In vivo targeting of acoustically reflective liposomes for intravascular and transvascular ultrasonic enhancement

OBJECTIVES: The purpose of this study was to target acoustically reflective liposomes to atherosclerotic plaques in vivo for ultrasound image enhancement. BACKGROUND: We have previously demonstrated the development of acoustically reflective liposomes that can be conjugated for site-specific acoustic enhancement. This study evaluates the ability of liposomes coupled to antibodies specific for different components of atherosclerotic plaques and thrombi to target and enhance ultrasonic images in vivo. METHODS: Liposomes were prepared with phospholipids and cholesterol using a dehydration/ rehydration method. Antibodies were thiolated for liposome conjugation with N-succinimidyl 3-(2-pyridyldithio) propionate resulting in a thioether linkage between the protein and the phospholipid. Liposomes were conjugated to antifibrinogen or anti-intercellular adhesion molecule-1 (anti-ICAM-1). In a Yucatan miniswine model, atherosclerosis was developed by crush injury of one carotid and one femoral artery and ingestion of a hypercholesterolemic diet. After full plaque development the arteries were imaged (20-MHz intravascular ultrasound catheter and 7.5-MHz transvascular linear probe) after injection of saline, unconjugated liposomes and antibody conjugated liposomes. RESULTS: Conjugated liposomes retained their acoustically reflective properties and provided ultrasonic image enhancement of their targeted structures. Liposomes conjugated to antifibrinogen attached to thrombi and fibrous portions of the atheroma, whereas liposomes conjugated to anti-ICAM-1 attached to early atheroma. CONCLUSIONS: Our data demonstrate that this novel acoustic agent can provide varying targeting with different antibodies with retention of intravascular and transvascular acoustic properties.     

A Mixed Micellar Formulation Suitable for the Parenteral Administration of Taxol

Taxol is a promising antitumor agent with poor water solubility. Intravenous administration of a current taxol formulation in a non-aqueous vehicle containing Cremophor EL may cause allergic reactions and precipitation upon aqueous dilution. In this study a novel approach to formulate taxol in aqueous medium for i.v. delivery is described. The drug is solubilized in bile salt (BS)/phospholipid (PC) mixed micelles. The solubilization potential of the mixed micelles increased as the total lipid concentration and the molar ratio of PC/BS increased. Precipitation of the drug upon dilution was avoided by the spontaneous formation of drug-loaded liposomes from mixed micelles. The formulation can be stored in a freeze-dried form as mixed micelles to achieve optimum stability, and liposomes can be prepared by simple dilution just before administration. As judged by a panel of cultured cell lines, the cytotoxic activity of taxol was retained when formulated as a mixed-micellar solution. Further, for the same solubilization potential, the mixed-micellar vehicle appeared to be less toxic than the standard nonaqueous vehicle of taxol containing Cremorphor EL.     

Mixed Micelles as Proliposomes for the Solubilization of Teniposide

The aqueous solubility of teniposide in detergent and phospholipid mixed micelles was investigated as functions of the detergents and lipids composing the mixed micelles, the molar ratio of detergent to phospholipid, and the total lipid concentration of the system. The polarity, the charge of the phospholipid, and its saturation affected the solubilization potential of the micelles. Physical chemical factors such as the pH, ionic strength, and temperature of the dispersion medium also altered the solubilization capacity of the system. The results are explained by the changes occurring in the critical micelle concentration and packing arrangements of the aggregates. The desired solubility of teniposide can be achieved by adjusting the studied parameters to the optimum values. Teniposide-containing mixed micelles were spontaneously converted to drug-containing vesicles upon aqueous dilution; therefore, the precipitation of the drug was totally eliminated. In conclusion, mixed micelles as proliposomes can be a suitable drug carrier system for insoluble compounds such as teniposide.