Greene Michelle K, Nogueira João C F, Tracey Shannon R, Richards Daniel A, McDaid William J, Burrows James F, Campbell Katrina, Longley Daniel B, Chudasama Vijay, Scott Christopher J
The Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
Department of Chemistry, University College London, London, UK.
Nanoscale. 2020 Jun 4;12(21):11647-11658. doi: 10.1039/d0nr02387f.
Antibody-targeted nanoparticles have shown exceptional promise as delivery vehicles for anticancer drugs, although manufacturability challenges have hampered clinical progress. These include the potential for uncontrolled and random antibody conjugation, resulting in masked or inactive paratopes and unwanted Fc domain interactions. To circumvent these issues, we show that the interchain disulfide of cetuximab F(ab) may be selectively re-bridged with a strained alkyne handle, to permit 'click' coupling to azide-capped nanoparticles in a highly uniform and oriented manner. When compared to conventional carbodiimide chemistry, this conjugation approach leads to the generation of nanoparticles with a higher surface loading of cetuximab F(ab) and with markedly improved ability to bind to the target epidermal growth factor receptor. Moreover, we show that entrapment of a camptothecin payload within these nanoparticles can enhance drug targeting to antigen-expressing pancreatic cancer cells, resulting in superior cytotoxicity versus the conventional nanoformulation. Collectively, this work highlights the critical need to develop refined methods for the construction of targeted nanoparticles that will accelerate their clinical translation through improved performance and manufacturability.
抗体靶向纳米颗粒作为抗癌药物的递送载体已展现出非凡的前景，尽管可制造性方面的挑战阻碍了其临床进展。这些挑战包括抗体偶联可能不受控制且随机，导致抗原结合位点被掩盖或失活，以及出现不必要的Fc结构域相互作用。为规避这些问题，我们证明西妥昔单抗F(ab)的链间二硫键可与带有张力炔基的分子选择性地重新桥连，从而允许以高度均匀且定向的方式与叠氮基封端的纳米颗粒进行“点击”偶联。与传统的碳二亚胺化学方法相比，这种偶联方法可生成表面负载更高的西妥昔单抗F(ab)纳米颗粒，且其结合靶表皮生长因子受体的能力显著提高。此外，我们还表明，将喜树碱负载于这些纳米颗粒内可增强药物对表达抗原的胰腺癌细胞的靶向作用，与传统纳米制剂相比，其细胞毒性更强。总体而言，这项工作凸显了开发精细方法构建靶向纳米颗粒的迫切需求，这将通过提高性能和可制造性来加速其临床转化。
