Barthold S, Kletting S, Taffner J, de Souza Carvalho-Wodarz C, Lepeltier E, Loretz B, Lehr C-M
Department Drug Delivery, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz-Centre for Infection Research (HZI), Saarbrücken, Germany.
J Mater Chem B. 2016 Apr 7;4(13):2377-2386. doi: 10.1039/c6tb00178e. Epub 2016 Mar 16.
Proteins and peptides represent a large fraction of the compounds currently in drug development pipelines. Their application however often depends on the use of carrier systems. Nanoparticles (NPs) are widely used such carrier systems for protein delivery. The aim of this study was to design a new drug delivery system (DDS), prepared under mild conditions in aqueous solution without the requirement of a stabilizer. The biodegradability and biocompatibility of the designed system was explored with a view to specifically determine its potential to facilitate the pulmonary delivery of proteins. As a first step, anionic and cationic water soluble starch-derivatives were synthesized. These starch polymers allowed for NP formation via coacervation, as well as protein loading. Physicochemical characterization of the prepared NPs was then carried out: NPs were found to have a narrow size distribution with an average size ranging from 140 to 350 nm, and a ζ-potential ranging from -10 to -35 mV, depending on the formulation conditions. In a proof of concept study, starch NPs were found to be readily degraded by the human enzyme α-amylase, and showed good biocompatibility with A549 cells after 4 h. Upon nebulization, NPs were seen to be internalized by air-liquid interface cultivated A549 cells as well as 16HBE14o cells. To evaluate the ability of starch NPs to load proteins of various characteristics, NPs were loaded with four model proteins/peptides possessing different molecular weights and isoelectric points - IgG1, RNAse A, insulin, and vancomycin. The greatest loading was achieved in the case of vancomycin with up to 23% drug loading and 43% encapsulation efficiency, indicating an optimal loading of proteins with an isoelectric point close to the pH of the NP suspension. In conclusion, starch NPs prepared by the developed mild and straightforward technique show potential as a safe platform for pulmonary delivery of proteins and peptides.
蛋白质和肽类占目前处于药物研发阶段化合物的很大一部分。然而，它们的应用通常依赖于载体系统。纳米颗粒（NPs）是广泛用于蛋白质递送的此类载体系统。本研究的目的是设计一种新的药物递送系统（DDS），该系统在温和条件下于水溶液中制备，无需稳定剂。对所设计系统的生物降解性和生物相容性进行了探索，以具体确定其促进蛋白质肺部递送的潜力。第一步，合成了阴离子型和阳离子型水溶性淀粉衍生物。这些淀粉聚合物可通过凝聚形成纳米颗粒，并实现蛋白质负载。然后对制备的纳米颗粒进行了物理化学表征：发现纳米颗粒具有窄的粒径分布，平均粒径范围为140至350nm，ζ电位范围为-10至-35mV，具体取决于配方条件。在概念验证研究中，发现淀粉纳米颗粒易于被人α-淀粉酶降解，并且在4小时后与A549细胞表现出良好的生物相容性。雾化后，纳米颗粒被气液界面培养的A549细胞以及16HBE14o细胞内化。为了评估淀粉纳米颗粒负载各种特性蛋白质的能力，用四种具有不同分子量和等电点的模型蛋白质/肽——IgG1、核糖核酸酶A、胰岛素和万古霉素对纳米颗粒进行了负载。万古霉素的负载量最大，药物负载量高达23%，包封率为43%，这表明等电点接近纳米颗粒悬浮液pH值的蛋白质具有最佳负载量。总之，通过所开发的温和且直接的技术制备的淀粉纳米颗粒显示出作为蛋白质和肽类肺部递送安全平台的潜力。
