|dc.description.abstract||Nanoparticles have demonstrated success in overcoming many barriers of therapeutic delivery. The advantages of these systems include increased drug loading, an ability to package poorly soluble and/or highly toxic drugs, and enhanced biodistribution compared to free drug. However, current nanoparticle-based therapeutics are hampered by low circulation half-life, burst release of drug and/or leakage, and off-target toxicity. A new class of nanocarriers attempts to address these issues by combining the advantages of two traditional systems: inorganic nanoparticles and liposomes. Nanoparticles enveloped in a lipid bilayer combine the monodisperse, pH and thermally stable, and inherent tracking capabilities of inorganic nanoparticles with the biocompatibility, long circulating half-life, and ability to deliver hydrophilic and hydrophobic molecules associated with liposomes. Anchoring the lipid bilayer into the nanoparticle surface further enhances these carriers by increasing membrane compatibility, stability and provides a sub-membrane space for therapeutic loading.
This dissertation involves a detailed discussion on the design and self-assembly of tethered membrane nanoparticles (TMN) and their application within the field of drug delivery. TMN were comprised of a silica nanoparticle core to which lipopolymers were functionalized. The lipopolymers were composed of a polyethylene glycol (PEG) polymer chain and phosphatidylethanolamine lipid. These exterior facing, anchored lipids directed the self-assembly of a lipid bilayer onto the nanoparticle surface with liposomes serving as the extraneous lipid source. By comparing the lipid concentration, hydrodynamic diameter and zeta potential, the amount of lipid needed to produce a stable, tethered bilayer membrane on the surface of a silica nanoparticle was determined to be a factor of 5:1 with regard to surface area of lipid to surface area of nanoparticle. Use of zwitterionic lipids reduced dependence on electrostatic interactions and membrane assembly formed via hydrophobic interactions and van der Waals attraction forces. Transmission electron microscopy images confirmed the presence of a supported lipid bilayer composed of three separate lipid formulations and encapsulation of 5(6)-carboxyfluorescein indicated a 15-20% release of dye over the course of 6 days depending on bilayer intactness.
Where possible, TMN were compared with the two traditional nanocarriers they were comprised of: silica nanoparticles and liposomes. Stability of each particle type was assessed in serum with TMN exhibiting greater stability over PEGylated silica. Macrophage uptake was used to examine the effect of lipid bilayer composition on expected circulation half-life. A PEGylated exterior was found to reduce TMN uptake by a factor of 13 – indicating the significant role a PEGylated exterior membrane can impart. Finally, TMN and liposomes loaded with doxorubicin were incubated with PC-3 prostate cancer cells. TMN exhibited similar toxicity to liposomal doxorubicin, demonstrating capability of the model system as a drug delivery paradigm.
Next generation delivery vehicles have already begun utilizing cell membrane coats as a way to evade host defense mechanisms, such as the mononuclear phagocyte system, and to increase circulation residence times. However, these systems are currently limited by their simplistic fusion of the membrane onto nanoparticle surfaces. This significantly reduces the array of membranes that can be properly incorporated due to surface interactions of the interior leaflet. The tethering technique developed herein provides an opportunity to enhance membrane environment recapitulation towards production of biomimetic drug carriers.
This work advances current capabilities of supported membranes on colloidal systems and paves the way for further investigation into the fundamentals controlling bilayer assembly upon tethered nanoparticle cores. The versatility of the developed system is the hallmark of this research, and provides a platform from which to tailor nanoparticle properties for specific disease states, drug loading or release profiles, and unique shapes or porosities. Application of the developed model system has shown efficacy in drug loading and the treatment of prostate cancer. The simplicity in modification of the current platform and the significant potential of tailorable attributes hold promise for the future generation of targeted, biomimetic nanoparticle-based therapies.||en_US