Selective delivery of cytotoxic compounds to cells by the LDL pathway

Abstract

Cancer cells need cholesterol to make new membrane. They get it either by de novo synthesis or from low-density lipoprotein (LDL), or both. Some types of cancer have very high LDL requirements. LDL particles, which circulate in the blood, contain a cholesteryl ester core surrounded by a phospholipid coat containing apoproteins that are recognized by LDL receptors on cell surfaces. After attachment to cells, LDL is endocytosed into lysosomes, where the core is exposed and hydrolyzed. A technique is known whereby LDL can be isolated, its core removed and replaced by a compatible lipophilic substance, and then reconstituted into intact LDL particles that are recognized and internalized by cells in the normal manner. A series of cytotoxic compounds has been synthesized, designed to be compatible with reconstituted LDL, and directed against cancers that copiously internalize LDL. They were evaluated by measuring the toxicity of reconstituted LDL toward test cells bearing LDL receptors. Selectivity was determined by comparison, either with mutant cells with few LDL receptors or with reconstituted methylated LDL (which is not recognized by LDL receptors) on normal cells. Two compounds, 19 and 25, were found that reconstitute well, kill or arrest the test cells at reasonably low concentrations, and are completely selective, suggesting that they are delivered to cells exclusively via the LDL pathway.

Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme

“…Because of their hydrophobic core, the nLDLs are expected to provide a mechanism for the transport of hydrophobic drugs. In addition, hydrophilic drugs can be converted to hydrophobic pro-drugs by chemical modifications as suggested by several laboratories (Lundberg et al, 2003, Firestone et al, 1984, Dubowchik and Firestone, 1995 thus increasing the arsenal of drugs that can be potentially targeted to GBM via nLDL.…”

“…It was previously suggested that plasma-derived LDL could be used as a drug delivery system for tumors expressing LDLR since its hydrophobic core has the possibility of incorporating lipophilic drugs (Firestone, 1994, Rensen et al, 2001. Drugs have been either directly loaded onto plasma LDL or the core lipids of LDL were replaced with drugs (Callahan et al, 1999, Ji et al, 2002, Chu et al, 2001, Vitols et al, 1985, Firestone et al, 1984, Dubowchik and Firestone, 1995, Vitols et al, 1990. Plasma LDL, however, is less than ideal as a targeting agent since it is difficult to isolate in large quantities and is variable in composition and size.…”

Induction of macrophage antitumor activity by acetylated low density lipoprotein containing lipophilic muramyl tripeptide.

“…Most lipoproteins can pass from the vascular system into the body tissues (13). Furthermore, it is now possible to sequester a variety of lipophilic drugs into lipoproteins (14)(15)(16)(17)(18)(19) '25I-labeled-acetyl-LDL ('25I-acetyl-LDL) was fractionated on a Sephadex G-15-120 column, dialyzed against buffer A, and filtered before use. Acetyl-LDL:MTP-PtdEtn Complex Formation.…”

Benzophenone-containing cholesterol surrogates

“…According to procedures by Firestone et al (27) and Cope and Ciganek (28), to a solution of 1.09 g (4.85 mmol) of 25, prepared according to the procedure of Wertheim (29), in 12 ml of dry CH 2 Cl 2 was added 1.3 ml (14.5 mmol) of (COCl) 2 and five drops of DMF. The mixture was stirred at 0ЊC for 2 h. The solvent was evaporated to give a light yellow solid, which was dissolved in 10 ml of dry ether.…”

“…A solution of 680 mg (1.9 mmol) of 3,5-dibromo-4-hydroxybenzophenone (27), mp 155-156ЊC, prepared by the method of Blakey, Jones, and Scarborough (30), and 61 mg (0.19 mmol) of tetrabutylammonium bromide in 2 ml of 2 M NaOH was treated with 365 mg (0.80 mmol) of 13 in 5 ml of EtOAc and heated at reflux for 4 days. The aqueous layer was removed and the EtOAc layer was washed with 2 ϫ 10 ml of water, dried, filtered, and evaporated to afford 1.1 g of residue, which was treated with 2 ϫ 10 ml of 1:4 EtOAc:hexane to precipitate excess 27 that was collected by filtration.…”