Liposome-Anchored Vascular Endothelial Growth Factor Aptamers

Abstract

Nuclease-resistant aptamers identified from randomized nucleic acid libraries represent a novel class of drug candidates. Aptamers are synthesized chemically and therefore can be readily modified with functional groups that modulate their properties. We report here on the preparation, initial characterization, and functional properties of a nuclease-resistant vascular endothelial growth factor (VEGF) aptamer anchored in liposome bilayers through a lipid group on the aptamer. While the high-affinity binding to VEGF is maintained, the plasma residence time of the liposome-anchored aptamer is considerably improved compared with that of the free aptamer. The lipid group attachment and/or liposome anchoring leads to a dramatic improvement in inhibitory activity of the aptamer toward VEGF-induced endothelial cell proliferation in vitro and vascular permeability increase and angiogenesis in vivo.

Inhibition of rat corneal angiogenesis by a nuclease-resistant RNA aptamer specific for angiopoietin-2

“…This effect should only be enhanced by the optimization of this aptamer for in vivo applications. For instance, modification of 11-1.41 with 2Ј-fluoro-pyrimidines and addition of the 3Ј inverted nucleotide cap improve resistance to degradation by plasma nucleases (38,39), but the truncated aptamer's small size (Ϸ13 kDa) allows rapid tissue diffusion and renal clearance (40,41). Therefore, modifications such as attachment of polyethylene glycol or liposomes, which enhance aptamer bioavailability, will likely enhance the aptamer's efficacy for both local and systemic applications in relevant disease models.…”

In Vitro Selection of RNA Aptamers That Bind to Cell Adhesion Receptors of Trypanosoma cruzi and Inhibit Cell Invasion

“…Keeping intact aptamers in the blood from hours to days has been accomplished by conjugation with high molecular weight carriers, such as polyethyleneglycol, or by embedding into liposomes (42). As an example, one aptamer to vascular endothelial growth factor (VEGF), patented as NX 1838 is currently been used in clinical trials as a potential therapeutic agent for agerelated macular degeneration (27).…”

Molecular recognition elements - DNA/RNA-aptamers to proteins

“…Этот маленький размер способствует быстрому выведению через почки за несколько минут. Чтобы пролонгировать время действия аптамеров, их модифицируют полиэтиленгликолем или другими агентами, или прикрепляют к поверхности липосом [21,25].…”

“…Для того чтобы защитить молекулы от действия неспецифических нуклеаз, при селекции используют пиримидиновые нуклеотиды, модифицированные по 2`-позициям рибозы (аминопроизводные и фторпроизводные) [18][19][20], используют липосомы в качестве носителя [21], проводят постселекционную модификацию гидроксильного радикала по 2`-положению введением метильных, аллильных, аминогрупп и т.д. [22][23][24].…”