The New Targeted Nanoparticles: Tf-Peg-PLL-PLGA Combined with Daunorubicin Overcome Hypoxia Induced Drug Resistance of K562 Cells

Drug resistance is a major obstacle in cancer chemotherapy, especially in the treatment of leukemia. Hypoxia is an inseparable component of the solid tumor microenvironment as well as the bone marrow (BM) microenvironment. In this study, we investigated the effect of the new nanoparticles polyethylene glycol (PEG)-poly L-lysine (PLL)-poly lactic-co-glycolic acid (PLGA) (PEG-PLL-PLGA) modified by transferrin (Tf) combined with daunorubicin (DNR) on K562 cells under hypoxia. We found the IC50 of DNR and DNR-PEG-PLL-PLGA in K562 cells increased under hypoxia, while the IC50 of DNR-Tf-PEG-PLL-PLGA in K562 cells decreased under hypoxia according to the results of MTT assay. The apoptosis of cells and the intracellular concentration of DNR were detected by flow cytometry (FCM). From the datas, we found that the new targeted nanoparticles can overcome hypoxia induced drug resistance of K562 cells. By targeting the transferrin receptor (TfR) on the surface of K562 cells, the new targeted drug led to an increase in intracellular accumulation of DNR. Transcription and Protein of P-glycoprotein (P-gp) and TfR increased in K562 cells under hypoxia, which probably had a relationship with the decreased degradation of the Hypoxia-Inducible Factor-1α (HIF-1α). We further detected the levels of HIF-1α, Bcl-2, Bax and Caspase-3 of K562 cells in transcription and protein under hypoxia regulated by DNR, DNR-PEG-PLL-PLGA and DNR-Tf-PEG-PLL-PLGA, respectively. DNR-Tf-PEG-PLL-PLGA had the best effect when compared with other groups. Furthermore, intravenous injection of DNR-Tf-PEG-PLL-PLGA expressed the best effect of suppressing proliferation of K562 cells injected to nude mice among the three drugs. Therefore, the new drug DNR-Tf-PEG-PLL-PLGA may be a potential cancer therapy for human leukemia.