INTRATUMORAL RADIOIMMUNOTHERAPY OF A HUMAN COLON-CANCER XENOGRAFT USING A SUSTAINED-RELEASE GEL

Low tumor uptake and normal tissue toxicity limit the efficacy of RIT for the treatment of solid tumors. In this study, an intratumoral inje ctable gel drug delivery system for local administration of RIT was ev aluated using the LS174T human colon cancer xenograft model in SCID mi ce. The injectable gel is a collagen-based drug delivery system design ed for intratumoral (i.t.) administration, which has previously been s hown to enhance drug retention at the injection site and reduce system ic drug exposure. We compared the local (tumor) retention and biodistr ibution of In-111-labeled NR-LU-10 monoclonal antibody given i.t. in t he injectable gel versus simple aqueous solution. In-111 gel given i.t . and In-111-NR-LU-10 given intraperitoneally (i.p.) were used as cont rols. The results showed that tumors treated with In-111-NR-LU-10 gel maintained the highest levels of radioactivity for up to 96 h. At 48 h after the administration of In-111-NR-LU-10 gel i.t., In-111-NR-LU-10 solution i.t., In-111 gel i.t., or In-111-NR-LU-10 i.p., the level of radioactivity remaining in each gram of tumor was 98, 49, 45, and 16% of the injected dose, respectively. It was estimated that if 100 mu C i of Y-90-NR-LU-10 were administered similarly, tumor treated with Y-9 0-NR-LU-10 gel i.t. would receive a dose of 90.0 Gy, whereas normal ti ssues in the same animal would receive a dose of approximately 2.43 Gy . In contrast, if Y-90-NR-LU-10 were delivered i.p., a comparable tumo r would receive a dose of 16.8 Gy and corresponding normal tissues wou ld receive 3.36 Gy. Consistent with these estimates, enhanced antitumo r efficacy was observed when Y-90-NR-LU-10 gel was administered i.t. T umor growth delay time was 6.9-fold (P < 0.01) longer in these animals (14.4 days) than in animals treated with Y-90-NR-LU-10 i.p. (2.1 days ). Systemic toxicity was also significantly reduced in gel-treated ani mals as monitored by loss of body weight. This study demonstrated that intratumoral delivery of Y-90-NR-LU-10 gel markedly increased the ret ention of the radioisotope in tumors, enhanced the antitumor efficacy, and reduced systemic toxicity compared to systemic administration of the radiolabeled antibody. This injectable gel drug delivery system ma y allow for improvement in the therapeutic index for RIT.