Complex Structures Made Simple – Continuous Flow Production of Core Cross‐Linked Polymeric Micelles for Paclitaxel Pro‐Drug‐Delivery
Advanced Materials, vol. 35, pp. e2210704
Abstract
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 (Dh = 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.
Authors 11
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Affiliation as printed
Leiden Academic Centre for Drug Research (LACDR) Leiden University Einsteinweg 55 Leiden 2333CC The Netherlands
Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, Leiden, 2333CC The Netherlands
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Fraunhofer Institute for Microengineering and Microsystems
Affiliation as printed
Fraunhofer Institute for Microengineering and Microsystems Carl‐Zeiss‐Str. 18–20 55129 Mainz Germany
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Affiliation as printed
Department for Biosciences University of Oslo Blindernveien 31 0371 Oslo Norway
Department for Biosciences, University of Oslo, Blindernveien 31, 0371 Oslo, Norway
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University Medical Center of the Johannes Gutenberg University Mainz
Affiliation as printed
Molecular and Cellular Oncology/Nanobiomedicine ENT Department University Medical Center Mainz Langenbeckstraße 1 55131 Mainz Germany
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Affiliation as printed
Leiden Academic Centre for Drug Research (LACDR) Leiden University Einsteinweg 55 Leiden 2333CC The Netherlands
Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, Leiden, 2333CC The Netherlands
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Max Planck Institute for Polymer Research
Affiliation as printed
Max Planck Institute for Polymer Research Ackermannweg 10 55128 Mainz Germany
Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
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Fraunhofer Institute for Microengineering and Microsystems
Affiliation as printed
Fraunhofer Institute for Microengineering and Microsystems Carl‐Zeiss‐Str. 18–20 55129 Mainz Germany
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University Medical Center of the Johannes Gutenberg University Mainz
Affiliation as printed
Molecular and Cellular Oncology/Nanobiomedicine ENT Department University Medical Center Mainz Langenbeckstraße 1 55131 Mainz Germany
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Kaloian Koynov corresponding
Max Planck Institute for Polymer Research
Affiliation as printed
Max Planck Institute for Polymer Research Ackermannweg 10 55128 Mainz Germany
Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany
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Fraunhofer Institute for Microengineering and Microsystems
Affiliation as printed
Fraunhofer Institute for Microengineering and Microsystems Carl‐Zeiss‐Str. 18–20 55129 Mainz Germany
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Leiden University · University Medical Center of the Johannes Gutenberg University Mainz
Affiliation as printed
Department of Dermatology University Medical Center of the Johannes Gutenberg University Mainz Langenbeckstraße 1 55131 Mainz Germany
Leiden Academic Centre for Drug Research (LACDR) Leiden University Einsteinweg 55 Leiden 2333CC The Netherlands
Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, Leiden, 2333CC The Netherlands
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