SOLID CORE-SHELL DRUG NANOPARTICLES FOR THERAPEUTIC DELIVERY

Open Access
Author:
Zahr, Alisar
Graduate Program:
Chemical Engineering
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
November 10, 2006
Committee Members:
  • Michael Pishko, Committee Chair
  • Christine Dolan Keating, Committee Member
  • Themis Matsoukas, Committee Member
  • Andrew Zydney, Committee Member
Keywords:
  • nanoparticles
  • drug delivery
  • cancer
Abstract:
Solid core-shell drug nanoparticles are poised to offer a solution to the challenges faced with the conventional administration of therapeutic agents. Engineering drug delivery carriers that can selectively target the diseased tissue, reduce systemic toxicity, increase drug absorption, and locally control the release of the drug are current unmet medical needs. One area that has generated much interest in the past 25 years is the delivery of anti-cancer agents. Core-shell drug nanoparticles can provide a new method in encapsulating anti-cancer agents within a polymeric nanometer sized shell while retaining the therapeutic agents’ biological activity. The focus of this dissertation was twofold: to fabricate solid core drug nanoparticles from water insoluble therapeutic agents and to encapsulate the nanoparticles within a polymeric nanometer scale shell, the nanoshell. The nanoshell composed of multilayer polyelectrolytes serves as a reactive surface which can be chemically modified with targeting ligands to assist the carrier in overcoming biological barriers. Nanoparticles of dexamethasone and paclitaxel, the chosen therapeutic agents, were prepared by a modified emulsification-solvent evaporation technique. Size analysis of the solid core nanoparticles was determined by laser light scattering, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). These three methods confirmed that the size of the core was within a range of 100-200 nm and with approximately an average size of 150 nm. This method in preparing solid core nanoparticles can be extended to additional therapeutic agents with limited water solubility for the treatment of other aliments. Electrostatic Layer-by-Layer self-assembly was used as a method for encapsulating solid core drug nanoparticles within nanoshells composed of multilayer polyelectrolytes. The surface and bulk morphologies of the encapsulated drug nanoparticles were determined by TEM indicated that a nanoshell composed of two polyelectrolyte layers of poly (allylamine hydrochloride) and poly (styrene sulfonate) was approximately 10 nm thick. The nanoscale precision achieved with LbL assembly provides control of surface properties of the core-shell carrier, which is important in the design of an efficacious delivery system. The exterior surface of the nanoshell was functionalized with biocompatible polymer poly (ethylene glycol) (PEG) to create a stealth drug delivery carrier. In vitro studies were performed and results showed that a PEG modified nanoshell can reduce the uptake of core-shell nanoparticles after 24 hours of incubation with phagocytic cells. In another in vitro study, the therapeutic efficacy of paclitaxel core-shell nanoparticles was retained upon fabrication and encapsulation within the polymeric nanoshells. Prolonged treatment with paclitaxel led to cell death by apoptosis or necrosis as evidenced by confocal microscopy. Finally, a targeted drug delivery system of core-shell nanoparticles was achieved by the chemical modification of a lipophilic nanoshell with the epidermal growth factor (EGF) protein. This protein was chosen because its receptor has been found to be overexpressed in many disease states including high grade brain tumors. The work presented in this thesis advances the field of nanotechnology by providing new strategies towards engineering surfaces on colloidal carriers for the selective and stealth delivery of water-insoluble therapeutic agents to diseased tissue.