Scale-up synthesis of a polymer designed for protein therapy

Here we report optimization and scale-up of a biodegradable polycation, poly(ethylene argininylaspartate diglyceride) (PEAD) for the purpose of clinical translation. This polycation complexes heparin to form a coacervate. The resultant complex coacervate acts as a vehicle for controlled delivery of therapeutic proteins and through the bioactivity of heparin, greatly increases the half lives of many therapeutic proteins. In an effort to translate this drug delivery platform commercially and clinically, it is necessary to consider the scale of the synthesis, the environmental impact and the cost of the production. Therefore, we substituted the more expensive and hazardous solvents in the reactions, optimized the reaction parameters for a higher yield, scaled up the synthesis capacity up to hundreds of grams per batch and reduced the polymer cost by nearly 90%. The resultant PEAD bears more positive charges than the counterpart made using our previous method, and thus less polymer is needed to complex heparin for coacervation. The material demonstrated good cytocompatibility with human umbilical vein endothelial cells at concentrations up to 5 mg/ml, nearly 500-times more cytocompatible than the commercially resourced polyethyleneimine. Basic fibroblast growth factor was loaded in the coacervate with loading efficiency above 99%. The cargo steadily released approximately 1% over 37 days in vitro without an initial burst, indicating a highly stable coacervate for sustained release. This study paves the way for the translation of this delivery platform and may inform the scale-up of similar polymers.