Triple negative breast cancer (TNBC), which has poor prognosis, easily develops drug resistance and metastasizes. In general, those TNBC characteristics are related to a high activation of the epithelial-mesenchymal transition (EMT) pathway, which is inhibited by shikonin (SKN). Therefore, the synergistic therapy of SKN and doxorubicin (DOX) will increase anti-tumor efficacy and reduce metastasis. In this study, we prepared the folic acid-linked PEG nanomicelle (NM) grafted with the DOX (denoted as FPD) to load the SKN. We prepared the SKN@FPD NM according to the effective ratio of dual drugs, where the drug loadings of DOX and SKN were 8.86 ± 0.21% and 9.43 ± 0.13%, with 121.8 ± 1.1 nm of its hydrodynamic dimension and 6.33 ± 0.16 mV of zeta potential, respectively. The nanomaterials significantly slowed down the release of DOX and SKN over 48 h, leading to the release of pH-responsive drugs. Meanwhile, the prepared NM inhibited the activity of MBA-MD-231 cells in vitro. Further in vitro study revealed that the SKN@FPD NM increased the DOX uptake and significantly reduced the metastasis of MBA-MD-231 cells. Overall, these active-targeting NMs improved the tumor-targeting of small molecular drugs and effectively treated TNBC.

To discuss the effect of hydrophobic groups of a polymer on the structural properties and function of polymer nanoparticles (NPs), we grafted chenodeoxycholic acid (CDCA) with pullulan (PU) to form hydrophobically modified PU (PUC). Three PUC polymers, namely, PUC-1, PUC-2, and PUC-3, with different degrees of substitution were designed by changing the feed ratio of CDCA and PU. ¹H-NMR spectra showed that the PUC polymer was successfully synthesized, and the degrees of hydrophobic substitution for PUC-1, PUC-2, and PUC-3 were calculated to be 10.66%, 13.92%, and 16.94%, respectively. The PUC NPs were prepared by the dialysis method and were shown to be uniformly spherical by transmission electron microscopy (TEM). The average sizes were about (220±10) nm, (203±7) nm, and (163±6) nm under dynamic light scattering (DLS) for PUC-1 NPs, PUC-2 NPs, and PUC-3 NPs, respectively. Drug release experiments showed that the three PUC/DOX NPs exhibited good sustained release. At 48 h, the IC₅₀ of doxorubicin in inhibiting colon cancer HCT116 cells was 0.0904 μg/mL. A cell study showed that PUC-3/DOX NPs had the highest uptake efficiency by HCT116 cells with the most cytotoxicity and inhibited the migration of HCT116 cells with the highest efficiency. The structural properties and function of polymer NPs were closely related to the hydrophobic groups in the polymer, and NPs with higher hydrophobicity showed a smaller size, higher drug capacity, and greater cell efficiency.