Date of Award

Winter 2013

Document Type


Degree Name

Doctor of Philosophy (PhD)


Micro and Nanoscale Systems

First Advisor

Yuri Lvov


In this dissertation, ultrasonication assisted Layer-by-Layer (LbL) technology for the preparation of multifunctional poorly water-soluble anticancer drug nanoparticles, paclitaxel and lapatinib, has been developed. Many FDA approved drugs are very low soluble in water; therefore, it is very difficult to load and control their release and targeting efficiently, which greatly confines their application. The development of this method will pave the way for the development and application of those low soluble anticancer drugs.

In the first part of this dissertation, the first approach for powerful ultrasonication, the top-down approach (sonicating bulk drug crystals in polyelectrolyte solution), was successfully applied for the preparation of the nanoparticles of paclitaxel. For this approach, a 200 nm diameter was a kind of "magic" barrier for colloidal particles prepared. This diameter barrier may be related to the nucleation size of the solvent vapor microbubbles. Consequently, agents enhancing bubbling formation (such as NH4HCO3) were applied to decrease paclitaxel colloid particles to 100-120 nm. Those paclitaxel nanoparticles were Layer-by-Layer coated with a 10-20 nm polycation/polyanion shell to provide aqueous colloidal stability and slower particle dissolution. However, a large obstacle of these powerful ultrasonication methods was a necessity of long ca 45 minutes high power ultrasonication which resulted in TiO2contamination from titanium electrode. The small amount of TiO2 contamination from ultrasonication did negatively affect the in vivotesting of this system in mice, and had to be removed before low toxicity of the Layer-by-Layer coated paclitaxel nanoparticles were observed.

In the second part of the dissertation, the second approach for sonication, the bottom-up approach (sonicating drug in a water-miscible organic solvent followed by slow water add-in) was successfully applied for the preparation of the nanoparticles of lapatinib and paclitaxel with less powerful sonication. By using polymeric excipients combined with non-ionic and anionic surfactants along with regular sonication, the prepared particle sizes was uniform at around 140-150 nm. Less sonication time (ca 15 minutes) and lower sonication power avoided TiO2 contamination. The amphiphiles attached to the hydrophobic nanoparticles and served as anchors for LbL shell. The inner LbL layers and surfactants minimized the surface free energy, thereby preventing crystal form changes and nanoparticles coalescence, while the outermost layers enhanced colloidal stability.

In the third part of the dissertation, LbL shells with PEGylation (using a block copolymer of poly-L-lysine (PLL) and PEG) for lapatinib were developed for enhanced colloidal stability in high molarity PBS buffer.

In the above proposed paclitaxel and lapatinib formulation, we obtained 150-200 nm with high drug content of 80-90% due to very thin capsule walls (ca 10 nm). The drug release time from the LbL capsules was found to be between 10 and 20 hours depending on the shell thickness. Washless Layer-by-Layer assembly was used: 1) addition of polycation in the amount that is enough to reverse surface charge of the dispersion to a high positive (+30 mV) value; 2) addition of polyanion in the amount that is enough to reverse surface charge of the dispersion to a high negative (-30 mV) value. No intermediate washing of nanoparticles was done until the shell was complete. The washless method had the advantage of time and energy saving, preservation of the sample structure and no losses of sample.

In the last part of the dissertation, we elaborated nanoformulation of two drugs in one nanocapsule locating paclitaxel in the core and lapatinib on the shell periphery. With this formulation, combining in one nanoparticle dual drugs, we reached the drugs' efficiency synergy. In a multidrug-resistant (MDR) ovarian cancer cell line, OVCAR-3, LbL lapatinib/paclitaxel nanocolloids mediated an enhanced cell growth inhibition in comparison with the LbL paclitaxel-only and LbL lapatinib-only treatment, not to say the free one drug treatment.