Manipulation of variables in local controlled release vincristine treatment in neuroblastoma.

INTRODUCTION: Local drug delivery minimizes systemic toxicity while delivering high-dose chemotherapy for neuroblastoma patients. We hypothesized that varying burst and maintenance dosing of implanted silk platforms would improve survival.

METHODS: Platforms were loaded with vincristine 25μg, 50μg, 100μg, and 200μg varying burst (released 1-4days postimplantation) and maintenance (over the next 20days) dosing. Orthotopic tumors were created in mice using human neuroblastoma KELLY cells. Silk platforms were implanted into tumors when volumewas >300mm3 . Tumor volume was monitored weekly with ultrasound. Experimental endpoints were tumor volumewas >1000mm3 or weight losswas >25%.

RESULTS: Drug release ranged from burst dosing of 18.2 to 80.9μg, maintenance of 5.0 to 111.6μg, and cumulative of 23.3 to 177.4μg. Animals treated with 200μg platform died 9-13days postimplantation, corresponding to 128.1-141.2μg released (toxic dose). Animals received 30.2±3.4μgday-one survived longer than those that received 10.1±1.1μg (p=0.03), suggesting <10.1μgday-one was insufficient. Tumors treated with 100μg or 50μg silk platform took longer to reach 1000 mm3 compared to those treated with control, 44.8±9.5days (p<0.001) and 26.7±6.7days (p<0.05), respectively, versus 7.0±1.7days. Overall survival correlated with higher burst (r=0.446, p=0.004) and maintenance dosing (r=0.353, p=0.02), Animal survival days=30.314+0.626 × (dose on day-one) - 0.020×(tumor volume at day-ten) (p<0.05).

CONCLUSION: Platform formulations can be manipulated to vary burst and maintenance dosing, summarized by an equation consisting of these variables.