Nanonetworks as Innovative Platforms for Therapeutic Solubilization and Delivery
Stevens, David Michael
PHARMACOLOGY Nanonetworks as Innovative Platforms for Therapeutic Solubilization and Delivery David Michael Stevens Dissertation under the direction of Professor Eva M. Harth Solubility remains the biggest obstacle in the development of new therapeutics and is the primary cause for clinical failure of promising drugs. The high lipophilicity of many chemotherapeutics and peptides imposes a major challenge for systemic administration and drug efficacy. Recent interest of pharmaceutical companies to apply nanoformulations stems from the interest to improve solubility, specificity, and efficacy for current, off-patent, and shelved drugs rather than creating new therapies. Numerous approaches have been investigated including poly(lactic-co-glycolic acid) (PLGA) formulations, lipid-based micelles, and pegylation of proteins, but these efforts often fall short of expectations due to rapid drug release, the use of non-degradable materials, and accumulation and toxicity in the liver. To overcome these obstacles, practical approaches have been developed for the formation of biodegradable nanoparticles and hydrogels via crosslinking reactions. Polyester nanoparticles, or “nanosponges,” are degradable, biocompatible networks synthesized using developed intermolecular crosslinking chemistries and are capable of encapsulating the therapeutic while enhancing the drug’s solubility in aqueous solution, and the crosslinking density of the nanosponge can be adjusted to allow customized drug release rates. The availability of functionalities such as allyl and amine groups on the surface of the particles allows for targeting ligand attachment for targeted drug delivery applications. Having the abilities of organ-specific delivery and adjustable drug release rates allows the tailoring of this drug delivery platform to meet the specific needs of various applications. The same concept of using crosslinking chemistries to form nanosponges can be used to form hydrogel materials under concentrated conditions, and these biodegradable hydrogels are capable of tunable swelling, drug encapsulation, and adjustable drug release rates. Methods to synthesize predictable and defined polymer precursors have been developed which allows for complete customization of the resulting nanosponges and hydrogels that can be used for various applications including cancer, diabetes, and bone healing. Approved _________________________________________________ Date_________ Eva M. Harth, Ph.D.