Accumulation of Doxorubicin Conjugates with Dendritic Polymers and Vector Protein in Normal and Tumor Cells in vitro

Introduction Anticancer agents available today on the market cannot guarantee satisfactory results. There are a number of factors that reduce the efficacy of the drugs. On the one hand, one of the ways to overcome these... [ view full abstract ]

Introduction
Anticancer agents available today on the market cannot guarantee satisfactory results. There are a number of factors that reduce the efficacy of the drugs. On the one hand, one of the ways to overcome these problems is using increased doses of a drug or application of high toxic agents, which often leads to serious side effects and raises the risk of multidrug resistance occurrence. But, on the other hand, one of the most effective ways to enhance the effectiveness of anticancer drugs is development of new methods for target delivery of chemotherapeutic agents into tumor cells. The aim of this study was a comparative analysis of accumulation of dendritic polymers conjugated with anticancer drug and vector protein in breast cancer and normal cells in vitro. In addition, removal of these drugs from cancer cells was also studied.
Methods
Polyamidoamine dendrimers of the second generation (G2) were used. Accumulation of doxorubicin (Dox), its conjugates with G2-dendrimers (G2-Dox) and recombinant third domain of alpha-fetoprotein as vector protein (3D-G2-Dox) in normal and cancer cells was studied by flow cytometry and laser confocal microscopy. The study objects were cells of peripheral blood mononuclear fraction of healthy donors and cells of breast adenocarcinoma lines MCF-7 and MCF-7/MDR1 differing in chemosensitivity.
Results
G2-Dox and 3D-G2-Dox accumulated in cancer cells of the both lines better than free Dox (p<0.05). However, removal of these drugs out of MCF-7 and MCF-7/MDR1 cells was significantly different: in the latter case free Dox was completely excluded from the cells in 24 hours, while Dox accumulating in composition with dendrimers still remained in the cells. It is important that 3D-G2-Dox (unlike G2-Dox) accumulated in normal cells worse than free Dox (p<0.01).
Discussion
The results indicate that using of 3D-G2-Dox is the most promising course because it accumulates in cancer cells better but in normal cells worse than free Dox. Furthermore, it can be assumed that applying of 3D-G2-Dox would be especially useful in cases of multi-drug resistance associated with the high expression of P-glycoprotein.
This work was supported by grant of Russian Scientific Foundation # 15-15-10013.