Phenylboronic acid-functionalized co-delivery micelles with synergistic effect and down-regulation of HIF-1alpha to overcome multidrug resistance

Multidrug resistance and metastasis of tumors are major obstacles in clinical chemotherapy. Enlightened by the characteristics of tumor cells, phenylboronic acid was installed in co-delivery micelles for selectively recognizing sialic acid on tumor cell membranes, which could not only enhance cellular uptake but also reduce drug efflux by drug-resistant MCF-7/ADR cells. Drug ratio was screened for exerting the maximized synergistic effect. The prepared co-delivery micelles with a hydrodynamic diameter of 98.84 nm exhibited lysosomal microenvironment-triggered drug release. The fabricated micelles released approximately 75% of camptothecin and doxorubicin under a simulated lysosomal condition, while the values of cumulative drug release of camptothecin and doxorubicin were both below 15% under a simulated plasma condition even after 3 days of incubation. The endocytosis of co-delivery micelles against drug-resistant MCF-7/ADR cells was 4.2 times higher than that of the physical mixture of free drugs, while the drug efflux of co-delivery micelles was 7 times lower than that of the mixture of free drugs. In addition, isobologram analysis showed co-delivery micelles exhibited enhanced synergistic antiproliferative effect on MCF-7/ADR cells. Moreover, wound healing and transwell assays showed that co-delivery micelles could impede cell migration and cell invasion even in the case of low drug concentration, which is possibly due to the downregulation of hypoxia inducing factor 1 alpha, matrix metalloproteinase-2, and matrix metalloproteinase-9. In summary, the co-delivery micelles could be beneficial for overcoming multidrug resistance and inhibiting metastasis.