A 14-3-3 mode-1 binding motif initiates gap junction internalization during acute cardiac ischemia. Smyth JW, Zhang SS, Sanchez JM, Lamouille S, Vogan JM, Hesketh GG, Hong T, Tomaselli GF, Shaw RM. 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. Molecular Biology of the Cell 29 (7): 773-880. Mechanistic studies are underway to probe the activity of the one promising anti-Staphylococcal agent, 5(18) (Figure 3). The high species- and compound-selectivities suggest a specific mechanism of action for each microbe, which appears to be unrelated to membrane disruption. Several members of our library of dendritic amphiphiles (Figure 2) have shown excellent activity against bacteria, fungi, and mycobacteria. 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.Ī second key challenge is developing water-soluble antimicrobial agents. Differential scanning calorimetry (DSC) and quartz crystal microbalance with dissipation monitoring (QCM-D) will be used to characterize these Nps.įour 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). 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. Constructing stable lipid-bilayer-coated Nps is the second goal. Attaching linkers to Nps to give stable linker-coated Nps is the first goal. The synthesis involves two steps-the coating of metal oxide Nps with linkers and the fusing of linker-coated Nps with liposomes. To achieve the ultimate goal-lipid-bilayer-coated Nps containing multiple agents, the basic nanoarchitecture must be constructed first. 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. Lipid-bilayer-coated nanoparticles (Nps) can be tailored to meet this challenge. The Gandour lab addresses both challenges.Įngineering drug delivery vehicles for specific drugs and target organs reamins a key challenge for future medicine. Any novel synthetic agents should be designed a priori with drug-like properties, especially water-solubility. New drug delivery vehicles are needed to enable delivering these known agents. Many superior agents are not drugs because their physiochemical properties prevent facile transport and targeting. Two key issues for drug delivery are (1) enabling the delivery of known active agents and (2) enhancing the delivery of novel agents. Program Focus Lipid-bilayer-coated nanoparticles for drug delivery and antimicrobial dendritic amphiphiles.
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