Journal
INTERNATIONAL JOURNAL OF NANOMEDICINE
Volume 10, Issue -, Pages 4535-4547Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/IJN.S85587
Keywords
PEG-PLL-PLGA nanoparticles; transferrin; tetrandrine; ultidrug resistance
Funding
- National Key Basic Research Program 973 of the People's Republic of China [2010CB732404]
- National Nature Science Foundation of the People's Republic of China [81170492, 81370673]
- National High Technology Research and Development Program 863 Projects of the People's Republic of China [2012AA022703]
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The study investigated the reversal of multidrug resistance (MDR) and the biodistribution of nanoparticles (NPs) that target leukemia cells in a nude mice model via a surface-bound transferrin (Tf). The cytotoxic cargo of daunorubicin (DNR) and tetrandrine (Tet) was protected in the NPs by an outer coat composed of polyethylene glycol (PEG)-poly-l-lysine (PLL)-poly(lactic-co-glycolic acid) (PLGA) NPs. Injection of DNR-Tet-Tf-PEG-PLL-PLGA NPs into nude mice bearing MDR leukemia cell K562/A02 xenografts was shown to inhibit tumor growth, and contemporaneous immunohistochemical analysis of tumor tissue showed the targeted NPs induced apoptosis in tumor cells. Targeted tumor cells exhibited a marked increase in Tf receptor expression, with noticeable decreases in P-glycoprotein, MDR protein, and nuclear factor kappa B, as assessed by quantitative real-time polymerase chain reaction and Western blot analysis. Moreover, the concentration of DNR was shown to increase in plasma, tumor tissue, and major organs. Flow cytometry analysis with a near-infrared fluorescent (NIRF) dye, NIR797, was used to study the effectiveness of Tf as a targeting group for leukemia cells, a finding that was supported by NIRF imaging in tumor-bearing nude mice. In summary, our studies show that DNR-Tet-Tf-PEG-PLL-PLGA NPs provide a specific and effective means to target cytotoxic drugs to MDR tumor cells.
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