TARGETED DELIVERY OF DOXORUBICIN VIA STERICALLY STABILIZED IMMUNOLIPOSOMES - PHARMACOKINETICS AND BIODISTRIBUTION IN TUMOR-BEARING MICE

Purpose, To evaluate benefits in tumor localization, availability, and noncancerous organ distribution of doxorubicin (DOX) delivered via sm all (less than or equal to 120 nm) sterically stabilized immunoliposom es targeted against a tumor-associated antigen in fibrosarcoma-bearing mice. Methods, DOX-loaded liposomes were prepared with (i) specific m onoclonal IgG(3) antibody (32/2, D-SSIL-32/2); (ii) non-specific IgG(3 ) (D-SSIL-IgG); or (iii) no IgG (D-SSL) on their surface. Equal DOX am ounts were injected intravenously via each type of liposome into BALB/ c mice carrying experimental lung metastases of a polyoma virus-induce d fibrosarcoma (A9 etc 220) expressing a polyoma virus-induced tumor-a ssociated antigen (PAA) on their surface. Metastases occurred mainly i n lung. Mice were treated at 3 stages of tumor development (micrometas tases, medium-size metastases, and large, necrotic metastases). Perfor mance evaluation was based on time-dependent quantification of DOX and DOX metabolites (DOX-M) in lung tumor, noncancerous organs, and plasm a. Results, (i) DOX delivered via both SSIL retained the prolonged cir culation time typical of DOX delivered via D-SSL. (ii) DOX accumulatio n in noncancerous organs was similar for all preparations. Low levels of DOX-M were obtained for all three preparations in all organs except liver, suggesting a similar processing. (iii) Preparations differed i n behavior in lung tumor depending on tumor size and microanatomy. Onl y at the micrometastases stage were the specifically targeted D-SSIL-3 2/2 superior to D-SSL and D-SSIL-IgG, delivering 2-4 times more drug i nto the tumor. (iv) DOX-M level in all three tumor stages was in the f ollowing order: D-SSIL-32/2 >> D-SSL >> D-SSIL-IgG, suggesting that DO X delivered as D-SSlL-32/2 is most available to tumor cells. Conclusio ns. The advantage of specific targeting of sterically stabilized lipos omes is expressed mainly in increasing availability of DOX to tumor ce lls in a way which is dependent on tumor microanatomy. The impact of t his advantage to therapeutic efficacy remains to be determined.