Dual-stimuli responsive injectable microgel/solid drug nanoparticle nanocomposites for release of poorly soluble drugs.
Dual-stimuli responsive injectable microgel/solid drug nanoparticle nanocomposites for release of poorly soluble drugs.
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DOI：
10.1039/c6nr07858c
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发表时间：
2017-05
期刊：
影响因子：
6.7
通讯作者：
A. Town;Marco Giardiello;R. Gurjar;M. Siccardi;M. Briggs;R. Akhtar;Tom O. McDonald
中科院分区：
文献类型：
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作者：
A. Town;Marco Giardiello;R. Gurjar;M. Siccardi;M. Briggs;R. Akhtar;Tom O. McDonald
一种用于药物输送的原位成形植入物（ISFI）结合了通过简单注射给药来提高患者治疗依从性的潜力。在这里，我们描述了一种可注射的纳米复合材料ISFI的制备，该材料由热敏性聚n -异丙基丙烯酰胺微凝胶和固体药物纳米颗粒组成。采用沉淀聚合法制备单分散聚（n -异丙基丙烯酰胺）或聚（n -异丙基丙烯酰胺-共丙烯胺）微凝胶，平均粒径约为550 nm，温度为25℃。这些微凝胶的浓缩分散体表现出双重刺激响应行为，在盐（生理离子强度）和体温（高于聚合物的较低临界溶液温度）的存在下形成形状持久的大块聚集体。这些双刺激反应微凝胶可以注射到琼脂糖凝胶组织模拟物中，导致颗粒快速聚集形成药物库。此外，微凝胶颗粒在其他负载纳米颗粒（如含染料聚苯乙烯纳米颗粒或洛匹那韦固体药物纳米颗粒）存在下聚集形成具有高负载包封效率的纳米复合材料。所得到的微凝胶和固体药物纳米颗粒纳米复合材料显示出至少120天的药物持续释放，并且通过将聚（n -异丙基丙烯酰胺）微凝胶与聚（n -异丙基丙烯酰胺-共丙烯胺）微凝胶混合来调节释放速度。细胞毒性研究表明，即使在高浓度下，微凝胶对MDCK-II细胞也没有毒性。总的来说，这些结果证明了一种新的、易于注射的纳米复合ISFI，它可以为水溶性差的药物提供长期持续释放，而不会突然释放。
An in situ forming implant (ISFI) for drug delivery combines the potential to improve therapeutic adherence for patients with simple administration by injection. Herein, we describe the preparation of an injectable nanocomposite ISFI composed of thermoresponsive poly(N-isopropylacrylamide) based microgels and solid drug nanoparticles. Monodisperse poly(N-isopropylacrylamide) or poly(N-isopropylacrylamide-co-allylamine) microgels were prepared by precipitation polymerisation with mean diameters of approximately 550 nm at 25 °C. Concentrated dispersions of these microgels displayed dual-stimuli responsive behaviour, forming shape persistent bulk aggregates in the presence of both salt (at physiological ionic strength) and at body temperature (above the lower critical solution temperature of the polymer). These dual-stimuli responsive microgels could be injected into an agarose gel tissue mimic leading to rapid aggregation of the particles to form a drug depot. Additionally, the microgel particles aggregated in the presence of other payload nanoparticles (such as dye-containing polystyrene nanoparticles or lopinavir solid drug nanoparticles) to form nanocomposites with high entrapment efficiency of the payload. The resulting microgel and solid drug nanoparticle nanocomposites displayed sustained drug release for at least 120 days, with the rate of release tuned by blending microgels of poly(N-isopropylacrylamide) with poly(N-isopropylacrylamide-co-allylamine) microgels. Cytotoxicity studies revealed that the microgels were not toxic to MDCK-II cells even at high concentrations. Collectively, these results demonstrate a novel, easily injectable, nanocomposite ISFI that provides long-term sustained release for poorly water-soluble drugs without a burst release.