Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA.
Laboratory of Drug and Gene Delivery System, Faculty of Pharma-Sciences, Teikyo University, Tokyo, Japan.
Nanomedicine. 2017 Nov;13(8):2565-2574. doi: 10.1016/j.nano.2017.07.005. Epub 2017 Jul 25.
Liposome-based drug formulations represent an exciting avenue of research as they increase efficacy to toxicity ratios. Current formulations rely on passive accumulation to the disease site where drug is taken up by the cells. Ligand mediated targeting increases the net accumulation of liposomes, however, an unexplored benefit is to potentially refine pharmacodynamics (PD) of a drug specifically to different cell types within diseased tissue. As a model system, we engineered cardiomyocyte- (I-1) and endothelial-targeted (B-40) liposomes to carry a VEGFR2 inhibitor (PTK787), and examined the effect of cell type-specific delivery on both pharmacokinetics (PK) and PD. Neovascularization in post-myocardial infarction was significantly reduced by B-40 liposomes loaded with PTK787 as compared to animals injected with I-1 liposomes, and profoundly more as compared to free PTK787. This study thus shows that the intraorgan targeting of drugs through cell type-specific delivery holds substantial promise towards lowering the minimal efficacious dose administered systemically.
基于脂质体的药物制剂代表了一个令人兴奋的研究方向，因为它们可以提高疗效与毒性的比值。目前的制剂依赖于被动积累到疾病部位，药物被细胞摄取。配体介导的靶向作用增加了脂质体的净积累，然而，一个尚未被探索的好处是有可能使药物的药效动力学（PD）专门针对病变组织内的不同细胞类型进行精细调整。作为一个模型系统，我们设计了靶向心肌细胞（I-1）和内皮细胞（B-40）的脂质体来携带 VEGFR2 抑制剂（PTK787），并研究了细胞类型特异性递送对药代动力学（PK）和药效学（PD）的影响。与注射 I-1 脂质体的动物相比，载有 PTK787 的 B-40 脂质体显著减少了心肌梗死后的新生血管形成，与游离 PTK787 相比则更为显著。因此，这项研究表明，通过细胞类型特异性递送实现药物的器官内靶向具有很大的潜力，可以降低系统给予的最小有效剂量。
