Dreaden Erik C, Morton Stephen W, Shopsowitz Kevin E, Choi Jae-Hyeok, Deng Zhou J, Cho Nam-Joon, Hammond Paula T
Koch Institute for Integrative Cancer Research, ‡Department of Chemical Engineering, and §Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology , 500 Main Street, Cambridge, Massachusetts 02142, United States.
ACS Nano. 2014 Aug 26;8(8):8374-82. doi: 10.1021/nn502861t. Epub 2014 Aug 11.
Active targeting of nanoscale drug carriers can improve tumor-specific delivery; however, cellular heterogeneity both within and among tumor sites is a fundamental barrier to their success. Here, we describe a tumor microenvironment-responsive layer-by-layer (LbL) polymer drug carrier that actively targets tumors based on two independent mechanisms: pH-dependent cellular uptake at hypoxic tumor pH and hyaluronan-directed targeting of cell-surface CD44 receptor, a well-characterized biomarker for breast and ovarian cancer stem cells. Hypoxic pH-induced structural reorganization of hyaluronan-LbL nanoparticles was a direct result of the nature of the LbL electrostatic complex, and led to targeted cellular delivery in vitro and in vivo, with effective tumor penetration and uptake. The nanoscale drug carriers selectively bound CD44 and diminished cancer cell migration in vitro, while co-localizing with the CD44 receptor in vivo. Multimodal targeting of LbL nanoparticles is a powerful strategy for tumor-specific cancer diagnostics and therapy that can be accomplished using a single bilayer of polyamine and hyaluronan that, when assembled, produce a dynamic and responsive cell-particle interface.
纳米级药物载体的主动靶向能够改善肿瘤特异性递送；然而，肿瘤部位内部和之间的细胞异质性是其成功的一个基本障碍。在此，我们描述了一种肿瘤微环境响应性层层（LbL）聚合物药物载体，它基于两种独立机制主动靶向肿瘤：在低氧肿瘤pH值下依赖pH的细胞摄取以及透明质酸对细胞表面CD44受体的靶向作用，CD44受体是乳腺癌和卵巢癌干细胞的一种特征明确的生物标志物。低氧pH诱导的透明质酸-LbL纳米颗粒的结构重组是LbL静电复合物性质的直接结果，并导致了体外和体内的靶向细胞递送，具有有效的肿瘤渗透和摄取。纳米级药物载体在体外选择性结合CD44并减少癌细胞迁移，同时在体内与CD44受体共定位。LbL纳米颗粒的多模态靶向是一种用于肿瘤特异性癌症诊断和治疗的强大策略，可通过使用单层聚胺和透明质酸来实现，当组装时，它们会产生一个动态且响应性的细胞-颗粒界面。
