Drug catalyzed polymerization yields one pot nanomedicines†

Paul Joshua Hurst, Kyle J. Gassaway, Mohammed Faris Abouchaleh, Nehal S. Idris, Chelsea R. Jones, Chris A. Dicksion, James S. Nowick and Joseph P. Patterson
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Abstract

Ring-opening polymerization (ROP) is a powerful method for the synthesis of biocompatible and biodegradable polyester-based amphiphilic block copolymers, which are an excellent nanomaterial class for a wide range of pharmaceutical applications. These block copolymers are synthesized using a catalyst, which is typically purified out. In a separate step, the purified block copolymers are then assembled and drug-loaded for medical use. This multistep process limits the scalability of these nanomaterials restraining their industrial use. Recently, we developed a synchronous polymerization and self-assembly process for polyester-based block copolymer nanomaterials coined Ring-Opening Polymerization-Induced Crystallization-Driven Self Assembly (ROPI-CDSA). In ROPI-CDSA, an organocatalyst facilitates the chain extension of mPEG with L-lactide, yielding semicrystalline self-assemblies. Here, we demonstrate that pharmaceuticals with similar functional groups to ROP organocatalysts can catalyze ROPI-CDSA reactions, resulting in the formation of drug-embedded nanomaterials. The major advantage of this one pot approach is that no additional synthetic steps or purification are required. As a proof-of-principle study, we use two antibiotic drug molecules, chlorhexidine, and trimethoprim, as catalysts. Chlorhexidine acts as a co-initiator and a catalyst leading to drug conjugation whereas trimethoprim acts solely as a catalyst leading to drug encapsulation. The resulting drug-embedded block copolymer nanoparticles retain potent antibacterial activity. We anticipate that this strategy can be extended to other examples of PISA for the scalable production of drug-loaded polymer suspensions.

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药物催化聚合产生一锅纳米药物†。
开环聚合(ROP)是合成生物相容性和可生物降解的聚酯基两性嵌段共聚物的一种有效方法。这些嵌段共聚物使用催化剂合成,催化剂通常会被提纯。在另一个步骤中,纯化后的嵌段共聚物被组装起来并载入药物,用于医疗用途。这种多步骤工艺限制了这些纳米材料的可扩展性,制约了它们的工业应用。最近,我们开发了一种聚酯基嵌段共聚物纳米材料的同步聚合和自组装工艺,命名为开环聚合-诱导结晶-驱动自组装(ROPI-CDSA)。在 ROPI-CDSA 中,一种有机催化剂可促进 mPEG 与 L-内酰胺的链延伸,从而产生半结晶自组装。在这里,我们证明了具有与 ROP 有机催化剂相似官能团的药物可以催化 ROPI-CDSA 反应,从而形成药物嵌入纳米材料。这种一锅法的主要优点是无需额外的合成步骤或纯化。作为原理验证研究,我们使用两种抗生素药物分子--洗必泰和曲美索普林作为催化剂。洗必泰既是协同引发剂,也是药物共轭的催化剂,而三甲氧苄啶则是药物包埋的催化剂。由此产生的嵌段共聚物纳米粒子具有很强的抗菌活性。我们预计,这种策略可以推广到 PISA 的其他实例中,从而实现药物负载聚合物悬浮液的规模化生产。
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