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Richard N. Zare

Gunilla B. Jacobson, Tatsiana Lobvkina, Yaping Zhao

We have specific interest in preparing nanoparticles of therapeutic compounds whose size and surroundings can be controlled. Important pharmaceutical issues, such as chemical and physical stability, dissolution rate, and therapeutic performance, are often related to particle size, morphology, and surface properties. By working on the nanoscale range new drug delivery systems can be explored, as well as increased target specificity along with lower dosage requirements and therefore lower unwanted side effects.

We are using supercritical carbon dioxide as an antisolvent in the preparation of our particles. When a fluid is taken above its critical temperature (Tc) and critical pressure (Pc), it exists in a condition called a supercritical fluid (SCF), Figure 1. It is the possibility of controlling the solvent properties of a SCF by small changes in temperature and pressure that make SCFs unique for the desired tight process control. Also, the high diffusivity of SCFs allows much faster diffusion into the liquid solvent and formation of supersaturation of the solute. This in turn allows for much smaller nanosized particles to be formed as well as control of the size distribution, as compared to using liquid antisolvents, or other techniques such as jet milling.

In addition, we are exploring the encapsulation of the nanoparticles by various means for the purpose of increasing their stability or their targeting or both. Encapsulation will also enable designed characteristics for distribution and release of the active compounds within the nanoparticles. The work ranges from fundamental studies of how nanoparticles are formed in supercritical fluids to how they can be used in pharmaceutical applications by studying their use in sustained release experiments and distribution in living organisms.

As an example, luciferin nanoparticles dispersed in the biodegradable polymer poly(lactic acid) (PLA) have been formed and tested both in vitro and in vivo. Bioluminescence imaging of transgenic mice that have been genetically engineered to universally express luciferase, shows a slow and sustained release of luciferin over 20 days upon subcutaneous injection of these particles (Figure 2). Using luciferin as a model drug we can explore the effect of particle size and composition on its distribution in vivo. This knowledge is then transferred to other therapeutics to optimize the particles for each specific drug.

Nanoparticle picture 1 Nanoparticle picture 2

Figure 1 (left). Phase diagram of carbon dioxide. Figure 2 (right). Bioluminescence image of luciferin/PLA particles 20 days post injection.