Date of Award

Spring 2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering

First Advisor

Yuri Lvov

Abstract

A combined effect of sonication and layer-by-layer assembly (LbL) enhances the solubility of many poorly soluble inorganic and organic materials by forming stable particles with ca. 200 nm size and up to 90 wt% of loading. The entire method is reproducible, easy-to-handle, and flexible for varying surface properties according to the application of the materials. The method develops good colloidal stability of materials in buffers and maintains architecture for future improvement. A top-down approach, with a combined effect of sonication and LbL assembly, ruptures the material and allows adsorption of oppositely charged polyelectrolytes simultaneously. Thus, the approach is applicable for low solubility anticancer drugs, dye pigments, anticorrosion agents, salts, and oxides. In comparison, the well-established bottom-up approach begins with the drug dissolved in an organic solvent. The nanoparticles precipitate from the solution through nucleation initiated by the addition of an aqueous polyelectrolyte solution under sonication. This process produces low solubility anticancer drugs nanoparticles ca. 200 nm with 30% of the yield.

Advancement of the bottom-up approach for paclitaxel formulation begins by addition of amphiphiles and pharmaceutical excipients during the drug nucleation process, which indirectly improves the shelf-life of the drug formulation. The amphiphiles adsorb onto the hydrophobic surface of the drug and play a dual role of decreasing recrystallization and acting as anchors to the multilayers of polycation/polyanion during LbL assembly. Incorporation of polyethylene glycol (PEG) moieties in LbL assembly improves further colloidal stability, as compared to the non-PEG shell composition. The nanoparticle diameters reduce to 160-180 nm, with 80 wt% loading capacity and concentration of 2-3 mg/mL. Varying the number of multilayers of the shell composition leads to controlled paclitaxel release rates, which can be extended for 10-20 hours.

To improve the nanoparticle circulation time, the particle surface is modified by excess PEG moieties. Indirectly, the surface properties of the particles advance by restricting serum protein adsorption. In vitro studies using the 4T1 cancer cell line help to direct further modification of the nanoparticle surface. The safety and tolerability of all constituents in the formulation are confirmed in mice via tail vein administration. The LbL shell architecture is developed further for anchoring tumor specific monoloclonal antibodies, 2C5. Here we report on the successful architecture of paclitaxel nanoparticles based upon PEG integrated LbL shell composition and conjugation of tumor specific biomolecules for longer circulation time as well as targeted delivery.

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