ** p<0.01). Furthermore, the S group developed a thicker granulation layer at the tissue/implant interface relative to the other groups (39+/-7 vs 25+/-2**, 21+/-1***, and 12+/-1 microm*** respectively) (*** p<0.001). After 6 weeks implantation in mice with ischemic hindlimbs, the S group implants also markedly augmented both limb reperfusion (87+/-14%) and limb survival (5/5), whereas ischemic limbs did not recover in PS, US and B groups. Stabilized rhbFGF incorporated in pH modified PLGA millicylinders effectively promotes site-directed in vivo angiogenesis and also enables preservation of ischemic hindlimb function.
Zhong
Yanqiang
Y
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA.
Zhang
Li
L
Ding
Amy G
AG
Shenderova
Anna
A
Zhu
Gaozhong
G
Pei
Ping
P
Chen
Ruth R
RR
Mallery
Susan R
SR
Mooney
David J
DJ
Schwendeman
Steven P
SP
D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry*; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006614:Hindlimb / Q000098:blood supply* / Q000473:pathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009336:Necrosis; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D012039:Regional Blood Flow / Q000187:drug effects
D043925:Angiogenesis Inducing Agents; D004337:Drug Carriers; D011108:Polymers; D011994:Recombinant Proteins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D005346:Fibroblast Growth Factors