Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, Leiden, 2333CC, The Netherlands.
Fraunhofer Institute for Microengineering and Microsystems, Carl-Zeiss-Str. 18-20, 55129, Mainz, Germany.
Adv Mater. 2023 May;35(21):e2210704. doi: 10.1002/adma.202210704. Epub 2023 Apr 6.
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 = 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.
将创新的纳米材料转化为医疗产品需要高效的制造技术，这些技术能够实现大规模高通量合成，并具有高度的重现性。医学中的药物载体包含一系列复杂的任务，需要多功能性。在这里，报告了一种在连续流过程中合成载前药的核交联聚合物胶束（CCPMs）的方法，该方法将胶束形成、核交联、功能化和纯化这通常分离的步骤结合到一个单一的过程中。基于二氢硫辛酸酰肼的基于还原响应的 CCPMs 是由硫醇反应性多肽（多聚肌氨酸嵌段聚（S-乙基磺酰基-L-半胱氨酸））和功能交联剂形成的，用于 pH 依赖性释放紫杉醇。精确控制的微流控过程允许生产具有低多分散性值（PDI <0.1）的球形胶束（D = 35nm），同时避免使用具有不利安全性的有毒有机溶剂和添加剂。通过狭缝叉指微混合器进行自组装和交联，每个系统每小时可生产 350-700mg 的 CCPMs，而通过在线切向流过滤进行的纯化可成功去除杂质（单体 ≤0.5%）。形成的载紫杉醇的 CCPMs 具有所需的 pH 响应释放特性，显示出稳定的药物包封，与 Abraxane（百时美施贵宝的商标）相比，毒性特征得到改善，并且在 B16F1-xenotransplanted 斑马鱼模型中具有治疗效率。反应性聚合物、功能交联剂和微流控的结合使得在单个过程中连续流合成治疗活性 CCPMs 成为可能。
