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Published on: September 27, 2013
Glypican-1 nanoliposomes for potentiating growth factor activity in therapeutic angiogenesis
Anthony J Monteforte1, Brian Lam1, Subhamoy Das1
1Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA.
Abstract:
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.
Insights
Glypisomes, a novel nanoliposomal carrier for glypican-1, enhance growth factor therapy for ischemic diseases. This therapeutic approach improves blood flow recovery and vessel formation, even in diabetic patients.
Area of Science:
- Vascular biology and regenerative medicine
- Biotechnology and drug delivery systems
- Diabetic complications and therapeutic strategies
Background:
- Therapeutic angiogenesis faces challenges in patients with comorbidities like diabetes, who exhibit reduced glypican-1 levels, hindering treatment efficacy.
- Glypican-1 acts as a crucial co-receptor for angiogenic growth factors, and its deficiency impairs vascular repair mechanisms.
- Existing angiogenic therapies are often ineffective in patients with long-term disease states and co-morbidities.
Purpose of the Study:
- To develop and evaluate a novel therapeutic enhancer, glypisomes, for improving angiogenic growth factor activity.
- To investigate the mechanism by which glypisomes enhance fibroblast growth factor 2 (FGF-2) mediated cellular processes.
- To assess the efficacy of glypisome-enhanced FGF-2 delivery in a preclinical model of hind limb ischemia, including in diabetic subjects.
Main Methods:
- Human skin biopsies were analyzed to determine glypican-1 levels in patients with type 2 diabetes.
- Glypican-1 was encapsulated in nanoliposomes to create glypisomes, and their effect on FGF-2 mediated endothelial cell functions (proliferation, migration, tube formation) was assessed in vitro.
- Glypican-1's role in FGF-2 uptake and endosomal processing was investigated.
- Alginate beads were used to co-deliver FGF-2 and glypisomes in a murine hind limb ischemia model, with outcomes measured by perfusion recovery and neovascularization.
Main Results:
- Human patients with type 2 diabetes showed reduced vascular glypican-1 levels.
- Glypisomes significantly enhanced FGF-2-induced endothelial cell proliferation, migration, and tube formation in vitro.
- Glypisomes improved FGF-2 trafficking, increasing cellular uptake and endosomal processing.
- Co-delivery of glypisomes with FGF-2 markedly improved hind limb perfusion recovery and vessel formation in both wild-type and diabetic mice compared to FGF-2 alone.
Conclusions:
- Glypisomes effectively enhance the activity of angiogenic growth factors like FGF-2.
- This novel nanoliposomal delivery system can overcome resistance to angiogenic stimuli in disease states such as diabetes.
- Glypisomes represent a promising strategy to improve the efficacy of localized angiogenic therapies for ischemic conditions.
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