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

Abstract

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.