Title: Aptamer Targeted Delivery of Synergistic Drug Combinations for Effective Cancer Therapy

Advisor: Samir Mitragotri

Abstract:

Potent chemotherapy combinations, identified and optimized in vitro, often fail in clinic because the current paradigm aims to deliver the constituent drugs at or near their individual maximum tolerated doses (MTD) for superior treatment efficacy. However, this strategy compounds the risk of treatment-related toxicity in patients due to non-specific accumulation of sub-optimal drugs ratios – with diminished therapeutic efficacies – at the tumor site. Consequently, there is a need for designing multi-drug regimens that adequately strike the difficult balance between safety and efficacy.
 
In this work, we first identified doxorubicin (DOX) and camptothecin (CPT), whose potency can be tuned by combining them in varying molar ratios to treat triple negative breast cancer (TNBC). Albeit causing toxicity to normal breast epithelial cells, the most efficacious in vitro ratio prevented the disease progression in an aggressive orthotopic human TNBC mouse tumor model at very low drug doses. Subsequently, we envisaged imparting cancer specificity to this promising combination for further enhancement in the treatment outcome. Since aptamers offer excellent advantages over other molecular targeting agents, we developed a modular framework for the aptamer-targeted delivery of drug combinations at synergistic molar ratios. An aptamer capable of exclusively recognizing an overexpressed TNBC marker was explored and identified for this application. These novel aptamer-drug conjugates, optimized over several design iterations, exhibited extremely toxic yet specific responses against TNBC cells in vitro. In vivo, they outperformed cocktails comprising equivalent doses of unconjugated drugs at unprecedentedly low drug doses. This design thus represents a generalizable strategy for the safe, consistent and effective delivery of empirically defined optimal molar ratios of a diverse set of chemo-oncology drugs. Thus, by enabling treatment at doses much lower than MTDs, the effective translation of chemotherapy cocktails into the clinic can be facilitated.