(476b) Aptamer-Peptide-Drug Conjugates: Delivery of Precise Synergistic Drug Ratios for Enhanced Cancer Selectivity
AIChE Annual Meeting
Wednesday, November 1, 2017 - 8:18am to 8:36am
To promote cancer specific uptake of our APDCs, we employ a well known aptamer AS1411 that targets overexpressed cell surface nucleolin on several types of cancer. Specifically, we chose a triple negative human metastatic breast cancer cell line, MDA-MB-231, that overexpresses cell surface nucleolin and has an intermediate response to chemotherapy. To make APDCs, chemotherapeutic drugs doxorubicin (DOX) and camptothecin (CPT), a previously employed combination for aggressive metastatic breast cancer, were loaded in a controlled covalent fashion to the aptamer using peptide scaffolds. Subsequent testing revealed that our APDCs are highly selective to nucleolin overexpressing breast cancer cells compared to a control epithelial cell line, MCF 10A. Systematic invitro evaluation of several drug combinations revealed a molar ratio dependent synergy, and drug ratios, 0.25 â¤ R â¤1 (R - CPT/DOX) were found to be significantly synergistic over others. Futhermore, certain molar ratios amongst these were found to be more effective at killing MDA-MB-231 cells compared to MCF-10A cells. Finally, we demonstrated that by delivering these synergistic molar ratios in a targeted fashion via APDCs, significant enhancement in toxicity exclusive to MDA-MB-231 cells can be obtained. These results reinforce the importance of delivering precise drug combination ratios in a targeted fashion to cancer cells so as to exploit the full potential of synergistic interactions of specific drug ratios in the tissue of interest.