Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, United States; KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon, 34141, South Korea.
Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road, Boston, MA, 02115, United States.
Biomaterials. 2017 Apr;123:118-126. doi: 10.1016/j.biomaterials.2017.01.040. Epub 2017 Jan 31.
Although PEGylated liposomes (PEG-LS) have been intensively studied as drug-delivery vehicles, the rigidity and the hydrophilic PEG corona of liposomal membranes often limits cellular uptake, resulting in insufficient drug delivery to target cells. Thus, it is necessary to develop a new type of lipid-based self-assembled nanoparticles capable of enhanced cellular uptake, tissue penetration, and drug release than conventional PEGylated liposomes. Herein, we describe a simple modification of bicellar formulation in which the addition of a PEGylated phospholipid produced a dramatic physicochemical change in morphology, i.e., the disc-shaped bicelle became a uniformly distributed ultra-small (∼12 nm) spherical micelle. The transformed lipid-based nanoparticles, which we termed hyper-cell-permeable micelles (HCPMi), demonstrated not only prolonged stability in serum but also superior cellular and tumoral uptake compared to a conventional PEGylated liposomal system (PEG-LS). In addition, HCPMi showed rapid cellular uptake and subsequent cargo release into the cytoplasm of cancer cells. Cells treated with HCPMi loaded with docetaxel (DTX) had an IC value of 0.16 μM, compared with 0.78 μM with PEG-LS loaded with DTX, a nearly five-fold decrease in cell viability, indicating excellent efficiency in HCPMi uptake and release. In vivo tumor imaging analysis indicated that HCPMi penetrated deep into the tumor core and achieved greater uptake than PEG-LS. Results of HCPMi (DTX) treatment of allograft and xenograft mice in vivo showed high tumoral uptake and appreciable tumor retardation, with ∼70% tumor weight reduction in the SCC-7 allograft model. Taken together, these findings indicate that HCPMi could be developed further as a highly competent lipid-based drug-delivery system.
虽然聚乙二醇化脂质体（PEG-LS）已被广泛研究作为药物递送载体，但脂质体膜的刚性和亲水性 PEG 冠常常限制细胞摄取，导致药物向靶细胞的递送不足。因此，有必要开发一种新型的基于脂质的自组装纳米颗粒，其具有比传统 PEG-LS 更高的细胞摄取、组织穿透和药物释放能力。在这里，我们描述了一种简单的双分子层制剂的修饰方法，即在其中添加 PEG 化磷脂会导致形态发生剧烈的物理化学变化，即盘状双分子层变成均匀分布的超小（约 12nm）球形胶束。我们将这种转化后的基于脂质的纳米颗粒称为超细胞渗透性胶束（HCPMi），与传统的 PEG 化脂质体系统（PEG-LS）相比，HCPMi 不仅在血清中表现出更长的稳定性，而且还具有更好的细胞和肿瘤摄取能力。此外，HCPMi 显示出快速的细胞摄取和随后的货物释放到癌细胞的细胞质中。用载有多西紫杉醇（DTX）的 HCPMi 处理的细胞的 IC 值为 0.16μM，而载有 DTX 的 PEG-LS 的 IC 值为 0.78μM，细胞活力降低近五倍，表明 HCPMi 的摄取和释放效率非常高。体内肿瘤成像分析表明，HCPMi 能够深入肿瘤核心并实现比 PEG-LS 更高的摄取。体内异体移植和异种移植小鼠的 HCPMi（DTX）治疗结果表明，HCPMi 具有很高的肿瘤摄取能力和明显的肿瘤抑制作用，在 SCC-7 异体移植模型中肿瘤重量减轻约 70%。综上所述，这些发现表明 HCPMi 可以进一步开发成为一种高效的基于脂质的药物递送系统。
