AN IMPROVED METHOD OF ENCAPSULATION OF DOXORUBICIN IN LIPOSOMES - PHARMACOLOGICAL, TOXICOLOGICAL AND THERAPEUTIC EVALUATION

We describe here an improved method of encapsulating doxorubicin in li posomes using phosphatidylcholine, cholesterol and synthetic tetramyri stoyl cardiolipin. With this new composition of lipids the entrapment of doxorubicin was found to be >90%. Cytotoxicity studies using vincri stine-resistant HL-60/VCR leukaemia cells showed that liposome-encapsu lated doxorubicin reverses multidrug resistance 5-fold compared with c onventional doxorubicin and at levels equivalent to that obtained usin g liposomes with natural cardiolipin. In normal mice, liposome-encapsu lated doxorubicin was much less toxic than the conventional drug. A do se of 25 mg kg(-1) i.v. of conventional doxorubicin produced 100% mort ality in mice by day 14, whereas liposomal doxorubicin exhibited only 10% mortality by day 60. Liposomal doxorubicin demonstrated enhanced a nti-tumour activity against murine ascitic L1210 leukaemia compared wi th conventional doxorubicin. At a dose of 15 mg kg(-1), liposomal doxo rubicin increased the median life span with 12 of 18 long-term (60 day s) survivors compared with only 3 of 18 with conventional drug. Mice i njected i.v. with liposomal doxorubicin had plasma levels 44-fold high er than conventional doxorubicin, producing significantly higher (P < 0.02) area under the plasma concentration curve. An altered tissue dis tribution was also observed with liposomal doxorubicin; cardiac tissue demonstrating at least 2-fold lower levels with liposomal doxorubicin probably accounting for its lower toxicity. This altered pharmacokine tics of liposome-encapsulated doxorubicin, providing enhanced therapeu tic advantage and the ability to modulate multidrug resistance, could be useful in a clinical setting.