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

Abstract Translating innovative nanomaterials to medical products requires efficient manufacturing techniques that enable large‐scale high‐throughput synthesis with high reproducibility. Drug carriers in medicine embrace a complex subset of tasks calling for multifunctionality. Here, the synthesisof pro‐drug‐loaded core cross‐linked polymeric micelles (CCPMs) in a continuous flow processis reported, 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 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 produces 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 (a trademark of Bristol‐Myers Squibb), 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.