Advanced Spatiotemporal Control of Drug and Gene Therapy via Bolus and Substrate Embedded Hyaluronic Acid Surface Functionalized Lipid Nanoparticles

• Main Author: Hayward, Stephen L
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2015
• Subjects: Biomedical engineering; Chemical engineering; Medicine
• ISBN: 1339247437; 9781339247434

The ability to regulate the biodistribution and pharmacokinetic profile of therapeutic cargo remains a challenge for biomedical research. This lack in precisely modulating the in vivo fate of drug and gene cargo following administration diminishes potency, challenges safety, and ultimately plagues the likelihood of therapeutic efficacy. Catalyzed by Richard Feynman’s 1959 lecture “Plenty of Room at the Bottom” and K. Eric Drexler’s prominent vision of molecular manufacturing, the field of nanotechnology has undergone exponential growth in both interest and application. Specifically, the use of nanotechnology in medicine is an emerging area that demonstrates great promise in drug delivery. The chief ambition of applying nanoscale principles in drug delivery is to mask the unfavorable characteristics of therapeutic cargo with the tunable properties of the nanocarrier. This effectively decouples the therapeutic mechanism of the drug from its in-transit behavior. Although substantial progress has been made, the ability to facilitate potency while circumventing toxicity remains elusive. To advance the field of “nanomedicine”, this dissertation focuses on developing a lipid nanocarrier that can achieve robust spatiotemporal control of therapeutic cargo. The lipid nanoparticle (LNP) system was engineered from biocompatible components and surface functionalized with hyaluronic acid (HA) to endow the decorated particles (HALNPs) with colloidal stability, high cargo entrapment, and the salient feature of active targeting for cell-specific uptake. Following optimization, the HALNP system was successfully employed for breast cancer therapy via targeted delivery of microRNA. This was the first study to use microRNA in combination with a translational nanocarrier as a standalone treatment for HER2 positive breast cancer. In a separate application, the targeting potential of the HALNPs was tested for the treatment of glioblastoma. This study validated that the HALNPs promoted preferential uptake into cancer cells over corresponding healthy brain tissue and demonstrated a novel chemotherapeutic delivery method. The HALNP platform was also used with an in vitro mechanobiology model to determine how changes in local microenvironment during cancer progression alter the functionality of targeting ligands to create smarter nanocarriers. Lastly, a novel substrate delivery platform comprising of HALNP embedded thin film assemblies was developed for the future creation of implantable devices.