Conjugation of squalene to gemcitabine as unique approach exploiting endogenous lipoproteins for drug delivery

Abstract

Once introduced in the organism, the interaction of nanoparticles with various biomolecules strongly impacts their fate. Here we show that nanoparticles made of the squalene derivative of gemcitabine (SQGem) interact with lipoproteins (LPs), indirectly enabling the targeting of cancer cells with high LP receptors expression. In vitro and in vivo experiments reveal preeminent affinity of the squalene-gemcitabine bioconjugates towards LP particles with the highest cholesterol content and in silico simulations further display their incorporation into the hydrophobic core of LPs. To the best of our knowledge, the use of squalene to induce drug insertion into LPs for indirect cancer cell targeting is a novel concept in drug delivery. Interestingly, not only SQGem but also other squalene derivatives interact similarly with lipoproteins while such interaction is not observed with liposomes. The conjugation to squalene represents a versatile platform that would enable efficient drug delivery by simply exploiting endogenous lipoproteins.

Ligand‐Installed Nanocarriers toward Precision Therapy

“…Moreover, it has been demonstrated in recent research that low‐density lipoproteins (LDLs) can facilitate cancer cell–specific drug delivery through specific internalization with cancer cells that are highly expressed with LDL receptors. For instance, the loading of lipoproteins with anticancer drugs (e.g., gemcitabine) has led to the demonstration of a high accumulation inside cancer cells (e.g., MDA‐MB‐231 breast cancer cells) with overexpressed LDL receptors, as tested both in vitro and in vivo, demonstrating the high selectivity of lipoproteins to cancer cells . In addition, some synthetic proteins have also been selected as targeting moieties for nanocarriers.…”

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

“…These nanoparticles are formed by nanoprecipitation of SQAd bioconjugates in water through hydrophobic interactions ( Figure 1). [28][29][30][31][32][33][34] Adenosine is an endogenous nucleoside with potential neuroprotective pharmacological activity through the targeting of its four receptors expressed throughout the body. 35,36 The "squalenoylation" of adenosine was previously found to increase its half-life, and to avoid adverse effects of free adenosine 33,34 , while the squalene moiety drives the assembly of the nanoparticles in water.…”

“…35,36 The "squalenoylation" of adenosine was previously found to increase its half-life, and to avoid adverse effects of free adenosine 33,34 , while the squalene moiety drives the assembly of the nanoparticles in water. Although the efficacy of squalene-based drugs has already been demonstrated in vivo on rodents 33,37 , the pharmacokinetics of such assembled systems is extremely hard to evaluate since the circulating prodrug is potentially present under three forms upon administration: assembled into nanoparticles, as free bioconjugates and bound to plasma proteins. 38 This partitioning can have important consequences on the transport and subsequent tissue/cell uptake of the drug.…”

“…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.…”

Dual controlled delivery of squalenoyl-gemcitabine and paclitaxel using thermo-responsive polymeric micelles for pancreatic cancer

“…PTX is already highly lipophilic and could be incorporated in the hydrophobic compartment of the polymer micelles, whereas gemcitabine in its parent form is highly water soluble and hence a synthetic more lipophilic 28 derivative was chosen; squalene-gemcitabine was synthesized by the amide coupling of squalenic acid with gemcitabine at the 4-amino position that results in the formation of an amphiphilic drug with its own self-assembly properties: Sq-gem forms nanoparticles of ca. 130 nm in solution.…”