An evaluation of carrier agents for desferoxamine, an up-regulator of vascular endothelial growth factor

Abstract

Avascularity and hypoxia result in avascular necrosis and play a negative role in fracture healing. The FDA-approved iron chelating agent, desferoxamine (DFO) in a liquid form, has been shown to induce angiogenesis and improve fracture healing through upregulation of the vascular endothelial growth factor. We were concerned that local injection of DFO would either fail to adequately deliver sufficient drug to the desired site or lead to undesired delivery to adjacent sites. Therefore, a sustained release delivery system was desirable to direct DFO to the intended site. Calcium sulfate pellets, collagen sponges, and demineralized cortical bone matrix were all evaluated as potentially controlled release systems for DFO using a fetal mouse metatarsal angiogenesis assay. Angiogenesis was analyzed using a vascularity grading scale, by measuring the mean vessel length of the 5 longest vessels, and by counting the mean number of vessels per metatarsal. Although there was some evidence of angiogenesis with all three carriers, DFO loaded CaSO4 pellets increased vascularity grading, the mean length of the five longest vessels, and the mean number of vessels, all by statistically significant margins versus the control. These results suggest that CaSO4 pellets could be used as a viable, nontoxic, controlled release system for DFO in clinical situations where increased angiogenesis and bone growth are desirable.

Evaluating effects of deferoxamine in a rat tibia critical bone defect model

“…7 As repeated injection of DFO may not be practical or effective clinically, recent in vitro work was undertaken and it was found that DFO can be incorporated into a calcium sulfate (CS) carrier and still maintain its angiogenic potential. 5 In tissue culture, DFO induces marked increases in vascularity of fetal mouse metatarsals and, in studies performed in our laboratory (Hertzberg et al), it is readily incorporated in calcium sulfate pellets and easily released from them. 6 So far, there have been no in vivo studies using DFO in a carrier in an impaired fracture healing model.…”

“…4,5 DFO is currently an FDA approved medication for the chelation of iron in the treatment of iron toxicity and has been used for many decades for this indication. It has been observed to induce upregulation of HIF (Hypoxia Inducible Factor) which in its turn upregulates VEGF (vascular endothelial growth factor).…”

Release kinetics of prolyl hydroxylase inhibitors from collagen barrier membranes

“…[9][10][11][12][13] In periodontal surgery regeneration a one-step strategy where prolyl hydroxylase inhibitors are released from a carrier into the defect to stimulate tissue regeneration would be desirable. 14 Here we propose a concept where collagen barrier membranes are loaded with prolyl hydroxylase inhibitors to induce a pro-angiogenic response in the tissue, thereby utilizing a biomaterial as carrier for prolyl hydroxylase inhibitors that is already clinically applied. However, so far it is unclear if collagen barrier membranes can serve as carriers for these prolyl hydroxylase inhibitors and whether the molecules maintain their pro-angiogenic capacity when released.…”

Bone substitute materials supplemented with prolyl hydroxylase inhibitors decrease osteoclastogenesis in vitro

“…[5][6][7][8] Strategies have therefore been developed where bone substitute materials release prolyl hydroxylase inhibitors to enhance angiogenesis and bone regeneration. [9][10][11][12] These "hypoxia mimetic agents" either inhibit the oxygenases directly or complex Fe 21 , thereby preventing hypoxia-inducible factor (HIF)21alpha degradation. The most commonly applied prolyl hydroxylase inhibitors are dimethyloxalylglycine (DMOG), desferrioxamine (DFO), and L-mimosine (L-MIM).…”

“…10 The current data from bone substitute materials loaded with prolyl hydroxylase inhibitors focuses on the pro-angiogenic and therefore anabolic effects of the biomaterial. 9,10 However, the impact of bone substitute materials loaded with prolyl hydroxylase inhibitors on bone resorption is unknown. It is therefore of clinical relevance to reveal the impact of the release kinetics of prolyl hydroxylase inhibitors from bone substitute materials on osteoclastogenesis.…”