Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Lipoproteins – e.g. – egg yolk proteins – cylomicrons – etc.
Patent
1992-05-06
1994-06-28
Wityshyn, Michael G.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Lipoproteins, e.g., egg yolk proteins, cylomicrons, etc.
436 71, 424450, 530402, C07K 308, C07K 1516
Patent
active
053248210
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a method of preparing a lipoprotein modified by incorporation of a lipophilic active substance as well as a pharmaceutical or cosmetic composition containing a lipoprotein modified in this way as an active ingredient.
BACKGROUND OF THE INVENTION
It is known that one of the current objectives of pharmaceutical research is to direct drugs to the target organs and/or cells in order to enhance therapeutic efficacy while reducing side effects. One of the means of achieving this objective consists of binding the drug to a molecule, a macromolecule for example, able to play the role of carrier (or "vector") of the drug and bring it specifically to the target organ or target cells.
A number of macromolecules or molecule combinations such as liposomes, nanocapsules, DNA, lectins, antibodies, and lipoproteins have already been used or proposed as biologically active carrier substances.
It is known that lipoproteins constitute an important group of serum proteins comprising a lipid core surrounded by an envelope containing in particular phospholipids and specific proteins (apolipoproteins).
Lipoproteins are the systems that store and carry lipids, particularly cholesterol.
It is known that lipoproteins are classified by density. A distinction is made between: g/cm.sup.3 and 1.063; and 1.21.
Lipoproteins have marked tropism for various cells that have apolipoprotein receptors; in addition, in certain cases, they may be captured by cells in the reticuloendothelial system (phagocytic cells).
Hence it can be seen that lipoproteins are capable of being useful drug carriers. It has already been proposed to use lipoproteins, LDLs in particular, as drug vectors (see, for example, International Patent Application PCT No. WO 86/07540 and European Patent Application No. 0277849).
The low-density lipoproteins (LDLs), which have been the most studied as drug vectors, are spherical particles with diameters of approximately 20 nm. Each particle has a core composed of about 1500 cholesterol ester molecules and an envelope composed of cholesterol, phospholipids, and apolipoproteins (apolipoprotein B or apo B).
Mammal cells have receptors that recognize apo B and bind the LDLs to their surfaces. After binding to the membrane surface of the cells, the LDLs are internalized by endocytosis and carried to the lysosomes where they are broken down to meet the needs of the cell, particularly its cholesterol needs.
If native LDLs, i.e. LDLs that are not chemically modified, are used, the LDL-drug complex behaves like the native LDLs, namely it remains in the bloodstream for two to three days and is recognized by cells that have the apo B receptor (S. M. Brown and J. L. Goldstein, Science, 232, 34-47, 1986). This is the case for cancer cells which have a high level of apo B receptor.
It is also known that chemically modified lipoproteins (acetylates, acetoacetylates, oxide compounds, lactosylates, etc.) are recognized and captured by cells in the reticuloendothelial system, particularly by macrophages. Here again, the (chemically modified) lipoprotein-drug complex behaves in the organism like the original modified lipoprotein and is captured by macrophages through the intermediary of the acetylated LDL receptor (scavenger receptor) (see, for example, J. M. Shaw et al., Proc. Natl. Acad. Sci. USA Vol. 85, pp. 6112-6116 (1988) and M. K. Bijsterbock et al., Molecular Pharmacology, 36, pp. 484-486 (1989)).
In the organism, the transfer of triglycerides and of cholesterol esters and phospholipid between the various classes of lipoproteins (LDLs, VLDLs, HDLs, and chylomicrons) is carried out by proteins known as transfer proteins which have a higher density than lipoproteins, and which are accordingly contained in the residue of ultracentrifuged human or animal plasma after separation of the lipoproteins. Such a centrifugation residue constitutes the fraction known as LPDS (lipoproteindeficient serum), which has in particular the properties of the transfer protein it contains. Some of these
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Duriez Patrick
Favre Gilles
Fruchart Jean-Charles
Medhi Samadi-Baboli
Monard Francoise
Sayala C.
Universite Droit et Sante Lille II
Universite Paul Sabatier (Toulouse III)
Wityshyn Michael G.
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