Tumor-targeted therapy based on nanoparticles is a popular research direction in the biomedical field. After decades of research and development, both the passive targeting ability of the inherent properties of NPs and the active targeting based on ligand receptor interaction have gained deeper understanding. Unfortunately, most targeted delivery strategies are still in the preclinical trial stage, so it is necessary to further study the biological fate of particles in vivo and the interaction mechanism with tumors. This article reviews different targeted delivery strategies based on NPs, and focuses on the physical and chemical properties of NPs (size, morphology, surface and intrinsic properties), ligands (binding number/force, activity and species) and receptors (endocytosis, distribution and recycling) and other factors that affect particle targeting. The limitations and solutions of these factors are further discussed, and a variety of new targeting schemes are introduced, hoping to provide guidance for future targeting design and achieve the purpose of rapid transformation of targeted particles into clinical application.

Pyrotinib (PYR) is a pan-HER kinase inhibitor that inhibits signaling via the RAS/RAF/MEK/MAPK and PI3K/AKT pathways. In this study, we aimed to investigate the antitumor efficacy of pyrotinib combined with adriamycin (ADM) and explore its mechanisms on HER2⁺ breast cancer. We investigated the effects of PYR and ADM on breast cancer in vitro and in vivo. MTT assay, Wound-healing, and transwell invasion assays were used to determine the effects of PYR, ADM or PYR combined with ADM on cell proliferation, migration, and invasion of SK-BR-3 and AU565 cells in vitro. Cell apoptosis and cycle were detected through flow cytometry. In vivo, xenograft models were established to test the effect of PYR, ADM, or the combined therapy on the nude mice. Western blotting was performed to assess the expression of Akt, p-Akt, p-65, p-p65, and FOXC1. The results indicated that PYR and ADM significantly inhibited the proliferation, migration, and invasion of SK-BR-3 and AU565 cells, and the inhibitory rate of the combination group was higher than each monotherapy group. PYR induced G1 phase cell-cycle arrest, while ADM induced G2 phase arrest, while the combination group induced G2 phase arrest. The combined treatment showed synergistic anticancer activities. Moreover, PYR significantly downregulated the expression of p-Akt, p-p65, and FOXC1. In clinical settings, PYR also exerts satisfactory efficacy against breast cancer. These findings suggest that the combination of PYR and ADM shows synergistic effects both in vitro and in vivo. PYR suppresses the proliferation, migration, and invasion of breast cancers through down-regulation of the Akt/p65/FOXC1 pathway.

Background

Apatinib is a new generation of small molecule tyrosine kinase inhibitor, which can highly selectively inhibit phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR-2). This study aimed to investigate the synergistic effects of apatinib and paclitaxel (PTX) on triple-negative breast cancer (TNBC) in vivo and in vitro, and to explore the molecular mechanism of the PI3K/p65/Bcl-xl pathway.

Methods

In vitro, 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) method, flow cytometry (FCM), wound healing assay, and transwell matrix assay were conducted to measure the effects of apatinib and PTX on cell viability, apoptosis, migration, and invasion in TNBC cell line MDA-MB-468. Western blot (WB) was conducted to detect protein expression levels of PI3K, p65, and Bcl-xl after the application of apatinib and PTX. In vivo, MDA-MB-468 tumor-bearing nude mice were treated with apatinib and PTX, and tumor growth was observed.

Results

In vitro, apatinib and PTX could synergistically suppress the cell viability, the combined group had the most obvious effect. Apatinib and PTX could promote apoptosis and suppress migration and invasion of TNBC cells. Apatinib could reduce the expression of p-PI3K, p65, and Bcl-xl proteins (P<0.05). In vivo, apatinib and PTX could inhibit tumor size and weight of model mice, and the combined agents had a more significant effect.

Conclusions

Apatinib could enhance the anti-tumor effect of PTX on TNBC cells through the PI3K/p65/Bcl-xl molecular pathway, and apatinib combined with PTX might be a promising option for TNBC treatment.