Developing Wound Dressings Using 2-deoxy-D-Ribose to Induce Angiogenesis as a Backdoor Route for Stimulating the Production of Vascular Endothelial Growth Factor.

Serkan Dikici,Muhammad Yar,Anthony J Bullock,Joanna Shepherd,Sabiniano Roman,Sheila Macneil

doi:10.3390/ijms222111437

Abstract

2-deoxy-D-Ribose (2dDR) was first identified in 1930 in the structure of DNA and discovered as a degradation product of it later when the enzyme thymidine phosphorylase breaks down thymidine into thymine. In 2017, our research group explored the development of wound dressings based on the delivery of this sugar to induce angiogenesis in chronic wounds. In this review, we will survey the small volume of conflicting literature on this and related sugars, some of which are reported to be anti-angiogenic. We review the evidence of 2dDR having the ability to stimulate a range of pro-angiogenic activities in vitro and in a chick pro-angiogenic bioassay and to stimulate new blood vessel formation and wound healing in normal and diabetic rat models. The biological actions of 2dDR were found to be 80 to 100% as effective as VEGF in addition to upregulating the production of VEGF. We then demonstrated the uptake and delivery of the sugar from a range of experimental and commercial dressings. In conclusion, its pro-angiogenic properties combined with its improved stability on storage compared to VEGF, its low cost, and ease of incorporation into a range of established wound dressings make 2dDR an attractive alternative to VEGF for wound dressing development.

Highlights

Background toIdentifying 2dDR as a Pro-Angiogenic Sugar2-deoxy-D-Ribose (2dDR) is a D-isomer of a deoxy pentose monosaccharide in which the hydroxyl group at the C-2 position is replaced by a hydrogen atom. 2dDR was discovered in 1930 by Phoebus Levene during his studies revealing DNA structure [1,2]
thymidine phosphorylase (TP) has an amino acid sequence identical to platelet-derived endothelial cell growth factor (PD-ECGF) [6,7] and, as previously stated, catalyses the phosphorylation of thymidine to thymine [8,9] and 2-deoxyribose-1-phosphate (2dDR1P). 2dDR1P will be dephosphorylated within the cytoplasm to 2dDR, which is the form that can pass through the cell membrane
In addition to the studies to demonstrate the pro-angiogenic properties of 2dDR, in recent years, a considerable progress has been made in developing dressings to stimulate angiogenesis by loading 2dDR into a range of carriers

Summary

Background to Identifying 2dDR as a Pro-Angiogenic Sugar

2-deoxy-D-Ribose (2dDR) is a D-isomer of a deoxy pentose monosaccharide in which the hydroxyl group at the C-2 position is replaced by a hydrogen atom. 2dDR was discovered in 1930 by Phoebus Levene during his studies revealing DNA structure [1,2]. 2dDR was shown to induce tubulogenesis [18,19], inhibit hypoxiainduced apoptosis [20], and increase VEGF and IL-8 production [21] of ECs in vitro supporting the early reports of 2dDR’s positive impact on proliferation and cell migration All of these studies contributed significantly to describe the potential of 2dDR to be used in the world of pro-angiogenic drugs. Nakajima et al reported that 10–100 μM of 2dLR inhibits both mRNA levels and secretion of IL-8 and VEGF by KB cells [21] and 100 μM 2dLR inhibits Matrigel invasion of tumours by suppressing MMP-9 in nude mice [37] All these studies are consistent on the anti-angiogenic activity of 2dLR, in 2003, Sengupta et al suggested that 2 nmol of 2dLR promotes an angiogenic response in a sponge granuloma model of angiogenesis [17]. As 2dDR is predominantly pro-angiogenic, we suggest that it is challenging to draw any simple relationship between sugar structure and angiogenic activity

Developing Dressings Containing 2dDR to Stimulate Angiogenesis

Understanding the Mechanism of Action of 2dDR

The Stability of 2dDR

The Pro-Angiogenic Potential of 2dDR Compared to VEGF

Findings

10. Conclusions