Improved Therapeutic Benefits of Doxorubicin by Entrapment in Anionic

When used as drug carriers, anionic l iposomes can reduce the chronic cardiac toxici ty and increase the ant i leukemic activity of doxorubic in (DXN; Adriamycin). Cont inuing investigations, reported here, have now establ ished the therapeut ic benefi ts of this mode of drug delivery. L iposome encapsulat ion caused a prolonged elevation in DXN plasma levels and a 2fold reduct ion in the exposure of cardiac t issue to the drug. This reduct ion, however, was not proport ional to the substantial decrease in chronic heart toxici ty observed in the earl ier study. In v ivo studies have demonstrated that the entrapped drug retains its full activity against Sarcoma 180 and signif icantly increases its action against Lewis lung carcinoma, as measured by reduced tumor volume. The increased ant ineoplast ic activity was again not proport ional to the increased associat ion of drug with tumor tissue. The effect of l iposome entrapment on the immune-suppressive activity of DXN was also examined to determine if factors other than the di rect del ivery of drug to tumor tissue might improve the therapeut ic response. The suppression of the humoral immune response and peripheral leukocyte counts by free DXN was nearly abol ished when the drug was administered in the l iposome form. These exper i ments suggest that the improved therapeut ic effect of encapsulation may be the outcome of three dif ferent mechanisms: (a) altered disposit ion into subcel lu lar compartments, which reduces cardiotoxici ty; (b) increased plasma drug exposure to tumor cells; and (c) signif icant reduct ion in the immune suppressive activity of DXN.