Cytotoxic Effects of Ionizing Radiation and Doxorubicin Conjugates with Dendritic Polymer and Vector Protein on Breast Cancer Cells in vitro

Introduction Dendrimers are perspective nanocarriers for anticancer drugs, but unfortunately their conjugates and complexes with drugs lack a targeted action that limits their application. Conjugation of dendrimers with... [ view full abstract ]

Introduction
Dendrimers are perspective nanocarriers for anticancer drugs, but unfortunately their conjugates and complexes with drugs lack a targeted action that limits their application. Conjugation of dendrimers with ligands for specific receptors on the tumor cells surface seems promising approach for increasing therapeutic efficiency and decreasing systemic toxicity of anticancer agents. The aim of the study was to evaluate cytotoxic effects of dendrimers conjugated with doxorubicin (Dox) and alpha-fetoprotein recombinant third domain (3D) as vector protein on cancer cells after single and combined application in vitro. Combined effects of ionizing radiation and dendrimers are of great interest because radiation therapy is well known to be used in the treatment of cancer patients in about half of all cases.
Methods
Polyamideamine dendrimers of the second generation (G2) were used after conjugation with 3D and Dox. The cytotoxic effects and intracellular distribution of Dox were studied by MTT-test, light and laser confocal microscopy 24 hours after ionizing radiation exposure of breast adenocarcinoma cells (MCF-7 and MCF-7/MDR1 lines) following by incubation with free Dox, G2-dendrimers loaded with Dox (G2-Dox), or conjugates of G2-dendrimers with 3D and Dox (3D-G2-Dox) during 2 hours.
Results
G2-Dox and 3D-G2-Dox significantly decreased number of MCF-7 cells by 10% and number of MCF-7/MDR1 cells by 25-30% as compared to control (p<0,05). Thus, free Dox exerted more pronounced cytotoxic effect on MCF-7 cells and the same effect on chemoresistant MCF-7/MDR1 cells as compared to the conjugates. For MCF-7 line using both conjugates in combination to irradiation was not effective because the conjugates did not increase the cytotoxic effects of radiation exposure. For MCF-7/MDR1 line subadditive effects were shown after the combined treatment with each drug and radiation. The highest synergy factor (0.91) was found for 3D-G2-Dox.
Discussion
In terms of overall cytotoxic effects on stable tumor cell lines, using the studied conjugates is justified only in combination with irradiation and only in the case of high expression of P-glycoprotein, which causes the multidrug resistance of cancer cell line MCF-7/MDR1.
This work was supported by grant of Russian Scientific Foundation # 15-15-10013.