Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Sci Transl Med. 2013 Nov 27;5(213):213ra167. doi: 10.1126/scitranslmed.3007049.
Nanoparticles are poised to have a tremendous impact on the treatment of many diseases, but their broad application is limited because currently they can only be administered by parenteral methods. Oral administration of nanoparticles is preferred but remains a challenge because transport across the intestinal epithelium is limited. We show that nanoparticles targeted to the neonatal Fc receptor (FcRn), which mediates the transport of immunoglobulin G antibodies across epithelial barriers, are efficiently transported across the intestinal epithelium using both in vitro and in vivo models. In mice, orally administered FcRn-targeted nanoparticles crossed the intestinal epithelium and reached systemic circulation with a mean absorption efficiency of 13.7%*hour compared with only 1.2%*hour for nontargeted nanoparticles. In addition, targeted nanoparticles containing insulin as a model nanoparticle-based therapy for diabetes were orally administered at a clinically relevant insulin dose of 1.1 U/kg and elicited a prolonged hypoglycemic response in wild-type mice. This effect was abolished in FcRn knockout mice, indicating that the enhanced nanoparticle transport was specifically due to FcRn. FcRn-targeted nanoparticles may have a major impact on the treatment of many diseases by enabling drugs currently limited by low bioavailability to be efficiently delivered though oral administration.
纳米颗粒有望对许多疾病的治疗产生巨大影响，但由于目前只能通过注射给药，其广泛应用受到限制。人们更倾向于口服纳米颗粒，但这仍然是一个挑战，因为它们在穿过肠上皮细胞时的传输效率有限。我们发现，靶向新生儿 Fc 受体（FcRn）的纳米颗粒可以有效地穿过肠上皮细胞，在体外和体内模型中均表现出良好的传输效果。在小鼠中，经口服给予的靶向 FcRn 的纳米颗粒穿过肠上皮细胞进入体循环，其平均吸收效率为 13.7%*小时，而非靶向纳米颗粒的吸收效率仅为 1.2%*小时。此外，含有胰岛素的靶向纳米颗粒作为治疗糖尿病的一种基于纳米颗粒的模型治疗药物，以临床相关的 1.1 U/kg 的胰岛素剂量进行口服给药，可在野生型小鼠中引发持久的降血糖反应。在 FcRn 敲除小鼠中，这种效果被消除了，这表明增强的纳米颗粒传输是由于 FcRn 特异性所致。通过使目前由于生物利用度低而受到限制的药物能够通过口服给予而得到有效递送，靶向 FcRn 的纳米颗粒可能会对许多疾病的治疗产生重大影响。
