Using Affinity To Provide Long-Term Delivery of Antiangiogenic Drugs in Cancer Therapy

Abstract

Antiangiogenic drugs encompass many of the different cancer drugs currently under clinical investigation. One of the drawbacks of antiangiogenic therapy, though, is that upon cessation of drug treatment tumors can recur with an accelerated growth rate. In this study we investigate the capacity of using affinity interactions between a polymer made from cyclodextrin and four antiangiogenic drugs, tranilast, SU5416, 2-methoxyestradiol, and silibinin, with the ultimate goal of creating delivery profiles on the order of antiangiogenic processes (needing weeks, rather than hours of delivery). In these systems, release rate is dependent on affinity, so using in silico molecular docking studies followed by surface plasmon resonance we determined that silibinin possesses the highest affinity among the drugs screened. Silibinin also showed a differential binding affinity among various cyclodextrins tested, with a greater affinity toward the larger molecular pocket of γ-cyclodextrin than for β-cyclodextrin. Release studies confirmed this affinity to translate into a slower, more sustained release of silibinin. Similarly we found this trend in the release of tranilast. Then using U87 human glioblastoma cells in a mouse xenograft model, we showed that affinity-based cyclodextrin polymers loaded with silibinin showed substantially longer release rates than nonaffinity control polymers; however, both were capable of inhibiting tumor growth in the time frame studied. From this work we showed three different, but chemically similar, polymers, each with a different release rate. Future work is on evaluating longer term tumor models where this longer release rate from affinity delivery systems might have additional advantages over polymers dependent only on diffusion.