Manipulation of variables in local controlled release vincristine treatment in neuroblastoma

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.

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%.

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).

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