脂酰酯封端的星形PLGA是一种简单智能的材料，可用于受控药物输送应用,Biomacromolecules

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脂酰酯封端的星形PLGA是一种简单智能的材料，可用于受控药物输送应用
Biomacromolecules ( IF 5.5 ) Pub Date : 2018-03-19 00:00:00 , DOI: 10.1021/acs.biomac.8b00130
Xiuxiu Wang ₁ , Ru Cheng ₁ , Liang Cheng _{1,

2} , Zhiyuan Zhong ₁

Affiliation

PLGA是丙交酯和乙交酯的共聚物，是最常用的可生物降解的聚合物之一，可用于包括药物输送和组织工程在内的多种生物医学应用。然而，尽管取得了令人瞩目的进步，基于PLGA的纳米治疗药物仍可能具有稳定性不足，药物泄漏和肿瘤部位药物释放缓慢的缺点，从而降低了其靶向能力和治疗效果。在这里，我们报道星光PLGA的直接修饰以硫辛酸（一种存在于人体中的天然抗氧化剂）结束，提供了一种智能材料（sPLGA-LA），该材料形成了可逆交联且具有生物响应性的多功能纳米颗粒（sPLGA XNP）。有趣的是，在23.0 wt％PEG-PDLLA存在下获得的sPLGA XNPs的流体动力学尺寸小，为73±1.2 nm，对稀释度和10％血清具有很高的稳定性，同时在还原性环境下快速不稳定。此外，sPLGA XNPs在理论载药量为13.3 wt％的情况下实现了亲脂性抗癌药物模型阿霉素（DOX）的有效载量，从而使载有DOX的sPLGA XNPs在生理条件下具有减少的药物泄漏，并在加速条件下显着加速了药物的释放。与线性和星形PLGA对照（分别表示为lPLGA NP和sPLGA NP）相比，谷胱甘肽条件为10 mM。共聚焦显微镜和流式细胞仪显示，用DOX加载的sPLGA XNP处理的B16F10黑色素瘤细胞中的DOX荧光明显强于lPLGA和sPLGA对应物。MTT分析显示，DOX-sPLGA XNP对B16F10细胞的抗肿瘤活性分别比DOX-sPLGA NP和DOX-1PLGA NP高2.4倍和4.2倍。尤其，体内药代动力学研究表明DOX-sPLGA XNP的循环时间延长了，并且比lPLGA NPs的控制大大改善了AUC。因此，以脂酰酯封端的星形PLGA成为一种简单智能的材料，可以更好地控制抗癌药物的输送。

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Lipoyl Ester Terminated Star PLGA as a Simple and Smart Material for Controlled Drug Delivery Application

PLGA, a copolymer of lactide and glycolide, is one of the most used biodegradable polymers that find a wide range of biomedical applications including drug delivery and tissue engineering. However, in spite of remarkable advancement, nanotherapeutics based on PLGA might have drawbacks of inadequate stability, drug leakage, and slow drug release at the tumor site, which reduces its targeting ability and therapeutic efficacy. Here, we report that direct modification of star PLGA ends with lipoic acid, a natural antioxidant present in our human body, affords a smart material (sPLGA-LA) that forms reversibly crosslinked and bioresponsive multifunctional nanoparticles (sPLGA XNPs). Interestingly, sPLGA XNPs obtained in the presence of 23.0 wt % PEG–PDLLA displayed a small hydrodynamic size of 73 ± 1.2 nm, high stability against dilution and 10% serum, while fast destabilization under a reductive environment. Moreover, sPLGA XNPs achieved efficient loading of lipophilic anticancer drug model, doxorubicin (DOX), at a theoretical drug loading content of 13.3 wt %, giving DOX-loaded sPLGA XNPs with reduced drug leakage under physiological conditions as well as significantly accelerated drug release under 10 mM glutathione condition compared with both linear and star PLGA controls (denoted as lPLGA NPs and sPLGA NPs, respectively). Confocal microscopy and flow cytometry displayed obviously stronger DOX fluorescence in B16F10 melanoma cells treated with DOX-loaded sPLGA XNPs than with lPLGA and sPLGA counterparts. MTT assays revealed that DOX-sPLGA XNPs caused 2.4- and 4.2-fold higher antitumor activity toward B16F10 cells than DOX-sPLGA NPs and DOX-lPLGA NPs, respectively. Notably, in vivo pharmacokinetics studies showed prolonged circulation time and significantly improved AUC for DOX-sPLGA XNPs over lPLGA NPs control. Hence, lipoyl ester terminated star PLGA emerges as a simple and smart material for better-controlled anticancer drug delivery.

更新日期：2018-03-19

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