通过改变纳米凝胶的大小来调节基于纳米凝胶的原位形成植入物中 HIV 药物的释放。

Tuning HIV drug release from a nanogel-based in situ forming implant by changing nanogel size.

机构信息

Department of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD, UK.

出版信息

J Mater Chem B. 2019 Jan 21;7(3):373-383. doi: 10.1039/c8tb01597j. Epub 2018 Dec 20.

Abstract

HIV is a global public health threat and requires life-long, daily oral dosing to effectively treat. This pill burden often results in poor adherence to the medications. An injectable in situ forming implant with tuneable drug release kinetics would allow patients to replace some of their daily pills with a single infrequent injection. In this work, we investigate how the size of poly(N-isopropylacrylamide) (polyNIPAm) nanogels influences the long-acting release behaviour of the HIV drug lopinavir from an in situ forming implant. Four sizes of polyNIPAm nanogels were prepared with mean diameters of 65, 160, 310 and 450 nm as characterised by dynamic light scattering. These nanogels all displayed synergistic dual stimuli responsive behaviour by aggregating only upon heating above 31 °C at physiological ionic strength. Mixing the nanogels with solid drug nanoparticles (SDNs) of lopinavir and exposing this concentrated dispersion to physiological temperature and ionic strength resulted in the in situ formation of nanocomposite implants. Three different loadings of the SDNs (33, 50 and 66% w/w) with each of the nanogels were prepared. The drug release behaviour and stability of these nanocomposite implants were then assessed in vitro over 360 hours. All samples displayed a single phase of drug release and application of the Ritger-Peppas equation indicated Fickian diffusion. Nanocomposites with the lowest loading of SDNs (33%) showed a linear relationship between nanogel diameter and the dissolution constant. These results show an attractive method for tuning the release of lopinavir from in situ loading implants with high drug loadings.

摘要

HIV 是一种全球性的公共卫生威胁,需要终身每日口服治疗。这种用药负担常常导致患者无法坚持用药。一种具有可调药物释放动力学的可注射原位形成植入物可以使患者用单次低频注射替代部分日常用药。在这项工作中,我们研究了聚 N-异丙基丙烯酰胺(polyNIPAm)纳米凝胶的大小如何影响 HIV 药物洛匹那韦从原位形成植入物中的长效释放行为。通过动态光散射法制备了四种不同大小的 polyNIPAm 纳米凝胶,平均直径分别为 65、160、310 和 450nm。这些纳米凝胶在生理离子强度下仅在 31°C 以上加热时才表现出协同的双重刺激响应聚集行为。将纳米凝胶与洛匹那韦的固体药物纳米颗粒(SDN)混合,并将这种浓缩分散体暴露于生理温度和离子强度下,会导致纳米复合植入物的原位形成。用每种纳米凝胶制备了三种不同 SDN 负载(33、50 和 66%w/w)的纳米复合植入物。然后在体外评估了这些纳米复合植入物在 360 小时内的药物释放行为和稳定性。所有样品均显示出单一的药物释放阶段,并且应用 Ritger-Peppas 方程表明为菲克扩散。具有最低 SDN 负载(33%)的纳米复合材料显示出纳米凝胶直径与溶解常数之间的线性关系。这些结果表明了一种有吸引力的方法,可以通过原位负载植入物以高载药量来调节洛匹那韦的释放。

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