Lin Kevin Y, Lo Justin H, Consul Nikita, Kwong Gabriel A, Bhatia Sangeeta N
Department of Chemical Engineering and ‡Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
ACS Nano. 2014 Sep 23;8(9):8776-85. doi: 10.1021/nn501129q. Epub 2014 Aug 19.
Antithrombotic therapy is a critical portion of the treatment regime for a number of life-threatening conditions, including cardiovascular disease, stroke, and cancer; yet, proper clinical management of anticoagulation remains a challenge because existing agents increase the propensity for bleeding in patients. Here, we describe the development of a bioresponsive peptide-polysaccharide nanocomplex that utilizes a negative feedback mechanism to self-titrate the release of anticoagulant in response to varying levels of coagulation activity. This nanoscale self-titrating activatable therapeutic, or nanoSTAT, consists of a cationic thrombin-cleavable peptide and heparin, an anionic polysaccharide and widely used clinical anticoagulant. Under nonthrombotic conditions, nanoSTATs circulate inactively, neither releasing anticoagulant nor significantly prolonging bleeding time. However, in response to life-threatening pulmonary embolism, nanoSTATs locally release their drug payload and prevent thrombosis. This autonomous negative feedback regulator may improve antithrombotic therapy by increasing the therapeutic window and decreasing the bleeding risk of anticoagulants.
抗血栓治疗是多种危及生命疾病（包括心血管疾病、中风和癌症）治疗方案的关键部分；然而，由于现有药物会增加患者出血的倾向，抗凝的恰当临床管理仍然是一项挑战。在此，我们描述了一种生物响应性肽 - 多糖纳米复合物的研发，该复合物利用负反馈机制根据不同的凝血活性水平自滴定抗凝剂的释放。这种纳米级自滴定可激活治疗剂，即纳米STAT，由一种可被凝血酶裂解的阳离子肽和肝素（一种阴离子多糖及广泛使用的临床抗凝剂）组成。在非血栓形成条件下，纳米STAT无活性地循环，既不释放抗凝剂也不会显著延长出血时间。然而，在应对危及生命的肺栓塞时，纳米STAT会在局部释放其药物载荷并预防血栓形成。这种自主负反馈调节器可通过扩大治疗窗口和降低抗凝剂的出血风险来改善抗血栓治疗。
