Strathclyde Institute of Pharmacy and Biomedical Sciences , University of Strathclyde , Glasgow G4 0RE , Scotland.
Center for Vaccine Research , Statens Serum Institut , DK-2300 Copenhagen , Denmark.
Mol Pharm. 2019 Oct 7;16(10):4372-4386. doi: 10.1021/acs.molpharmaceut.9b00730. Epub 2019 Sep 6.
Cationic liposomes prepared from dimethyldioctadecylammonium bromide (DDAB) and trehalose 6,6'-dibehenate (TDB) are strong liposomal adjuvants. As with many liposome formulations, within the laboratory DDAB:TDB is commonly prepared by the thin-film method, which is difficult to scale-up and gives high batch-to-batch variability. In contrast, controllable technologies such as microfluidics offer robust, continuous, and scale-independent production. Therefore, within this study, we have developed a microfluidic production method for cationic liposomal adjuvants that is scale-independent and produces liposomal adjuvants with analogous biodistribution and immunogenicity compared to those produced by the small-scale lipid hydration method. Subsequently, we further developed the DDAB:TDB adjuvant system to include a lymphatic targeting strategy using microfluidics. By exploiting a biotin-avidin complexation strategy, we were able to manipulate the pharmacokinetic profile and enhance targeting and retention of DDAB:TDB and antigen within the lymph nodes. Interestingly, redirecting these cationic liposomal adjuvants did not translate into notably improved vaccine efficacy.
由二甲基双十八烷基溴化铵 (DDAB) 和海藻糖 6,6'-二硬脂酸酯 (TDB) 制备的阳离子脂质体是强有力的脂质体佐剂。与许多脂质体配方一样，在实验室中，DDAB:TDB 通常通过薄膜法制备，这种方法难以放大规模，批次间变异性高。相比之下，微流控等可控技术可提供稳健、连续且与规模无关的生产。因此，在这项研究中，我们开发了一种与规模无关的阳离子脂质体佐剂的微流控生产方法，该方法生产的脂质体佐剂与小规模脂质水合方法生产的脂质体佐剂具有类似的生物分布和免疫原性。随后，我们进一步开发了 DDAB:TDB 佐剂系统，通过微流控技术包含一种淋巴靶向策略。通过利用生物素-亲和素复合物策略，我们能够操纵药代动力学特征，并增强 DDAB:TDB 和抗原在淋巴结中的靶向和保留。有趣的是，将这些阳离子脂质体佐剂重新定向并没有转化为显著提高疫苗效力。
