Tuning small molecule release from polymer micelles: Varying H2S release through cross linking in the micelle core,European Polymer Journal

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Tuning small molecule release from polymer micelles: Varying H2S release through cross linking in the micelle core
European Polymer Journal ( IF 5.8 ) Pub Date : 2020-12-01 , DOI: 10.1016/j.eurpolymj.2020.110077
Ryan J Carrazzone ₁ , Jeffrey C Foster ₁ , Zhao Li ₁ , John B Matson ₁

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Polymer micelles, used extensively as vehicles in the delivery of active pharmaceutical ingredients, represent a versatile polymer architecture in drug delivery systems. We hypothesized that degree of crosslinking in the hydrophobic core of amphiphilic block copolymer micelles could be used to tune the rate of release of the biological signaling gas (gasotransmitter) hydrogen sulfide (H2S), a potential therapeutic. To test this hypothesis, we first synthesized amphiphilic block copolymers of the structure PEG-b-P(FBEA) (PEG = poly(ethylene glycol), FBEA = 2-(4-formylbenzoyloxy)ethyl acrylate). Using a modified arm-first approach, we then varied the crosslinking percentage in the core-forming block via addition of a 'O,O'-alkanediyl bis(hydroxylamine) crosslinking agent. We followed incorporation of the crosslinker by 1H NMR spectroscopy, monitoring the appearance of the oxime signal resulting from reaction of pendant aryl aldehydes on the block copolymer with hydroxylamines on the crosslinker, which revealed crosslinking percentages of 5, 10, and 15%. We then installed H2S-releasing S-aroylthiooxime (SATO) groups on the crosslinked polymers, yielding micelles with SATO units in their hydrophobic cores after self-assembly in water. H2S release studies in water, using cysteine (Cys) as a trigger to induce H2S release from the SATO groups in the micelle core, revealed increasing half-lives of H2S release, from 117 ± 6 min to 210 ± 30 min, with increasing crosslinking density in the micelle core. This result was consistent with our hypothesis, and we speculate that core crosslinking limits the rate of Cys diffusion into the micelle core, decreasing the release rate. This method for tuning the release of covalently linked small molecules through modulation of micelle core crosslinking density may extend beyond H2S to other drug delivery systems where precise control of release rate is needed.

中文翻译：

调节聚合物胶束中小分子的释放：通过胶束核心中的交联改变 H2S 的释放

聚合物胶束广泛用作活性药物成分递送的载体，代表了药物递送系统中的多功能聚合物结构。我们假设两亲性嵌段共聚物胶束疏水核心的交联程度可用于调节生物信号气体（气体递质）硫化氢（H2S）的释放速率，硫化氢是一种潜在的治疗剂。为了验证这一假设，我们首先合成了结构为 PEG-bP(FBEA) 的两亲性嵌段共聚物（PEG = 聚乙二醇，FBEA = 丙烯酸 2-(4-甲酰基苯甲酰氧基)乙酯）。然后，我们使用改进的臂优先方法，通过添加“O,O”-烷二基双（羟胺）交联剂来改变核心形成嵌段中的交联百分比。我们通过 1H NMR 光谱跟踪交联剂的掺入，监测嵌段共聚物上侧链芳基醛与交联剂上羟胺反应产生的肟信号的出现，结果显示交联百分比为 5%、10% 和 15%。然后，我们在交联聚合物上安装了释放 H2S 的 S-芳酰硫肟 (SATO) 基团，在水中自组装后，在其疏水核心中产生了具有 SATO 单元的胶束。使用半胱氨酸 (Cys) 作为触发器诱导胶束核心 SATO 基团释放 H2S 的水中 H2S 释放研究表明，随着交联的增加，H2S 释放的半衰期从 117 ± 6 分钟延长至 210 ± 30 分钟胶束核心的密度。这一结果与我们的假设一致，我们推测核心交联限制了半胱氨酸扩散到胶束核心的速率，从而降低了释放速率。这种通过调节胶束核心交联密度来调节共价连接小分子释放的方法可能会超出 H2S 范围，扩展到需要精确控制释放速率的其他药物递送系统。

更新日期：2020-12-01

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