Nanostructured Interfaces for Targeted Drug Delivery

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ABSTRACTProject Summary: Nanostructured Interfaces for Targeted Drug DeliveryIntellectual Merit of the Proposed ActivityCurrently, the main problems associated with systemic drug administration are the necessity of a large drug dose to achieve high local concentration, non-specific toxicity, and other adverse side-effects due to high drug doses. Targeted drug delivery can bring a solution to all these problems. With the emergence of stealth liposomes (liposomes covered with polyethylene glycol), the use of liposomes as drug delivery vehicles has received a new impetus, and several successes have been reported. In order to further improve upon different therapies, clinically active stealth liposomes need to include site-directed ligands to enhance their specificity for the pathological site. Peptides that recognize specific cell types or specific macromolecules on the cell surface can serve as targeting agents. The project focuses on engineering peptide-amphiphiles, and designing nanostructured interfaces that specifically target fractalkine, a novel adhesion molecule on the surface of endothelial cells that is expressed only at sites of infection or inflammation. The hypothesis of this research is that fractalkine can serve as a specific target moiety for drug delivery targeting. The PIs group is the first one that is engineering fractalkine-targeted drug delivery systems. The proposed approach will utilize fractalkine as of the N-terminus of the fractalkine receptor (NTFRpeptide-amphiphile), as the bullet. Preliminary work in the PIs lab has demonstrated that liposomes functionalized with the NTFR bind preferentially to inflamed human umbilical vein endothelial cells (HUVECs) in a concentration dependant manner. In addition, targeting of liposomes to inflamed HUVECs over healthy HUVECs is significantly increased when two adhesion receptors are employed, and the interface of the liposome is functionalized with NTFR that binds to fractalkine, and a second peptide-amphiphile that binds to 5 1 integrin. This one year project will engineer different formulations of fractalkine-targeted stealth liposomes, with nanostructured interfaces composed of peptide-amphiphiles that bind to the target(s), and polyethylene glycol of varying density and molecular weight. The designs will be evaluated in vitro in terms of binding, specificity, and internalization efficiency.Broader Impacts of the Proposed ResearchFractalkine has been detected in a variety of diseases such as: cardiac allograft rejection; prostate, lung, and colorectal cancer; pulmonary arterial hypertension; AIDS; atherosclerotic coronary artery disease, the leading cause of death in the USA; rheumatoid arthritis; and other inflammatory conditions. Therefore, the selection of fractalkine as a target for drug delivery is of great therapeutic value. This project will be the seed for future interdisciplinary research at the interface of synthetic chemistry, biology, nanotechnology, and engineering, with applications such as targeted drug delivery, and biosensors.