New Strategy for Controlled Release of Liposomal Contents

Iowa State University, Ames IA

Investigators

Abstract

ID: MPS/DMR/BMAT(7623) 1005515 PI: Zhao, Yan ORG: Iowa State University Title: New Strategy for Controlled Release of Liposomal Contents INTELLECTUAL MERIT: The objective of this proposal is to design and synthesize oligomers capable of forming nanometer-sized hydrophilic pores in lipid bilayers. The central hypothesis is that facially amphiphilic oligomers developed recently in the PI's laboratory have several critical features as pore-forming materials. This hypothesis is based on structural features found in natural pore-forming proteins and in preliminary studies. To test the central hypothesis and accomplish the overall objective of this proposal, the PI proposes to pursue the following two specific objectives: (1) Control the conformation of pore-forming oligomers in lipid bilayers. In the preliminary study, the PI has prepared oligocholate foldamers with nanometer-sized internal hydrophilic channels. When incorporated into lipid bilayers, the proper matching between the chain length of the foldamer and the thickness of the membrane was found critical to the folding. Four independent strategies (i.e., hydrophilic anchoring, hydrophobic matching, pi-pi interactions, and ion-pairing) are proposed to control the folding of the oligomers in lipid bilayers. The conformations of these molecules will be characterized by fluorescence resonance energy transfer (FRET), fluorescence quenching, UV-vis, and solid-state NMR spectroscopy. (2) Control the permeability of lipid bilayers by pore-forming oligomers. The foldamers in question form helical structures with a hydrophilic pore and a cholesterol-like exterior. A dodecamer and a cyclic trimer were found to allow the passage of carboxyfluorescein (CF) across lipid bilayers in the preliminary study. By controlling the conformation of the oligocholates, reversible ligation of shorter foldamer strands, and reversible aggregation of cyclic oligomers, the PI expects to regulate the traffic through the pore by temperature, metal ions, and molecular or redox signals. BROADER IMPACTS: The proposed research is expected to have several broad impacts in the chemical and pharmaceutical industries. Liposomes are already used clinically to deliver drugs (e.g., doxorubicin); pore-forming materials may improve the efficacy of the drugs by controlling the timing and location of release. Delivery of hydrophilic molecules across a hydrophobic membrane barrier is not only important to drug delivery but also to clinical research, molecular biology, and sensor development. Pore-forming materials that can be easily synthesized will open up many avenues in these applications. The two PIs bring complementary expertise to the proposed research. The Zhao group is experienced with design and synthesis of conformationally controllable materials and the Hong group with biophysical characterization of membrane-bound peptides and proteins. Collaboration will not only help the PIs explore research areas difficult for either one alone but also challenge the students to think more creatively. Working together with co-workers with dissimilar backgrounds, students will be exposed to very different thinking and problem-solving styles. This kind of collaboration will prepare them to work effectively in a team environment in their future careers and tackle problems that require coordinated efforts from multiple disciplines. Both PIs already have undergraduate students working in the lab. In the past summers, underrepresented undergraduate students recruited through ISU?s Program for Women in Science and Engineering (PWSE) have participated in the research. The PIs will continue this effort, taking advantage of the attractiveness of biomimetic chemistry to attract students to science.