Complex Structures Made Simple - Continuous Flow Production of Core Cross-Linked Polymeric Micelles for Paclitaxel Pro-Drug-Delivery.

Translating innovative nanomaterials to medical products requires efficient manufacturing techniques that enable large-scale high-throughput synthesis and high reproducibility. Drug carriers in medicine embrace a complex subset of tasks calling for multi-functionality. Here, we report the synthesis of pro-drug-loaded core cross-linked polymeric micelles (CCPMs) in a continuous flow process, which combines the commonly separated steps of micelle formation, core cross-linking, functionalization, and purification into a single process. Redox-responsive CCPMs are formed from thiol-reactive polypept(o)ides of polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine) and functional cross-linkers based on dihydrolipoic acid hydrazide for pH-dependent release of paclitaxel. The precisely controlled microfluidic self-assembly and purification process allows the production of spherical micelles (D h = 35 nm) with low polydispersity values (PDI<0.1) while avoiding toxic organic solvents and additives with unfavorable safety profiles. Self-assembly and cross-linking via slit interdigital micromixers produce 350-700 mg of CCPMs/h per single system, while purification by online tangential flow filtration successfully removes impurities (unimer ≤ 0.5%). The formed paclitaxel-loaded CCPMs possess the desired pH-responsive release profile, display stable drug encapsulation, an improved toxicity profile compared to Abraxane, and therapeutic efficiency in the B16F1-xenotransplanted zebrafish model. The combination of reactive polymers, functional cross-linkers, and microfluidics enables the continuous-flow synthesis of therapeutically active CCPMs in a single process. This article is protected by copyright. All rights reserved.