Aptamer Directed Synergistic Drug Delivery

Cancer patients suffer from extreme side effects of traditional chemotherapy due to the inability of chemotherapeutic drugs to exclusively inhibit the growth of cancer cells thereby harming healthy cells. Triple negative breast cancer is the form of breast cancer that is most difficult to treat because the cells lack HER2 receptors and hormone receptors that are targeted on other breast cancer cells. Oligonucleotide aptamers have been shown to target cancer specific biomarkers on tumor cells with high affinity and specificity. Our targeting molecule is a single-stranded DNA aptamer, AS1411, which binds to overexpressed nucleolin receptors on MDA MB 231 triple negative breast cancer cells. Furthermore, combining chemotherapeutic drugs at specific molar ratios leads to higher cell growth inhibition as compared to single drugs. Hence, we coupled targeted drug delivery with combination drug therapy to deliver drugs specifically and synergistically to triple negative breast cancer cells. We conjugated the aptamer with chemotherapeutic drugs, doxorubicin and camptothecin, using a peptide scaffold as the carrier. We evaluated several free drug and peptide-conjugated drug combinations to determine the most synergistic combination. Molar ratios of 1:4 for free doxorubicin to free camptothecin and 1:1 for peptide-doxorubicin to peptide-camptothecin were found to be the most synergistic combinations. Conjugating these drugs to the aptamer at the optimal molar ratios will potentially enable us to specifically deliver chemotherapeutic drugs at significantly lower doses.