Abstract
Significant low density lipoprotein (LDL) uptake by tumour cells led to the use of LDL as a discriminatory vehicle for the delivery of cytotoxic drugs. In the current study, the lipophilic elliptinium derivative, elliptinium-oleate (OL-NME), was incorporated into LDL to reach an incorporation level of 400 molecules per LDL particle. The OL-NME-LDL complex showed cytotoxic effects on normal human fibroblasts while the cytotoxicity was not observed on receptor-defective human fibroblasts, indicating the ability of the complex to be preferentially metabolised by the LDL receptor. In vivo metabolism of the complex was related to the LDL receptor pathway. The metabolic clearance was the same for native LDL (17.1 ml h-1) and OL-NME-LDL complex (16.2 ml h-1). LDL incorporated OL-NME enhanced the anti-tumour activity against murine B16 melanoma model; this resulted from increased efficacy for OL-NME-LDL at doses equal to free 9-OH-NME (157 vs 76 of Increase Life Span (ILS) (%) values after intraperitoneal (i.p.) drug injection on i.p. implanted tumour model and 45 vs -2 ILS (%) values after intravenous drug injection on subcutaneous implanted tumour model). These data suggest that LDL improves the potency of lipophilic cytotoxic drugs against tumours that express LDL receptor activity.
Highlights
The recovery of 9-oleoyloxy-N2-methyl ellipticinium oleate (OL-NME) into low density lipoprotein (LDL) was not significantly different when the micro emulsions were obtained with free cholesterol and sphingomyelin (83 ± 2 vs 88 ± 8)
These compounds increased the stability of the micro emulsion since the density of the micro emulsion particles remained unchanged during incubation as compared to the particles before incubation and they were readily separated from the LDL after a 20 h incubation at 37°C
All the drug not incorporated into lipoproteins was quantitatively recovered in the micro emulsion layer after density gradient ultracentrifugation
Summary
9-Oleyloxy-hydroxy-N2-methyl ellipticinium oleate (OL-NME) was synthesised as described by Samadi-Baboli et al (1990). Foetal calf serum (FCS), RPMI 1640, phosphate buffered saline (PBS), penicillin, streptomycin and glutamine were obtained form Intermed (Strasbourg, France). SAMADI-BABOLI et al. Human skin fibroblasts from a normo-cholesterolemic donor (nF) were a generous gift from Pr Soleilhavoup (Faculte de Medecine Toulouse, France) and receptor-negative fibroblasts (FH: Familial Hypercholesterolemia in its homozygous form: no activity of the LDL receptor was shown by the Goldstein and Brown procedure (Goldstein & Brown, 1974) from Prs P. Human LDL were isolated, as previously described (SamadiBaboli et al, 1990), from the plasma of individual healthy fasted volunteers by rate-zonal ultracentrifugation in sodium bromide gradient (Patsh et al, 1974) using a TG-65 ultracentrifuge and Ti-14 zone rotor (Kontron Instruments, France). The LDL were stored at 4°C for no longer than 2 weeks
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