Microdistribution of Fluorescently-labeled Monoclonal Antibody in a Peritoneal Dissemination model of Ovarian Cancer

摘要

The microdistribution of therapeutic monoclonal antibodies within a tumor is important for determining clinical response. Nonuniform microdistribution predicts therapy failure. Herein, we developed a semiquantitative method for measuring microdistribution of an antibody within a tumor using in situ fluorescence microscopy and sought to modulate the microdistribution by altering the route and timing of antibody dosing. The microdistribution of a fluorescently-labeled antibody, trastuzumab (50-μg and 150-μg intraperitoneal injection (I.p.), and 100-ng intravenous injection (I.v.)) was evaluated in a peritoneal dissemination mouse model of ovarian cancer. In addition, we evaluated the microdistribution of concurrently-injected (30-μg I.p. and 100-μg I.v.) or serial (two doses of 30-μg I.p.) trastuzumab using in situ multicolor fluorescence microscopy. After the administration of 50-μg I.p. and 100-μg I.v. trastuzumab fluorescence imaging showed no significant difference in the central to peripheral signal ratio (C/P ratio) and demonstrated a peripheral-dominant accumulation, whereas administration of 150-μg I.p. trastuzumab showed relatively uniform, central dominant accumulation. With concurrent-I.p.-I.v. injections trastuzumab showed slightly higher C/P ratio than concurrently-injected I.p. trastuzumab. Moreover, in the serial injection study, the second injection of trastuzumab distributed more centrally than the first injection, while no difference was observed in the control group. Our results suggest that injection routes do not affect the microdistribution pattern of antibody in small peritoneal disseminations. However, increasing the dose results in a more uniform antibody distribution within peritoneal nodules. Furthermore, the serial I.p. injection of antibody can modify the microdistribution within tumor nodules. This work has implications for the optimal delivery of antibody based cancer therapies.