Inhibition of VEGF mediated corneal neovascularization by anti-angiogenic peptide nanofibers

Abstract

Atypical angiogenesis is one of the major symptoms of severe eye diseases, including corneal neovascularization, and the complex nature of abnormal vascularization requires targeted methods with high biocompatibility. The targeting of VEGF is the most common approach for preventing angiogenesis, and the LPPR peptide sequence is known to strongly inhibit VEGF activity by binding to the VEGF receptor neuropilin-1. Here, the LPPR epitope is presented on a peptide amphiphile nanofiber system to benefit from multivalency and increase the anti-angiogenic function of the epitope. Peptide amphiphile nanofibers are especially useful for ocular delivery applications due to their ability to remain on the site of interest for extended periods of time, facilitating the long-term presentation of bioactive sequences. Consequently, the LPPR sequence was integrated into a self-assembled peptide amphiphile network to increase its efficiency in the prevention of neovascularization. Anti-angiogenic effects of the peptide nanofibers were investigated by using both in vitro and in vivo models. LPPR-PA nanofibers inhibited endothelial cell proliferation, tube formation, and migration to a greater extent than the soluble LPPR peptide in vitro. In addition, the LPPR-PA nanofiber system led to the prevention of vascular maturation and the regression of angiogenesis in a suture-induced corneal angiogenesis model. These results show that the anti-angiogenic activity exhibited by LPPR peptide nanofibers may be utilized as a promising approach for the treatment of corneal angiogenesis.

Ocular delivery of proteins and peptides: Challenges and novel formulation approaches

“…Recently, a group of researchers have demonstrated significant inhibition of endothelial cell proliferation and migration and aberrant capillary formation by delivering LPPR peptide that binds specifically to the VEGF receptor, NRP-1 as nanofibers. Furthermore, subconjunctival injection of LPPR-PA nanofiber expressively inhibited corneal neovascularization in rat model (81.3%) compared to bevacizumab (51.2%) on day 14 indicating its effectiveness in treating angiogenesis-related disorders [159]. …”

Heparin mimetic peptide nanofiber gel promotes regeneration of full thickness burn injury

“…HM-PA peptide nanofibers mimic the activity heparin and form a biocompatible gel at neutral pH. The HM-PA peptide nanofibers were previously shown to bind growth factors, enhance osteochondrogenic differentiation, improve the success of pancreatic islet transplantation and stimulate the repair of normal and diabetic wound injuries [1,13,28,36], and our present observations suggest that the growth factor-binding, water-retaining and glycosaminoglycan-mimicking features of HM-PA peptide nanofibers are also effective for stimulating the repair of full-thickness burn injuries. In particular, HM-PA peptide nanofiber-treated wounds had higher skin appendage formation, wound closure and re-epithelialization rates, as well as lower granulation tissue areas and thinner crust formation, at days 7 and 14 of the recovery Fig.…”

Therapeutic approaches for corneal neovascularization

“…Since the angiogenic activity of VEGF is mediated through its receptors, the blocking of receptor-ligand interactions is a promising approach for anti-VEGF therapies [ 95 ]. These agents impede the activity of VEGF by inhibiting tyrosine kinase in the intracellular part of the VEGF receptor [ 96 ].…”