ENHANCED TUMOR ACCUMULATION AND PROLONGED CIRCULATION TIMES OF MICELLE-FORMING POLY(ETHYLENE OXIDE-ASPARTATE) BLOCK COPOLYMER-ADRIAMYCIN CONJUGATES

Micelle-forming block copolymer-drug conjugates offer a new vehicle design for drug delivery that may be useful for the targeting of tumors. We have investigated the biodistribution of poly (ethylene oxide-aspartate) block copolymer-adriamycin conjugates (PEO-PAsp(ADR)) in murine colon adenocarcinoma 26 (C-26) tumor-bearing mice after intravenous (i.v.) injection. For PEO-PAsp(ADR) conjugates, long circulation times in blood and a concomitant reduced uptake in the major organs of the reticuloendothelial system (RES) (i.e., liver and spleen) were demonstrated. This was consistent with the in vivo persistence of a micellar core/shell structure in which the conjugate is known to adopt. In this micellar structure, the PAsp(ADR) blocks are surrounded by a palisade of PEO chains. An enhanced accumulation in tumors of the micelle-forming PEO-PAsp (ADR) conjugates after 24 h (ca. 10% dose per g tumor), relative to free ADR (ca. 0.90% dose per g tumor), was demonstrated. Further, peak levels of PEO-PAsp (ADR) conjugate in the heart (ca. 1.7% dose per g organ) were lower than for free ADR (ca. 6.2% dose per g organ). The results indicate that ADR associated with the micelle-forming PEO-PAsp (ADR) conjugates is more efficaciously delivered to tumor sites than free ADR.