Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China.
J Control Release. 2015 Jul 10;209:101-9. doi: 10.1016/j.jconrel.2015.04.029. Epub 2015 Apr 24.
Collagen, a primary component of the extracellular matrix (ECM), is highly expressed in a variety of cancers and influences the tumor microenvironment by increasing the recruitment of macrophages and endothelial cells. Therefore, collagen is a highly promising target for cancer therapy. The collagen-binding domain (CBD) can dynamically bind to collagen and achieve the sustained release of CBD-fused protein in the collagen network. Here, we developed a collagen-binding epidermal growth factor receptor (EGFR) antibody fragment for targeting the collagen-rich ECM in tumors. The single chain fragment variable (scFv) of cetuximab was fused to CBD (CBD-scFv) and expressed in Pichia pastoris. CBD-scFv preserved the antigen binding domain and anti-tumor activity of cetuximab in vitro. Moreover, CBD-scFv displayed a collagen binding ability due to the function of CBD. In vivo experiments revealed that CBD-scFv bound to collagen and achieved sustained release in tumors. Furthermore, CBD-scFv significantly suppressed the growth of tumors in A431 xenografts. Therefore, CBD-scFv had a potential therapeutic value for the collagen-rich carcinomas. The specific target and sustained release of CBD-scFv in tumors could be a new approach for targeted drug delivery in cancer therapy.
胶原蛋白是细胞外基质（ECM）的主要成分之一，在多种癌症中高度表达，并通过增加巨噬细胞和内皮细胞的募集来影响肿瘤微环境。因此，胶原蛋白是癌症治疗的一个极具前景的靶点。胶原结合域（CBD）可以动态结合胶原蛋白，并在胶原蛋白网络中实现 CBD 融合蛋白的持续释放。在这里，我们开发了一种胶原结合型表皮生长因子受体（EGFR）抗体片段，用于靶向肿瘤中富含胶原蛋白的细胞外基质。西妥昔单抗的单链片段可变区（scFv）与 CBD 融合（CBD-scFv）并在毕赤酵母中表达。CBD-scFv 在体外保留了西妥昔单抗的抗原结合结构域和抗肿瘤活性。此外，由于 CBD 的功能，CBD-scFv 显示出胶原结合能力。体内实验表明，CBD-scFv 与胶原蛋白结合，并在肿瘤中实现持续释放。此外，CBD-scFv 显著抑制了 A431 异种移植瘤的生长。因此，CBD-scFv 对富含胶原蛋白的癌具有潜在的治疗价值。CBD-scFv 在肿瘤中的特异性靶向和持续释放可能为癌症治疗中的靶向药物输送提供一种新方法。
