PURPOSE: @entity68058 is a @entity9800 -polymer conjugate prepared by linking @entity9800 ( @entity1191 ) to a hydrophilic, cyclodextrin-based, linear polymer through @entity13507 bonds. In previous studies, these polymer conjugates with high molecular weights (ca 90 kDa) have shown significant antitumor effects against @entity1 @entity694 xenografts. The pharmacokinetics of @entity68058 in plasma of @entity35 and its biodistribution in @entity19 bearing @entity1 LS174T @entity694 is reported here. METHODS: @entity35 were injected intravenously with three different doses of @entity68058 . Serial plasma samples were analyzed for polymer-bound and unconjugated @entity1191 by high-performance liquid chromatography (HPLC). Concentration vs time data were modeled using non-compartmentalized methods and compared to @entity1191 alone injected intravenously at an equivalent dose. Tumor-bearing @entity19 were injected intravenously with @entity68058 and intraperitoneally with @entity1191 alone, and sacrificed after 24 and 48 h, and serum, heart, liver, spleen, lungs and @entity5 collected. Tissue samples were extracted and analyzed for polymer-bound and unconjugated @entity1191 by HPLC. RESULTS: Plasma concentrations and the area under the curve for polymer-bound @entity1191 are approximately 100-fold higher than those of unconjugated @entity1191 or @entity1191 alone, injected intravenously at an equivalent dose. The plasma half-life of @entity68058 ranges from 17 -20 h and is significantly greater than that of @entity1191 alone (1.3 h). When @entity1191 is conjugated to polymer, the biodistribution pattern of @entity1191 is different from that taken alone. At 24 h post injection, the total @entity1191 per gram of tissue is the highest in @entity5 tissue when compared to all other tissues tested. Tumor concentrations of active @entity1191 released from the conjugate are more than 160-fold higher when administered as a polymer conjugate rather than as @entity1191 alone. CONCLUSIONS: The studies presented here indicate that intravenous administration of @entity68058 , a cyclodextrin based polymer- @entity1191 conjugate, gives prolonged plasma half-life and enhanced distribution to @entity5 tissue when compared to @entity1191 alone. The data also show that active @entity1191 is released from the conjugate within the @entity5 for an extended period of time. These effects likely play a significant role in the enhanced antitumor activity of @entity68058 when compared to @entity1191 alone or @entity2600 .

Pharmacokinetics and biodistribution of the XXXX -polymer conjugate @entity68058 in @entity35 and @entity5 -bearing @entity19 .

@entity1 :: ('9606', 'Species') :: ['human'] @entity2600 :: ('MESH:C051890', 'Chemical') :: ['irinotecan'] @entity19 :: ('10090', 'Species') :: ['mice', 'nude mice'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor'] @entity694 :: ('MESH:D003110', 'Disease') :: ['colon carcinoma', 'colon carcinoma tumors'] @entity1191 :: ('CHEBI:27656', 'Chemical') :: ['CPT'] @entity9800 :: ('MESH:D002166', 'Chemical') :: ['camptothecin'] @entity35 :: ('10116', 'Species') :: ['Sprague-Dawley rats', 'rats'] @entity68058 :: ('MESH:C542292', 'Chemical') :: ['IT-101'] @entity13507 :: ('CHEBI:35701', 'Chemical') :: ['ester']
@entity9800 :: (MESH:D002166,Chemical) :: ['camptothecin']
