Peptide-Functionalized Nanoinhibitor Restrains Brain Tumor Growth by Abrogating Mesenchymal-Epithelial Transition Factor (MET) Signaling

Abstract

Malignant gliomas are the most common primary brain tumors and are associated with aggressive growth, high morbidity, and mortality. Aberrant mesenchymal-epithelial transition factor (MET) activation occurs in approximately 30% of glioma patients and correlates with poor prognosis, elevated invasion, and increased drug resistance. Therefore, MET has emerged as an attractive target for glioma therapy. In this study, we developed a novel nanoinhibitor by conjugating MET-targeting cMBP peptides on the G4 dendrimer. Compared to the binding affinity of the free peptide ( K = 3.96 × 10 M), the binding affinity of the nanoinhibitor to MET increased 3 orders of magnitude to 1.32 × 10 M. This nanoinhibitor efficiently reduced the proliferation and invasion of human glioblastoma U87MG cells in vitro by blocking MET signaling with remarkably attenuated levels of phosphorylated MET ( pMET) and its downstream signaling proteins, such as pAKT and pERK1/2. Although no obvious therapeutic effect was observed after treatment with free cBMP peptide, in vivo T2-weighted magnetic resonance imaging (MRI) showed a significant delay in tumor growth after intravenous injection of the nanoinhibitor. The medium survival in mouse models was extended by 59%, which is similar to the effects of PF-04217903, a small molecule MET inhibitor currently in clinical trials. Immunoblotting studies of tumor homogenate verified that the nanoinhibitor restrained glioma growth by blocking MET downstream signaling. pMET and its downstream proteins pAKT and pERK1/2, which are involved in the survival and invasion of cancer cells, decreased in the nanoinhibitor-treated group by 44.2%, 62.2%, and 32.3%, respectively, compared with those in the control group. In summary, we developed a peptide-functionalized MET nanoinhibitor that showed extremely high binding affinity to MET and effectively inhibited glioma growth by blocking MET downstream signaling. To the best of our knowledge, this is the first report of therapeutic inhibition of glioma growth by blocking MET signaling with a novel nanoinhibitor. Compared to antibodies and chemical inhibitors in clinical trials, the nanoinhibitor blocks MET signaling and provides a new approach for the treatment of glioma with the advantages of high efficiency, affordability, and, most importantly, potentially reduced drug resistance.

Dual functionalized brain-targeting nanoinhibitors restrain temozolomide-resistant glioma via attenuating EGFR and MET signaling pathways

“…Toward the development of an effective simultaneous inhibition strategy of EGFR and MET activation in TMZ-resistant glioma, we looked for a rational design of nanoinhibitor simultaneously targeting EGFR and MET, and developed a nanoinhibitor, BIP-MPC-NP, which can simultaneously mitigate EGFR and MET activation by conjugating Inherbin3 26 (denoted as EGFR-binding peptide, EBP) and cMBP 28,36 (denoted as METbinding peptide, MBP) on the surface of NHS-PEG 8 -Mal modified MPC-NPs (Fig. 1b).…”

“…cMBP peptide targets ligand due to its high binding affinity to MET and application in tumor imaging 36 . Nanoinhibitors containing cMBP peptides conjugated on the G4 PEGylated dendrimer have been shown to efficiently reduce the proliferation and invasion of human glioblastoma cells by blocking MET signaling with remarkably attenuated levels of phosphorylated MET and its downstream signaling proteins, such as pAKT and pERK1/2 28 . However, with the presence of BBB, glioma patients hardly benefit from immunological therapy 30 .…”

“…Inherbin3 has exhibited the reduction of the EGFR signaling in tumor cells and the suppression of tumor growth in vivo via targeting EGFR and inhibits the EGFR phosphorylation 25,26 . cMBP, a MET targeting peptide which has been developed for tumor imaging and gene delivery 27 , has a therapeutic efficacy to block MET signaling and provides a potential approach for the treatment of glioma 28 . However, glioma patients hardly benefit from targeting therapy because of the presence of blood-brain-barrier (BBB), a tightly sealed filter formed by blood vessels that prevents unwanted biomolecules and drugs from accessing the brain tissue 29,30 .…”

<p>PAMAM Dendrimer Nanomolecules Utilized as Drug Delivery Systems for Potential Treatment of Glioblastoma: A Systematic Review</p>

“…76 Another example of such specific tumor-targeting dendrimer construct is that by Wu and colleagues (2018). 77 However, here the intention is not only for tumor-targeting but for suppression of specific tumor protein targets using the dendrimer conjugate as well. Specifically, they conjugated a MET-targeting peptide, cMBP, to G4 PAMAM dendrimers for targeting of U87MG cells in vitro.…”

Novel Peptide CM 7 Targeted c-Met with Antitumor Activity

“…The proportion of MET gene amplification or protein overexpression in Chinese patients with gastric cancer is about 6% and 13%, respectively [15]. Both HGF and its receptor, the tyrosine kinase c-Met, have proved to be a promising target for cancer therapy or diagnosis [16][17][18], but their interactions are complex and remain poorly understood, so they need to be further explored and studied. Currently, drugs targeting c-Met are mainly small-molecule drugs, which are highly toxic and have considerable side effects and production costs.…”