Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, People's Republic of China.
University of Chinese Academy of Sciences , Beijing 100039, People's Republic of China.
Nano Lett. 2017 Jul 12;17(7):4526-4533. doi: 10.1021/acs.nanolett.7b02129. Epub 2017 Jun 26.
Targeted delivery of chemotherapeutic drugs to the desired lesion sites is the main objective in malignancy treatment, especially in highly metastatic malignancies. However, extensive studies around the world on traditional targeting strategies of recognizing either overexpressed receptors or microenvironments in tumors show great limitations, owing to the off-target effect and tumor homogeneity. Integration of both receptor-mediated targeting (RMT) and environment-mediated targeting (EMT) enhances the tumor accumulation and subsequent cell uptake at the same time, which may avoid these limitations. Herein, a dual targeting nanogel of PMNG engineered with both phenylboronic acid (PBA) and morpholine (MP) was reported for not only RMT via specific recognition of sialyl (SA) epitopes but also EMT toward extracellular acidity. Further engineering the nanoparticles via loading doxorubicin (DOX) brought a novel dual targeting system, that is, PMNG/DOX. PMNG/DOX demonstrated a greater targeting effect to both primary and metastatic B16F10 melanoma than the single PBA-modified nanogel (PNG) with only RMT in vitro and in vivo. Moreover, PMNG/DOX was also proved to be highly potent on inhibiting primary tumor growth as well as tumor metastasis on B16F10 melanoma-grafted mouse model. The results demonstrated the dual targeting design as a translational approach for drug delivery to highly metastatic tumor.
将化疗药物靶向递送到所需的病变部位是恶性肿瘤治疗的主要目标，特别是在高度转移性恶性肿瘤中。然而，世界各地对传统靶向策略的广泛研究，无论是识别肿瘤中过度表达的受体还是微环境，都显示出很大的局限性，这是由于脱靶效应和肿瘤同质性。将受体介导的靶向（RMT）和环境介导的靶向（EMT）相结合，同时增强了肿瘤的积累和随后的细胞摄取，这可能避免了这些局限性。本文报道了一种同时具有苯硼酸（PBA）和吗啉（MP）的 PMNG 双靶向纳米凝胶，不仅可以通过特异性识别唾液酸（SA）表位进行 RMT，还可以通过细胞外酸度进行 EMT。通过进一步将纳米粒子工程化装载多柔比星（DOX），构建了一种新型的双重靶向系统，即 PMNG/DOX。PMNG/DOX 与仅具有 RMT 的单 PBA 修饰纳米凝胶（PNG）相比，在体外和体内均对原发性和转移性 B16F10 黑色素瘤具有更大的靶向作用。此外，PMNG/DOX 还被证明在抑制 B16F10 黑色素瘤移植小鼠模型中的原发性肿瘤生长和肿瘤转移方面非常有效。结果表明，双重靶向设计是一种将药物递送到高度转移性肿瘤的转化方法。
