Glypican-1 nanoliposomes for potentiating growth factor activity in therapeutic angiogenesis.
Therapeutic angiogenesis is a highly appealing concept for treating tissues that become ischemic due to vascular disease. A major barrier to the clinical translation of angiogenic therapies is that the patients that are in the greatest need of these treatments often have long term disease states and co-morbidities, such as diabetes and obesity, that make them resistant to angiogenic stimuli. In this study, we identified that human patients with type 2 diabetes have reduced levels of glypican-1 in the blood vessels of their skin. The lack of this key co-receptor in the tissue may make the application of exogenous angiogenic growth factors or cell therapies ineffective. We created a novel therapeutic enhancer for growth factor activity consisting of glypican-1 delivered in a nanoliposomal carrier (a "glypisome"). Here, we demonstrate that glypisomes enhance FGF-2 mediated endothelial cell proliferation, migration and tube formation. In addition, glypisomes enhance FGF-2 trafficking by increasing both uptake and endosomal processing. We encapsulated FGF-2 or FGF-2 with glypisomes in alginate beads and used these to deliver localized growth factor therapy in a murine hind limb ischemia model. Co-delivery of glypisomes with FGF-2 markedly increased the recovery of perfusion and vessel formation in ischemic hind limbs of wild type and diabetic mice in comparison to mice treated with FGF-2 alone. Together, our findings support that glypisomes are effective means for enhancing growth factor activity and may improve the response to local angiogenic growth factor therapies for ischemia.
Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA.
Anthony J
AJ
Monteforte
Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA.
Brian
B
Lam
Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA.
Subhamoy
S
Das
Division of Pharmacology & Toxicology, University of Texas at Austin, Austin, TX, USA; Institute for Neuroscience, University of Texas at Austin, Austin, TX, USA; Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA.
Somshuvra
S
Mukhopadhyay
Diabetes Research Group, Department of Life Sciences and Institute for Applied Health Research, Glasgow Caledonian University, Glasgow G4 0BA, UK.
Catherine S
CS
Wright
Diabetes Research Group, Department of Life Sciences and Institute for Applied Health Research, Glasgow Caledonian University, Glasgow G4 0BA, UK.
Patricia E
PE
Martin
Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA.
Andrew K
AK
Dunn
Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA; Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA; The Institute for Computational Engineering and Sciences, University of Texas at Austin, Austin, TX, USA; Institute for Biomaterials, Drug Delivery and Regenerative Medicine, University of Texas at Austin, Austin, TX, USA. Electronic address: abbaker@austin.utexas.edu.
Aaron B
AB
Baker
D000464:Alginates / Q000737:chemistry; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D016503:Drug Delivery Systems; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D020723:Glucuronic Acid / Q000737:chemistry; D053673:Glypicans / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006603:Hexuronic Acids / Q000737:chemistry; D006614:Hindlimb / Q000098:blood supply; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000473:pathology / Q000628:therapy; D007700:Kinetics; D008081:Liposomes; D008820:Mice, Obese; D053758:Nanoparticles / Q000737:chemistry*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000098:blood supply; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D000464:Alginates; D053673:Glypicans; D006603:Hexuronic Acids; D008081:Liposomes; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D020723:Glucuronic Acid; D051057:Proto-Oncogene Proteins c-akt
Angiogenesis; Fibroblast growth factor-2 (FGF-2); Glypican-1; Ischemia; Neovascularization; Peripheral arterial disease; Proteoliposomes; Vascular endothelial growth factor (VEGF)