The dynamic and versatile nature of diseases such as cancer has been a pivotal challenge for developing efficient and safe therapies. The discovery of the anti-neoplastic activity in FTY720 (Gilenya ®), an FDA-approved drug for the treatment of multiple sclerosis, is a pinnacle for the world of chemotherapy. FTY720 has been shown to inhibit cancer progression through the down-regulation of essential nutrient transporter proteins, selectively inducing starvation and apoptosis in cancer cells. Although this novel approach to cancer therapy holds much promise, the instigation of bradycardia (decreased heart rate) and immune suppression brought on at the anti-neoplastic dose of FTY720 prohibits its application to cancer therapy. An acid-cleavable prodrug, FTY-k-PEG, was designed to limit the toxicity of FTY720 while possessing the capability to release the original drug utilizing low-cost, scalable synthetic methodology. Under physiological pH, FTY-k-PEG remains intact yet exhibits efficient hydrolysis in pH 5.0, with 81% of drug released after 28 hours. FTY-k-PEG demonstrated nearly identical efficacy in a Bcr-Abl + leukemia model without inducing bradycardia or lymphopenia.
Co-delivery of synergistic therapies within a single nano carrier can enhance efficacy, lower toxicity, normalize release profiles, and increase specificity. Synergism was explored between FTY720 and Dasatinib, a tyrosine kinase inhibitor currently used to treat Bcr-Abl+ leukemia, and an acid-cleavable prodrug formulation for Dasatinib was developed utilizing homo- and heterobifunctional ketal crosslinkers conjugated to a precursor with high efficiency and straightforward purification. A nanoparticle was designed to co-deliver FTY720, Dasatinib, and nucleic acid within an acid-degradable shell, previously shown to enhance endosomal escape. Lastly, methods were explored to maximize therapeutic efficacy and minimize waste by utilizing materials with restorative properties as the polymer backbone. Resveratrol is a well-studied antioxidant with chemical moieties suitable for polymerization and necessitates macromolecular-assisted delivery owing to its poor bioavailability. PRIMA-1 is a small-molecule drug designed to target mutant p53, a pro- apoptotic protein mutated in over 50% of all human cancers. Formulation for a co-polymer of RSV and PRIMA-1 was investigated to amplify therapeutic effects without increasing toxicity.
In summary, this dissertation explores synthetic methodologies to enhance current therapeutics by limiting toxicity and increasing efficacy.