National Engineering Research Center of Industrial Crystallization Technology, State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University , Tianjin 300072, P. R. China.
CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST) No. 11 Beiyitiao, Zhongguancun, Beijing 100190, China.
ACS Nano. 2017 Apr 25;11(4):4086-4096. doi: 10.1021/acsnano.7b00781. Epub 2017 Mar 28.
Tumor metastasis is one of the big challenges in cancer treatment and is often associated with high patient mortality. Until now, there is an agreement that tumor invasion and metastasis are related to degradation of extracellular matrix (ECM) by enzymes. Inspired by the formation of natural ECM and the in situ self-assembly strategy developed in our group, herein, we in situ constructed an artificial extracellular matrix (AECM) based on transformable Laminin (LN)-mimic peptide 1 (BP-KLVFFK-GGDGR-YIGSR) for inhibition of tumor invasion and metastasis. The peptide 1 was composed of three modules including (i) the hydrophobic bis-pyrene (BP) unit for forming and tracing nanoparticles; (ii) the KLVFF peptide motif that was inclined to form and stabilize fibrous structures through intermolecular hydrogen bonds; and (iii) the Y-type RGD-YIGSR motif, derived from LN conserved sequence, served as ligands to bind cancer cell surfaces. The peptide 1 formed nanoparticles (1-NPs) by the rapid precipitation method, owing to strong hydrophobic interactions of BP. Upon intravenous injection, 1-NPs effectively accumulated in the tumor site due to the enhanced permeability and retention (EPR) effect and/or targeting capability of RGD-YIGSR. The accumulated 1-NPs simultaneously transformed into nanofibers (1-NFs) around the solid tumor and further entwined to form AECM upon binding to receptors on the tumor cell surfaces. The AECM stably existed in the primary tumor site over 72 h, which consequently resulted in efficiently inhibiting the lung metastasis in breast and melanoma tumor models. The inhibition rates in two tumor models were 82.3% and 50.0%, respectively. This in vivo self-assembly strategy could be widely utilized to design effective drug-free biomaterials for inhibiting the tumor invasion and metastasis.
肿瘤转移是癌症治疗中的一大挑战,通常与患者高死亡率有关。直到现在,人们普遍认为肿瘤的侵袭和转移与细胞外基质(ECM)的酶降解有关。受天然 ECM 形成的启发和我们小组开发的原位自组装策略的启发,我们在此基于可变形层粘连蛋白(LN)模拟肽 1(BP-KLVFFK-GGDGR-YIGSR)原位构建了一种人工细胞外基质(AECM),用于抑制肿瘤侵袭和转移。肽 1 由三个模块组成,包括 (i) 用于形成和追踪纳米颗粒的疏水双芘 (BP) 单元;(ii) 倾向于通过分子间氢键形成和稳定纤维结构的 KLVFF 肽基序;和 (iii) 源自 LN 保守序列的 Y 型 RGD-YIGSR 基序,作为与癌细胞表面结合的配体。肽 1 通过快速沉淀法形成纳米颗粒(1-NPs),这是由于 BP 的强疏水性相互作用。静脉注射后,由于 RGD-YIGSR 的增强渗透和保留(EPR)效应和/或靶向能力,1-NPs 有效地在肿瘤部位积聚。积聚的 1-NPs 同时在实体瘤周围转化为纳米纤维(1-NFs),并在与肿瘤细胞表面上的受体结合后进一步交织形成 AECM。AECM 在原发性肿瘤部位稳定存在超过 72 小时,从而有效地抑制了乳腺癌和黑色素瘤肿瘤模型中的肺转移。两种肿瘤模型的抑制率分别为 82.3%和 50.0%。这种体内自组装策略可广泛用于设计有效的无药物生物材料,以抑制肿瘤侵袭和转移。