This invention is a novel composition of matter that facilitates delivery of agents (e.g. diagnostic, therapeutic, imaging, etc.) into cells
It has been found that cells acquire exogenous cholesterol, a constituent of animal cell membranes, through multiple mechanisms involving structurally distinct cell surface receptors. Whereas cholesteryl esters are incorporated into lipoprotein particles that bind to LDL and HDL receptors, free cholesterol can bind directly to cell surface receptors. These principles were used to design novel mimics of free cholesterol. The compounds of this invention allow a variety of chemical moieties to bind cellular membranes and be delivered into cells.
The present invention utilizes novel chemical compounds for a more preferred transport of diagnostic, imaging, and therapeutic agents into the cell allowing for these agents to be more accessible to different parts of the cell.
The present invention includes a cholesterylamine that is coupled to a linker from the amine. A negative charge at a spatial distance from the cholesterylamine can facilitate entry of the cell. The negative charge allows more efficient binding to the receptors on the surface of the cell compared to the LDL and HDL receptors.
The cholesterylamine-linkers of the present invention mimic free cholesterol by binding directly to free cholesterol receptors on cell surfaces. This provides an efficient and effective method of introducing useful agents into cells.
Other cholesterol derivatives used in delivering agents into cells may be hindered by competition between the cell surface receptors and serum lipoproteins present in media typically used for cell culture. The present invention has been observed to bind mammalian cell surfaces with high efficacy and submicromolar affinity, even in the presence of serum. This allows for the lead compounds to more efficiently enter the cell to be released.
These compounds are useful as probes of membrane biology and can be useful tools for the delivery molecules with limited permeability into cells both in vitro and in vivo.