(591g) Enhancing Therapeutic Efficacy of Self-Assembling Prodrugs with Supramolecular Chemistry

Chemical modification of small molecule hydrophobic drugs is a clinically proven strategy to devise prodrugs with enhanced treatment efficacy. While this prodrug strategy improves the parent drug's water solubility and pharmacokinetic profile, it typically compromises the drug's potency against cancer cells due to the retarded drug release rate and reduced cellular uptake efficiency. We report here the supramolecular design of self-assembling prodrugs with much improved water solubility while maintaining high potency against cancer cells. The direct use of anticancer drugs to create their own nanostructures allows for fine-tuning and optimization of the drug loading and their physicochemical properties in a precise manner through molecular engineering of the underlying prodrug building units. We found that our rationally designed self-assembing prodrugs are capable of associating into one-dimensional nanostructures of various physiochemical properties in aqueous solution with a width of approximately 10 nm and lengths on the scale of several micrometers. We further evaluated the stability of resulting filaments of different surface chemistries in both cell medium and human serum, and their gelation ability in physiological condition. More importantly, our results suggest that this platform of prodrugs exhibit much greater efficacy against various cancer cells relative to the clinically used prodrug both in vitro and in vivo. We believe these findings open a new avenue for rational design of supramolecular prodrugs for more effective cancer treatment.