Drug delivery strategies for therapeutic angiogenesis and antiangiogenesis

Abstract

Introduction: Angiogenesis is essential to human biology and of great clinical significance. Excessive or reduced angiogenesis can result in, or exacerbate, several disease states, including tumor formation, exudative age-related macular degeneration (AMD) and ischemia. Innovative drug delivery systems can increase the effectiveness of therapies used to treat angiogenesis-related diseases.

Areas covered: This paper reviews the basic biology of angiogenesis, including current knowledge about its disruption in diseases, with the focus on cancer and AMD. Anti- and proangiogenic drugs available for clinical use or in development are also discussed, as well as experimental drug delivery systems that can potentially improve these therapies to enhance or reduce angiogenesis in a more controlled manner.

Expert opinion: Laboratory and clinical results have shown pro- or antiangiogenic drug delivery strategies to be effective in drastically slowing disease progression. Further research in this area will increase the efficacy, specificity and duration of these therapies. Future directions with composite drug delivery systems may make possible targeting of multiple factors for synergistic effects.

Figure 1. This schematic diagram depicts the angiogenic and antiangiogenic responses at a capillary level

The cancer cells in tumor tissue secrete angiogenic growth factors that bind to their respective receptors on the endothelial cells lining the capillaries, leading to recruitment of disorganized blood vessels infiltrating the tumor. This leaky vasculature allows entry of the systemically injected vector (e.g., a PEGylated nanoparticle) into tumor tissue, whereas the vector cannot pass across the mature walls of normal tissue vessels. This results in passive targeting of the tumor by the enhanced permeability and retention effect. Antiangiogenic drugs, such as VEGF-TRAP and bevacizumab, block the angiogenic effect of the growth factors. Therapeutic angiogenesis for the treatment of ischemic diseases or vascularization of a tissue-engineered construct is achieved by controlled local delivery of proangiogenic factors using a synthetic delivery scaffold (e.g., fibrin hydrogel loaded with non-covalently or covalently bound growth factors).

Figure 2

A, a – c. Antibodies against PlGF and VEGFR2 inhibit tumor angiogenesis compared with nonspecific antibody IgG₁, particularly in combination (A, d). PlGF antibody also enhances the effect of gemcitabine, measured by tumor volume (B), and inhibits excessive recruitment of macrophages; the latter is not enhanced by coadministration of anti-VEGFR-2 (C). Adapted with permission from [140].

Figure 3. Tumor vasculature is highlighted by green fluorescence, overlaid with red-fluorescent liposomes

The two sections shown are 50 µm apart in the tumor tissue, with a large difference in liposome migration from one part of the tumor to the other. Scale bar: 50 µm. Adapted with permission from [151].

Figure 4

A. Transscleral drug delivery device. B. Device made with TEGDM reservoir and PEGDM/COL membrane that can be loaded with various drug solutions. C. Capsule sutured onto rabbit eye sclera 3 days after implantation. Arrowhead indicates suture site. D. Distribution of model drug FD40 (green) around implantation site at day 3. Cell nuclei dyed stained blue. FD40 reaches RPE. Adapted with permission from [166]. CO: Choroids; RE: Retina; RPE: Retinal pigment epithelium; SC: Sclera.

Figure 5

A. Images of scaffolds implanted subcutaneously in the ischemic hindlimb model of a rat taken on day 14 after implantation. The images show that the capillary number is higher in the PEtU-PDMS/Fibrin + GF scaffold implant group (lower right) than in the PEtU-PDMS/Fibrin only group (lower left) and least in the bare PEtU-PDMS scaffold group. B. In vivo images of hindlimb blood perfusion monitored by laser Doppler perfusion imaging in rats. The left limb is the nonischemic control limb and the right limb is the ischemic limb treated with the PEtU-PDMS/Fibrin + GF implant. Images in the upper row were taken immediately after ischemia induction and the lower row images were taken 14 days after scaffold implantation. In colored images, normal blood flow is represented by red and reduced blood flow by blue. Blood perfusion markedly increased 14 days after implantation, as seen in the colored images of the right hindlimb. Adapted with permission from [193].