Glypican-1 nanoliposomes for potentiating growth factor activity in therapeutic angiogenesis

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 enhancing 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.

Biomaterials and Nanotherapeutics for Enhancing Skin Wound Healing

“…One method to overcome this resistance is to deliver co-receptors in a proteoliposome along with the growth factors. This was tested in a diabetic mouse model and showed improved diabetic wound healing (Das et al, 2016a,c) and enhanced ischemic revascularization (Jang et al, 2012; Das et al, 2014, 2016b; Monteforte et al, 2016)(Figure 5). There are various other lipid NPs, which have shown promise for treating peripheral vascular disease and critical limb ischemia, reviewed elsewhere (Tu et al, 2015).…”

Extracellular Matrix, a Hard Player in Angiogenesis

“…Glypican acts as a co-receptor or promoter of many angiogenic growth factors, including VEGF, FGFs, PDGF, heparin-binding EGF (HB-EGF), HGF, and IGF-1 [191]. A recent study indicates that the delivery of glypican-1 by nanoliposomes to the site of ischemic injury could function as an enhancer for growth factor activity, thus improving the response to local angiogenic therapies for the treatment of ischemia [192]. This represents another important example of the potential employment of ECM molecules/fragments for therapy purposes.…”

Transmembrane Stem Cell Factor Protein Therapeutics Enhance Revascularization in Ischemia without Mast Cell Activation

“…Our studies suggest that endothelial cells use a combination of clathrin and caveolin-mediated pathways to internalize tmSCFPLs and tmSCFNDs while EPCs use only a clathrin-mediated pathway to internalize these treatments. Notably, the size of proteoliposomes used here was chosen as it was the optimal size for delivering other therapeutic membrane proteins to induce angiogenesis and endothelial cell activation in our previous studies 36,40,41,44 . One potential explanation for the differences in uptake mechanism between the treatments may be that the size of the therapeutic compounds.…”

“…have identified mechanisms of therapeutic resistance to growth factors 36,[40][41][42][43][44] , including the loss of cell surface proteoglycans 36,[40][41][42][43][44] and expression of angiogenesis inhibiting growth factors 45 .…”