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Long-Circulating Nanoparticles

Polymeric nanoparticles have been extensively studied for use as intravascular drug delivery vehicles. Polymeric particles potentially offer many advantages over traditional intravascular methods of drug delivery. They can be used to encapsulate sensitive therapeutic agents, thus protecting them from degradation and clearance in the vasculature while maintaining a steady plasma concentration. Furthermore, sustained drug concentrations in the blood reduce the required dose thus reducing the possibility of side effects. Sustained release also decreases the dosing frequency thereby increasing patient compliance.
Unfortunately polymeric particles are rapidly cleared from circulation by the reticuloendothelial system (RES) preventing their effective use as sustained drug delivery vehicles. When polymeric particles are introduced into vascular circulation they are opsononized and subsequently removed from vascular circulation by macrophages primarily located in the liver, spleen and lungs. Previous attempts to improve vascular circulation have focused on coating the particles with polymer brushes, such as polyoxamines, polyoxamers, and polyethylene glycol, to prevent opsononization. However, circulation lifetimes of surface-
modified particles are still limited.

We are studying a novel method of increasing intravascular particle circulation by anchoring the nanoparticles to the surface of red blood cells (RBCs). We have found that particles adhered to RBCs can indeed escape phagocytosis due to the ability of RBCs to evade macrophages. This method is motivated by the strategy adopted by certain bacteria, for example hemobartonella, that adhere to RBCs and can remain in circulation for several weeks.

Targeted Drug Delivery

The majority of therapeutics in use today are not targeted to the site of disease in the body. Instead, they are delivered systemically and become evenly distributed throughout the body due to the lack of a targeting moiety. This method of delivery greatly reduces the efficacy of therapeutics because there are many biological barriers that must be overcome before reaching the target site. Non-targeted delivery also causes negative side effects associated with the delivery of large doses of therapeutics and drug activation in non target sites. Targeting therapeutics to specific sites in the body will increase the efficacy of drugs while reducing the dose required along with negative side effects. The delivery of drugs to hard to reach places, such as the brain, may also be possible.

It is known that cells, tissues, and organs all display unique markers that may be useful as targets for drug delivery. The development of microbial peptide display libraries, such as phage and bacterial cell surface display, has made it easier to exploit the heterogeneity among the different cell and tissue types. The use of these large peptide libraries allows the identification of peptide - receptor interactions of the desired affinity and specificity by employing various in vitro selection methods. These libraries also provide a means to discover novel cell and tissue markers.

In this collaborative project with Prof. Patrick Daugherty (Chemical Engineering, UCSB), we are using bacterial cell surface peptide display libraries to discover peptides that have strong binding affinity and specificity for various cells, tissues, and organs. These peptides will then be used as targeting ligands on drug carriers and gene delivery vectors.