Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
J Control Release. 2013 Jan 28;165(2):110-8. doi: 10.1016/j.jconrel.2012.11.007. Epub 2012 Nov 16.
A novel, EGFR-targeted nanomedicine has been developed in the current study. Glutaraldehyde crosslinked albumin nanoparticles with a size of approximately 100nm were loaded with the multikinase inhibitor 17864-L(x)-a platinum-bound sunitinib analogue-which couples the drug to methionine residues of albumin and is released in a reductive environment. Albumin nanoparticles were surface-coated with bifunctional polyethylene glycol 3500 (PEG) and a nanobody-the single variable domain of an antibody-(Ega1) against the epidermal growth factor receptor (EGFR). EGa1-PEG functionalized nanoparticles showed a 40-fold higher binding to EGFR-positive 14C squamous head and neck cancer cells in comparison to PEGylated nanoparticles. 17864-L(x) loaded EGa1-PEG nanoparticles were internalized by clathrin-mediated endocytosis and ultimately digested in lysosomes. The intracellular routing of EGa1 targeted nanoparticles leads to a successful release of the kinase inhibitor in the cell and inhibition of proliferation whereas the non-targeted formulations had no antiproliferative effects on 14C cells. The drug loaded targeted nanoparticles were as effective as the free drug in vitro. These results demonstrate that multikinase inhibitor loaded nanoparticles are interesting nanomedicines for the treatment of EGFR-positive cancers.
在本研究中开发了一种新型的、针对 EGFR 的纳米药物。用戊二醛交联白蛋白纳米粒，其粒径约为 100nm，负载多激酶抑制剂 17864-L(x)-一种与白蛋白甲硫氨酸残基结合的铂结合舒尼替尼类似物，在还原环境中释放。白蛋白纳米粒表面涂有双功能聚乙二醇 3500(PEG)和纳米抗体-针对表皮生长因子受体(EGFR)的抗体的单可变结构域-(Ega1)。与 PEG 化纳米粒相比，EGa1-PEG 功能化纳米粒对 EGFR 阳性的 14C 头颈部鳞状癌细胞的结合能力提高了 40 倍。17864-L(x)负载的 EGa1-PEG 纳米粒通过网格蛋白介导的内吞作用被内化，并最终在溶酶体中被消化。EGa1 靶向纳米粒的细胞内途径导致激酶抑制剂在细胞内成功释放并抑制增殖，而未靶向的制剂对 14C 细胞没有抗增殖作用。载药靶向纳米粒与游离药物在体外同样有效。这些结果表明，负载多激酶抑制剂的纳米粒是治疗 EGFR 阳性癌症的有前途的纳米药物。
