Therapeutic Angiogenesis: Controlled Delivery of Angiogenic Factors

Abstract

Therapeutic angiogenesis aims at treating ischemic diseases by generating new blood vessels from existing vasculature. It relies on delivery of exogenous factors to stimulate neovasculature formation. Current strategies using genes, proteins and cells have demonstrated efficacy in animal models. However, clinical translation of any of the three approaches has proved to be challenging for various reasons. Administration of angiogenic factors is generally considered safe, according to accumulated trials, and offers off-the-shelf availability. However, many hurdles must be overcome before therapeutic angiogenesis can become a true human therapy. This article will highlight protein-based therapeutic angiogenesis, concisely review recent progress and examine critical challenges. We will discuss growth factors that have been widely utilized in promoting angiogenesis and compare their targets and functions. Lastly, since bolus injection of free proteins usually result in poor outcomes, we will focus on controlled release of proteins.Blood vessels that carry oxygen, nutrients, cells and signals are critical in both developmental and adult physiology. Without sufficient blood supply, tissues and organs cannot maintain regular activities. On the other hand, induction of neovasculature provides a potential strategy to treat many ischemic illnesses, especially cardiovascular diseases (CVDs) including coronary and peripheral arterial diseases. The morbidity, mortality and cost of CVDs are highlighted by the latest statistics from the American Heart Association [1]: an estimated 82,600,000 American adults (≥20 years old) have one or more types of CVDs; CVDs caused 813,804 of all 2,243,712 deaths (33.6%) or one of every 2.9 deaths in 2007, and coronary heart disease caused approximately one of every six deaths. The direct and indirect cost of CVD was estimated to be US$286 billion in 2007. The amount is higher than the $228 billion spent on cancer and benign neoplasms. As a potential therapy to revascularize ischemic tissues, including ischemic heart, therapeutic angiogenesis has drawn much attention in the last 20 years.Neovasculature can be obtained by three approaches based on different mechanisms: promoting expression of angiogenic genes, supplying potent angiogenic factors and delivering progenitor or stem cells. No matter which approach is used, angiogenic activity has to be precisely controlled in order to achieve stable vascularization. For cell delivery, the

Generation and characterization of ABBV642, a dual variable domain immunoglobulin molecule (DVD-Ig) that potently neutralizes VEGF and PDGF-BB and is designed for the treatment of exudative age-related macular degeneration

“…The recognition of the proximally retained PDGF-BB by the pericyte-bound PDGFR-b initiates the proliferation and migration of the pericytes along the growing neovascularization. 27 The critical role of PDGF-BB/PDGFR-b interaction for pericyte recruitment and capillary maturation has been demonstrated through gene knockout, 34 ectopic delivery of competing PDGF-BB, 35 blocking the PDGF-BB/PDGFRb interaction by external agents, 18 or deletion of the PDGF-BB heparin sulfate proteoglycans binding motif. 36 Established subretinal vessels may have sufficient pericyte coverage to be resistant to anti-VEGF monotherapy.…”

Supramolecular hydrogels encapsulating bioengineered mesenchymal stem cells for ischemic therapy

“…Despite the great effort to introduce functional moieties on CB [6], 21 mono-amination of CB [6] is still difficult and complicated. 22,23 We previously reported the method to synthesize CB [6]-HA derivative via Michael addition between thiol (SH) modied HA and mono-allyloxy CB [6]. However, there were unreacted thiol groups on HA backbone, resulting in selfcrosslinking by disulde bonding.…”

“…18 In addition, supramolecular hydrogels can be injected without toxic chemical reaction due to the fast crosslinking by the strong host-guest interaction between cucurbit [6]uril (CB [6]) and diaminohexane (DAH) attached to the HA backbone.…”

“…However, there have been few clinical trials for the direct protein delivery, since their activities cannot be maintained for a sufficient time to regenerate blood vessels. 6 Second, gene therapy has been investigated for the manipulation of host chromosomes by gene delivery with viral or non-viral vectors including adeno-associated virus, lenti-virus and synthetic polymer vesicles.…”

“…To achieve the high crosslinking density and facile synthesis, we carried out mono-functionalization of CB [6], which is a big challenge for various biomedical applications 19,20 ( Fig. 1A).…”