The role of the low density lipoprotein receptor in targeted drug delivery mediated by anionic liposomes.

摘要

Anionic liposomes have long been proposed as ideal carriers for the delivery of drugs and other macromolecules. Fundamental to the practical development of anionic liposomal formulations for use in drug delivery is the characterization of the cellular mechanisms involved in their uptake. The present work examines how the characteristics of anionic liposomal formulations impact the cellular mechanisms involved in their uptake.; Association of liposomal aqueous contents and liposomal lipid with CV1-P and CHO wild type cells, which both express the low density lipoprotein receptor (LDLr), and CHOld1A7, which lacks the LDLr, was measured. Additionally, CHOld1A7 was transfected with the human LDLr and further association studies were performed using the anti-LDLr and anti-apolipoprotein B100 (apoB100) monoclonal antibodies, IgG C7 and IgG 5E11, respectively.; Association of liposomes composed of 75–100 mole percent egg phosphatidylglycerol (ePG), a fluid anionic phospholipid, with cells was found to be mediated by LDL and the classical LDLr. Binding of liposomes composed of 75–100 mole percent ePG was blocked by the anti-LDLr antibody IgG C7 and the anti-apoB100 antibody IgG 5E11. Cellular association of 75–100 mole percent ePG vesicles in a serum free growth medium allowing for a maximal LDLr expression led to the functional delivery of a series of model liposome dependent drugs. Findings strongly indicate that 75–100 mole percent ePG liposomes interact with the LDLr in an apoB100-dependent fashion, and the interaction results in the delivery of contents to cells. An attractive strategy would be to utilize these ePG liposomes for targeted drug delivery to highly proliferative cancer cells known to over express the LDLr.; Serum, but not LDL or HDL, induced association of 25–50 mole percent ePG liposomes with both CV1-P and CHO wild type, but not CHOld1A7. This form of liposome binding appears not to involve LDL or LDLr, but requires a receptor, currently unknown, and a serum component other than LDL or HDL. Findings indicate that LDLr is not involved in the interaction of 25–50 mole percent ePG vesicles with cells, and that CHO1dlA7 lacks at least one other surface protein in addition to LDLr.