Professor of Chemistry
Program Focus
Lipid-bilayer-coated nanoparticles for drug delivery and antimicrobial dendritic amphiphiles.
Two key issues for drug delivery are (1) enabling the delivery of known active agents and (2) enhancing the delivery of novel agents. Many superior agents are not drugs because their physiochemical properties prevent facile transport and targeting. New drug delivery vehicles are needed to enable delivering these known agents. Any novel synthetic agents should be designed a priori with drug-like properties, especially water-solubility. The Gandour lab addresses both challenges.
Engineering drug delivery vehicles for specific drugs and target organs reamins a key challenge for future medicine. Lipid-bilayer-coated nanoparticles (Nps) can be tailored to meet this challenge. A strategy for design and construction of complex functional Nps (Figure 1) for drug-delivery applications is under development in collaboration with Professor Alan Esker and three outside collaborators, who are developing molecular modeling algorithms to simulate assembling these Nps. To achieve the ultimate goal—lipid-bilayer-coated Nps containing multiple agents, the basic nanoarchitecture must be constructed first. The synthesis involves two steps—the coating of metal oxide Nps with linkers and the fusing of linker-coated Nps with liposomes. Attaching linkers to Nps to give stable linker-coated Nps is the first goal. Constructing stable lipid-bilayer-coated Nps is the second goal. Both goals depend on the chemical structure of the linker; therefore, a small library of linkers is being synthesized to define the structure–property space. Differential scanning calorimetry (DSC) and quartz crystal microbalance with dissipation monitoring (QCM-D) will be used to characterize these Nps.
Four objectives are to: i) screen a linker library to assay their ability to insert into lipid bilayers by utilizing multilamellar vesicles (DSC), ii) characterize linker-coated planar metal oxide surfaces and liposome fusion onto linker modified planar metal oxide surfaces to create tethered lipid bilayers (QCM-D), iii) study linker-coated Nps interactions with supported and tethered phospholipid bilayers (QCM-D), and iv) probe interactions between tethered lipid-bilayer-coated Nps and supported and tethered lipid bilayers on planar surfaces (QCM-D). Completing these studies will confirm the structure and utility of these Nps, and set the stage for developing strategies for loading these Nps with multiple drugs.
A second key challenge is developing water-soluble antimicrobial agents. Several members of our library of dendritic amphiphiles (Figure 2) have shown excellent activity against bacteria, fungi, and mycobacteria. The high species- and compound-selectivities suggest a specific mechanism of action for each microbe, which appears to be unrelated to membrane disruption. Mechanistic studies are underway to probe the activity of the one promising anti-Staphylococcal agent, 5(18) (Figure 3). The minimal inhibitory concentration (MIC) of 1.1 μg/mL is slightly better than that (2.2 μg/mL) of vancomycin, the drug of last resort in Staphylococcal infections.
Selected Publications
Savage, A. M.; Li, Y.; Matolyak, L. E.; Doncel, G. F.; Turner, S. R.; Gandour, R. D. Anti-HIV Activities of Precisely Defined, Semirigid, Carboxylated Alternating Copolymers. J. Med. Chem. 2014, 57, 6354–6363.