VCAM-1 directed immunoliposomes selectively target tumor vasculature in vivo

Abstract

Targeting the tumor vasculature and selectively modifying endothelial functions is an attractive anti-tumor strategy. We prepared polyethyleneglycol modified immunoliposomes (IL) directed against vascular cell adhesion molecule 1 (VCAM-1), a surface receptor over-expressed on tumor vessels, and investigated the liposomal targetability in vitro and in vivo. In vitro, anti-VCAM-1 liposomes displayed specific binding to activated endothelial cells under static conditions, as well as under simulated blood flow conditions. The in vivo targeting of IL was analysed in mice bearing human Colo 677 tumor xenografts 30 min and 24 h post i.v. injection. Whereas biodistribution studies using [3H]-labelled liposomes displayed only marginal higher tumor accumulation of VCAM-1 targeted versus unspecific ILs, fluorescence microscopy evaluation revealed that their localisations within tumors differed strongly. VCAM-1 targeted ILs accumulated in tumor vessels with increasing intensities from 30 min to 24 h, while control ILs accumulated in the tumor tissue by passive diffusion. ILs that accumulated in non-affected organs, mainly liver and spleen, primarily co-localised with macrophages. This is the first morphological evidence for selective in vivo targeting of tumor vessels using ILs. VCAM-directed ILs are candidate drug delivery systems for therapeutic anti-cancer approaches designed to alter endothelial function.

Targeted Liposomal Delivery of TLR9 Ligands Activates Spontaneous Antitumor Immunity in an Autochthonous Cancer Model

“…Targeting of angiogenic vessels is an attractive approach to specifically deliver reagents into tumors, especially if tumor-specific targeting molecules have not been identified. Several investigators have described in vivo tumor-homing capacities of liposomes tagged with tumor endothelium-specific peptides or Abs such as RGD and NGR peptides and VCAM-1-specific Abs (31)(32)(33). Similar to these studies, we also observed that vascular-directed lipid vesicles localize to different intratumoral compartments compared with nonspecific control liposomes (31,33).…”

“…Several investigators have described in vivo tumor-homing capacities of liposomes tagged with tumor endothelium-specific peptides or Abs such as RGD and NGR peptides and VCAM-1-specific Abs (31)(32)(33). Similar to these studies, we also observed that vascular-directed lipid vesicles localize to different intratumoral compartments compared with nonspecific control liposomes (31,33). Lipid particles coated with cyclic RGD as targeting ligand for ␣ v ␤ 3 integrin, for instance, specifically bind to the tumor vessel wall, whereas control liposomes extravasate into tumor parenchyma (31).…”

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

“…The binding affinity of the ligands influences the tumor penetration owing to the "binding-site barrier." For targets in which cells are readily reachable, usually the tumor vasculature, because of the dynamic flow environment of the bloodstream, high affinity binding appears to be preferable (Adams et al, 2001;Gosk et al, 2008;Danhier et al, 2010). Various anti-cancer therapeutics, grouped under the name "ligand targeted therapeutics," are classified into different classes based on the approach of drug delivery (Allen, 2002;Danhier et al, 2010).…”

“…Consequently, in this strategy, ligand-targeted nanocarriers bind to and kill angiogenic blood vessels and indirectly, the tumor cells that these vessels support, mostly in the tumor core. The advantages of the tumoral endothelium targeting are; i) there is no need of extravasation of nanocarriers to achieve to their targeted site, ii) the binding to their receptors is directly possible after intravenous injection, iii) the possible risk of emerging resistance is reduced due to the genetically stability of endothelial cells as compared to tumor cells, and iv) the majority of endothelial cells markers are expressed whatever the tumor type, involving an ubiquitous approach and an ultimate broad application spectrum (Gosk et al, 2008;Danhier et al, 2010). The major targets of the tumoral endothelium include:…”

Liposomes and Nanotechnology in Drug Development: Focus On Pancreatic Cancer

“…A variety of ligands has been used such as antibody fragments and mononuclear antibody and used for macromolecules which are peptides and proteins small molecules that include carbohydrates and folic acid. The binding similarity of ligands effects the cancer penetration due to its binding location barrier and dynamic blood flow [30,31]. The active target treatment of nano-liposomes not only could improve the targeting effect in pancreatic cancer, but also could decrease the toxic and side-effect.…”