THE USE OF TRANSMEMBRANE PH GRADIENT-DRIVEN DRUG ENCAPSULATION IN THE PHARMACODYNAMIC EVALUATION OF LlpoSOMAL DOXORUBICIN

The toxicity and efficacy properties of doxorubicin entrapped inside liposomes are sensitive to the physical characteristics of the vesicle carrier system. Studies addressing such relationships must use preparation procedures with the ability to independently vary vesicle size, lipid composition and drug to lipid ratio while maintaining high trapping efficiencies,. The transmembrane pH gradient-driven encapsulation technique allows such liposomal doxorubicin formulations to be prepared. Pharmacokinetic, toxico1og:y and antiturnour studies with these systems have revealed several important relatio'nships between liposome physical properties and biological activity. The acute toxicity of liposomal doxorubicin is related primarily to the ability of the 1iposomt:s to retain doxorubicin after administration. Including cholesterol and increasing the degree of acyl chain saturation of the phospholipid component in the liposomes significantly decreases drug leakage in the blood, reduces cardiac tissue accumula.tion of doxorubicin and results in increased LD,,values. In contrast, the efficacy 01' liposomal doxorubicin is most influenced by liposome size. Specifically, liposomes with a diameter of approximately 100 nm or less exhibit enhanced circulation lifetimes and antitumour activity. While these relationships appear to be rather straightforward, there exist anomalies which suggest