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 25 μg, 50 μg, 100 μg, and 200 μg varying burst (released 1–4 days postimplantation) and maintenance (over the next 20 days) dosing. Orthotopic tumors were created in mice using human neuroblastoma KELLY cells. Silk platforms were implanted into tumors when volume was > 300 mm3. Tumor volume was monitored weekly with ultrasound. Experimental endpoints were tumor volume was > 1000 mm3or weight loss was > 25%. Results Drug release ranged from burst dosing of 18.2 to 80.9 μg, maintenance of 5.0 to 111.6 μg, and cumulative of 23.3 to 177.4 μg. Animals treated with 200 μg platform died 9–13 days postimplantation, corresponding to 128.1–141.2 μg released (toxic dose). Animals received 30.2 ± 3.4 μg day-one survived longer than those that received 10.1 ± 1.1 μg (p = 0.03), suggesting < 10.1 μg day-one was insufficient. Tumors treated with 100 μg or 50 μg silk platform took longer to reach 1000 mm3compared to those treated with control, 44.8 ± 9.5 days (p < 0.001) and 26.7 ± 6.7 days (p < 0.05), respectively, versus 7.0 ± 1.7 days. 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.