Circulating Lipoproteins: A Trojan Horse Guiding Squalenoylated Drugs to LDL-Accumulating Cancer Cells

Abstract

Selective delivery of anticancer drugs to rapidly growing cancer cells can be achieved by taking advantage of their high receptor-mediated uptake of low-density lipoproteins (LDLs). Indeed, we have recently discovered that nanoparticles made of the squalene derivative of the anticancer agent gemcitabine (SQGem) strongly interacted with the LDLs in the human blood. In the present study, we showed both in vitro and in vivo that such interaction led to the preferential accumulation of SQGem in cancer cells (MDA-MB-231) with high LDL receptor expression. As a result, an improved pharmacological activity has been observed in MDA-MB-231 tumor-bearing mice, an experimental model with a low sensitivity to gemcitabine. Accordingly, we proved that the use of squalene moieties not only induced the gemcitabine insertion into lipoproteins, but that it could also be exploited to indirectly target cancer cells in vivo.

Squalene-Adenosine Nanoparticles: Ligands of Adenosine Receptors or Adenosine Prodrug?

“…Cells were washed with PBS, and medium was replaced with normal medium or medium supplemented with LPDS instead of FBS. Cells were then incubated for 24 hours to enhance LDLR expression, as proven by Western blot [protocol from Sobot et al (2017a); Supplementary Fig. 2)], and subsequently treated with fluorescently labeled SQAd NPs (10 mg/ml).…”

Albumin-driven disassembly of lipidic nanoparticles: the specific case of the squalene-adenosine nanodrug

“…49,50 To monitor the impact of plasma components on the SQAd nanoparticles dispersion, we have performed SANS experiments with SQAd nanoparticles in fetal bovine serum (FBS), which, in addition to BSA, contains tens of other proteins 18 and lipoproteins particles whom previous studies have shown their importance for SQAd transport and targeting. [37][38][39] For comparison, Figure 2A first shows the SANS patterns of 0.4 mg/ml SQAd nanoparticles in D 2 O (blue circles). This signal is typical of hydrogenated spherical nanoparticles dispersed in a deuterated solvent.…”

“…This assumption is in line with previously proposed transport of squalene-gemcitabine by albumin. 37,39 The nanoparticles are thus playing the…”

“…In 2010, Bildstein et al have shown that uptake of the drugs by the cells was influenced by the concentration and the nature of extracellular proteins. 29 It was later shown by radio-analysis of plasma fractions and molecular dynamic simulations that low density lipoproteins (LDL) 37 and to a lesser extent human serum albumins 37,39,40 participated in the uptake of squalene-gemcitabine bioconjugates. However, the specificity of the SQAd interactions with these biomolecules remains unknown.…”

Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

“…[186][187][188] Nanomedicine formulations of gemcitabine can take advantage of the EPR effect to increase gemcitabine content within tumor tissues upon intravenous injection. [189][190][191][192] Having more gemcitabine distributed into tumor tissues will provide them the chance to kill tumor cells or inhibit tumor cell growth. …”