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All cells are surrounded by a plasma membrane that separates its internal contents from the environment. This membrane forms an effective barrier that prevents unregulated exchange of molecules between the cytoplasm and the external environment of the cell. To permeate the plasma membrane, specific transport proteins (carrier proteins and channel proteins) are needed for the selective passage of small molecules across the membrane (see Figure 1). Larger (especially charged) molecules for which no transport mechanism exists cannot cross cell membranes under normal conditions. Examples of large molecules include glucose and ATP. Yet large molecules such as ATP can provide critically needed energy to maintain the metabolic demand of the cells. It is a question of science that seeks a way to deliver ATP, a large molecule, to the bilayers of the cell.

Figure 1. Permeability of the membrane bilayer Gases, small hydrophobic molecules, and small polar uncharged molecules such as water and ethanol are examples of permeable molecules. Larger polar molecules and charged molecules are not permeable. ATP is a charged molecule and does not freely enter cells.

The ideal system for delivery of large molecules would couple both specificity and efficiency. Three primary approaches have been used to bypass the plasma membrane barrier: permeabilization, micro-injection, and liposomal delivery. Permeabilization, which allows entry of materials found in the external medium, has been attained by electroporation and by pore-forming proteins or detergents. However, the lack of specificity and difficulty in controlling this technique limit its application predominantly to basic research. Indeed, as soon as pores are formed in cell membranes by permeabilization, many unwanted molecules can also be transported, loading the cells with toxic chemicals or losing important membrane gradients. While micro-injection allows more specificity than permeabilization techniques, this is a time-consuming and technically challenging procedure and has therefore limited clinical applications.

Our approach to bypass the plasma membrane barrier is to load compounds into lipid vesicles for liposomal delivery. Lipid vesicles can be filled with a variety of medications and, because of their similarity to cell membranes, often are not toxic. They also protect their loads from being diluted or degraded prior to reaching the target cell. As demonstrated schematically in Figure 2, there are four types of interaction between liposomes and cell membranes:

a. Adsorption; under appropriate circumstances, liposomes can adsorb to almost any cell type. Adsorbed lipid vesicles can also exchange lipids with cell membranes and might then be able to fuse with cells.

b. Endocytosis; this method of delivery occurs in a limited class of cells that readily phagocytose particles, but has the major drawback that the contents are often then digested by the lysosome of the cell.

c. Lipid exchange; this interaction involves the transfer of individual lipid molecules from the vesicle into the plasma membrane, but the aqueous contents do not directly enter the cell.

d. Fusion; in this interaction, the lipid vesicle fuses directly with cell membrane and deliver its contents into the cytosol.

Figure 2. Schematic depiction of the interactions between lipid vesicles and cell membrane. Lipid vesicles can interact with the cell membranes in four ways: a. adsorption, b. endocytosis, c. lipid exchange, d. fusion. Of these, the most promising approach is direct fusion.

Of the four types of interaction, fusion directly delivers vesicle contents into the cytosol, which is a much more efficient and rapid process, but also the most technically-difficult type of interaction to achieve. Our wound healing drug candidate, being developed under the clinical name WHD-1, addresses these challenges.

Summary/Overview

Fusogenic Lipid Vesicle Delivery System

Application of Technology on Wound Healing

• Summary
• Healing Rates on Mice
• Increased Levels of VEGF
• Healing Rates on Swine
• Development Plan

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