Killing cancer cells or inhibiting cancer growth via blocking cancer signaling pathways has been an effective strategy for the development of anti-cancer drugs and the clinical treatment of cancer. The most often used therapeutic agents for blocking cancer signaling pathways mainly include antibodies, kinase inhibitors, nucleic acid aptamers and polypeptides. Different from this, Prof. Zhen Liu and his team have achieved on inhibiting cancer growth by using molecularly imprinted nanoparticles (MIPs).
Breast cancer is the most common tumor among women and has become the most frequent cause of cancer death in women in less developed regions and the second most common cause of death in more developed regions. Human epidermal growth factor receptor-2 (HER2) is a member of the epidermal growth factor receptor (EGFR) family with a molecular mass of 185 kDa and overexpressed in 20-30% of breast cancer. HER2+ breast cancer is usually associated with low therapeutic efficacy, high cancer metastasis and poor clinical outcomes. The EGFR family consists of four closely related receptors: HER1, HER2, HER3 and HER4. These receptors all include three domains: an extracellular domain which is similar among the four receptors, a short transmembrane region and an intracellular tyrosine kinase domain. The extracellular domain has four sub-domains (I–IV). HER2 plays a critical role in the survival, expansion and dissemination of breast cancer through a variety of intracellular signaling cascades. Heterodimerization of HER2 with other EGFRs such as HER1 or HER3 at the extracellular subdomain II of HER2 induces phosphorylation of highly conserved tyrosine residues within the intracellular tyrosine kinase domain and triggers several downstream signaling events such as the mitogen-activated protein kinase/extracellular-related kinase 1/2 (MAPK/ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways which regulate cell proliferation, survival, migration, angiogenesis, and metastasis. Among the heterodimers, the HER2/HER3 dimer is the most potent EGFR signaling dimer. Thus, preventing the dimerization of HER2 with other EGFRs, especially HER3, provides an effective treatment for HER2+ breast cancer.
The Liu group presents molecularly imprinted NPs that can block the HER2 signaling pathway and thereby inhibit the growth of HER2+ breast cancer. The principle of HER2 targeting and HER2+ cancer growth inhibition by the nanoMIP is illustrated in following Scheme. Different from above mentioned existing antibodies and inhibitors that are used to treat HER2+ breast cancer, which target HER2 through binding one of its domains or sub-domains, the imprinted NPs target HER2 via binding with its glycans. HER2 is a glycoprotein containing 7 N-glycosylation sites on its extracellular domain. All the N-glycans are enzymatically digested and purified as the templates for the imprinting. The nanoMIP was prepared using a state-of-the-art imprinting approach called boronate affinity controllable oriented surface imprinting. The obtained glycan-imprinted NPs can bind almost all HER2 glycans. Because of their bigger size as compared with the EGFR members, once binding with HER2, the glycan-imprinted NPs block the dimerization of HER2 with other EGFR members due to steric hindrance, resulting in blocking of the downstream signaling pathways and thereby inhibition of the growth of HER2+ breast cancer. In vitro experiments demonstrated that the nanoMIP specifically targeted HER2+ cells and inhibited cell proliferation at a 30% decrease. In vivo test indicated that the mean tumor volume of nanoMIP-treated group was only about a half of that of non-treated groups. Thus, this study not only provided a new access to the treatment of HER2+ breast cancer but also presented promising potential of nanoMIPs for cancer therapy.
Scheme 1. Illustration of the principle of blocking the HER2 signaling pathway via HER2 glycan-imprinted nanoparticles.
This paper was published on line in Angewandte Chemie International Edition on June 5(https://onlinelibrary.wiley.com/doi/10.1002/anie.201904860) as a Hot paper. Yueru Dong, Wei Li, Zikuan Gu, Rongrong Xing, Yanyan Ma, Qi Zhang, and Zhen Liu. Inhibition of HER2-Positive Breast Cancer Growth by Blocking the HER2 Signaling Pathway with HER2 Glycan-Imprinted Nanoparticles. Angew. Chem. Int. Ed., 2019, DOI: 10.1002/anie.201904860.