Development and evaluation of a tumor vasculature targeted liposome delivery system for a novel anti-vascular agent, combretastatin A4

Tumor vasculature targeting avoids problems with existing cancer chemotherapy such as limited accessibility of target cells in solid tumors, poor penetration of drugs and drug delivery systems into solid tumor tissue. Vascular endothelial cells in and around solid tumors over-express certain cell adhesion molecules upon irradiation of these tumors for therapeutic purposes. To explore the potential of this radiation induced expression of cell adhesion molecules for targeting drug carriers, in this study I have developed and characterized liposome carriers containing anti-vascular drug, combretastatin A4 (CA4), for targeted delivery to the radiation altered tumor vasculature.; Liposomes composed of hydrogenated soybean phosphatidylcholine, cholesterol, distearoyl phosphoethanolamine-PEG-2000 conjugate (DSPE-PEG) and DSPE-PEG-maleimide were prepared by the lipid film hydration and extrusion process. Cyclic arginine-glycine-aspartic acid (RGD) peptides with affinity for alphavbeta3-integrins over-expressed on radiation activated tumor vascular endothelial cells were coupled to the distal end of poly(ethylene glycol)-coated long circulating liposomes. The formulation was optimized and evaluated in vitro and in vivo. In order to improve physical and chemical stability of the delivery system and hence enhance its shelf life, a lyophilized formulation and process were developed.; Formulations contained small unilamellar liposomes of about 120 nm in diameter. Targeted liposomes showed significantly higher binding to the cultured human umbilical vein endothelial cells in vitro compared to non-targeted liposomes. These liposomes accumulated selectively in radiation activated tumor vasculature compared to nonirradiated tumors. CA4 incorporated into the targeted liposomes in combination with irradiation delayed tumor growth by 5.1 days in a single dose of 14.5 mg/Kg body weight. However, no significant tumor growth retardation was observed when CA4 was administered in free form (emulsion dosage form) even at a drug dose of almost six times that used in the targeted liposomes. The lyophilized formulation showed better stability at 4°C and 25°C than liquid product.; A stable and effective targeted liposome delivery system was developed for CA4 to take this drug selectively to irradiated tumor vasculature. This targeted delivery system could potentially increase the anti-cancer activity as well as the therapeutic utility of the drug compared to existing solution dosage forms.