Depot-Based Delivery Systems for Pro-Angiogenic Peptides: A Review

Abstract

Insufficient vascularization currently limits the size and complexity for all tissue engineering approaches. Additionally, increasing or re-initiating blood flow is the first step toward restoration of ischemic tissue homeostasis. However, no FDA-approved pro-angiogenic treatments exist, despite the many pre-clinical approaches that have been developed. The relatively small size of peptides gives advantages over protein-based treatments, specifically with respect to synthesis and stability. While many pro-angiogenic peptides have been identified and shown promising results in vitro and in vivo, the majority of biomaterials developed for pro-angiogenic drug delivery focus on protein delivery. This narrow focus limits pro-angiogenic therapeutics as peptides, similar to proteins, suffer from poor pharmacokinetics in vivo, necessitating the development of controlled release systems. This review discusses pro-angiogenic peptides and the biomaterials delivery systems that have been developed, or that could easily be adapted for peptide delivery, with a particular focus on depot-based delivery systems.

Keywords: angiogenesis; biomaterials; controlled release; depot-based; drug delivery; hydrogels; review.

Figure 1

A schematic of the process of angiogenesis. Angiogenesis is a process tightly controlled by a number of factors. (A) Ischemic tissue release pro-angiogenic signals, which diffuse into nearby tissue. (B) Pericytes detach from nearby vessels, and ECs form sprouts. (C) ECs proliferate and migrate towards the signal gradient. (D) ECs align into immature vessels. (E) Pericytes are recruited to the new vessels. (F) Vasculature is remodeled and stabilized. Many of the factors involved in this process have been exploited for pharmacological intervention, either supplementing them for pro-angiogenic applications, or inhibiting them for anti-angiogenic applications. EC, endothelial cell; HIF-1α, hypoxia-inducible factor-1α; VEGF, vascular endothelial growth factor; Ang2, angiopoietin 2; PDGF, platelet-derived growth factor; MMPs, matrix metalloproteinases; PLGF, placenta growth factor; SDF-1, stromal cell-derived factor-1; FGF, fibroblast growth factor; Ang1, angiopoietin 1 (Ziche et al., ; Hirota and Semenza, ; Adams and Alitalo, ; Lieu et al., ; Chu and Wang, ; Brudno et al., 2013).

Figure 2

Schematic of drug release from biomaterial depots. Release of drugs from depot-based biomaterials can be controlled by a number of mechanisms. (A) Drug is encapsulated within a biomaterial with large enough mesh/pore size to allow for diffusive release of the encapsulated drug. (B) Drug is tethered to a biomaterial that degrades in response to enzyme expression and releases the drug upon degradation of the biomaterial. (C) Drug is tethered to the biomaterial by the enzymatically cleavable tether, and released upon linker cleavage. (D) Diffusive release of encapsulated drug is prolonged by affinity interactions between the material and the drug. (E) Diffusive release of encapsulated drug is prolonged by delayed dissolution of the drug. (F) Drug is encapsulated within a degradable biomaterial and released as the material degrades. Not to scale.