Hu Yun, Hoerle Reece, Ehrich Marion, Zhang Chenming
Department of Biological Systems Engineering, Virginia Tech, Blacksburg, VA 24061, USA.
Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, VA 24061, USA.
Acta Biomater. 2015 Dec;28:149-159. doi: 10.1016/j.actbio.2015.09.032. Epub 2015 Sep 30.
Lipid-polymer hybrid nanoparticles (NPs), consisting of a polymeric core and a lipid shell, have been intensively examined as delivery systems for cancer drugs, imaging agents, and vaccines. For applications in vaccine particularly, the hybrid NPs need to be able to protect the enclosed antigens during circulation, easily be up-taken by dendritic cells, and possess good stability for prolonged storage. However, the influence of lipid composition on the performance of hybrid NPs has not been well studied. In this study, we demonstrate that higher concentrations of cholesterol in the lipid layer enable slower and more controlled antigen release from lipid-poly(lactide-co-glycolide) acid (lipid-PLGA) NPs in human serum and phosphate buffered saline (PBS). Higher concentrations of cholesterol also promoted in vitro cellular uptake of hybrid NPs, improved the stability of the lipid layer, and protected the integrity of the hybrid structure during long-term storage. However, stabilized hybrid structures of high cholesterol content tended to fuse with each other during storage, resulting in significant size increase and lowered cellular uptake. Additional experiments demonstrated that PEGylation of NPs could effectively minimize fusion-caused size increase after long term storage, leading to improved cellular uptake, although excessive PEGylation will not be beneficial and led to reduced improvement.
This paper reports the engineering of the lipid layer that encloses a polymeric nanoparticle, which can be used as a carrier for drug and vaccine molecules for targeted delivery. We demonstrated that the concentration of cholesterol is critical for the stability and uptake of the hybrid nanoparticles by dendritic cells, a targeted cell for the delivery of immune effector molecules. However, we found that hybrid nanoparticles with high cholesterol concentration tend to fuse during storage resulting in larger particles with decreased cellular uptake. This problem is subsequently solved by PEGylating the hybrid nanoparticles. With increased research and clinical applications of lipid-polymer hybrid nanoparticles in drug and vaccine delivery, this work will significantly impact the design of the hybrid nanoparticles for minimized molecule release during circulation and increased bioavailability of the target molecules.
脂质-聚合物杂化纳米颗粒（NPs）由聚合物核心和脂质外壳组成，作为癌症药物、成像剂和疫苗的递送系统已得到深入研究。特别是在疫苗应用中，杂化纳米颗粒需要能够在循环过程中保护包裹的抗原，易于被树突状细胞摄取，并具有良好的稳定性以进行长期储存。然而，脂质组成对杂化纳米颗粒性能的影响尚未得到充分研究。在本研究中，我们证明脂质层中较高浓度的胆固醇能够使脂质-聚（丙交酯-共-乙交酯）酸（脂质-PLGA）纳米颗粒在人血清和磷酸盐缓冲盐水（PBS）中更缓慢、更可控地释放抗原。较高浓度的胆固醇还促进了杂化纳米颗粒的体外细胞摄取，提高了脂质层的稳定性，并在长期储存过程中保护了杂化结构的完整性。然而，高胆固醇含量的稳定杂化结构在储存过程中往往会相互融合，导致尺寸显著增加并降低细胞摄取。额外的实验表明，纳米颗粒的聚乙二醇化可以有效最小化长期储存后融合引起的尺寸增加，从而提高细胞摄取，尽管过度聚乙二醇化并无益处且会导致改善效果降低。
本文报道了包裹聚合物纳米颗粒的脂质层的工程设计，该纳米颗粒可作为药物和疫苗分子靶向递送的载体。我们证明胆固醇浓度对于树突状细胞（免疫效应分子递送的靶细胞）对杂化纳米颗粒的稳定性和摄取至关重要。然而，我们发现高胆固醇浓度的杂化纳米颗粒在储存过程中容易融合，导致颗粒变大且细胞摄取减少。随后通过对杂化纳米颗粒进行聚乙二醇化解决了这个问题。随着脂质-聚合物杂化纳米颗粒在药物和疫苗递送中的研究和临床应用不断增加，这项工作将对杂化纳米颗粒的设计产生重大影响，以在循环过程中最小化分子释放并提高靶分子的生物利用度。
