Squalene-Based Nano-Assemblies Improve the Pro-Autophagic Activity of Trehalose

Abstract

The disaccharide trehalose is a well-established autophagy inducer, but its therapeutic application is severely hampered by its low potency and poor pharmacokinetic profile. Thus, we targeted the rational design and synthesis of trehalose-based small molecules and nano objects to overcome such issues. Among several rationally designed trehalose-centered putative autophagy inducers, we coupled trehalose via suitable spacers with known self-assembly inducer squalene to yield two nanolipid-trehalose conjugates. Squalene is known for its propensity, once linked to a bioactive compound, to assemble in aqueous media in controlled conditions, internalizing its payload and forming nanoassemblies with better pharmacokinetics. We assembled squalene conjugates to produce the corresponding nanoassemblies, characterized by a hydrodynamic diameter of 188 and 184 nm and a high stability in aqueous media as demonstrated by the measured Z-potential. Moreover, the nanoassemblies were characterized for their toxicity and capability to induce autophagy in vitro.

Cannabidiol as Self-Assembly Inducer for Anticancer Drug-Based Nanoparticles

“…Otherwise, the incubation of MeT-5A with 8B showed a GI 50 value of 2.1 ± 0.5 µM, that is about four times higher than that obtained for mesothelioma tumor cells (0.43 ± 0.01 µM, Table 2), indicating a lower effect in normal cells. These data are in agreement with the observation that intracellular levels of reduced glutathione are upregulated in a number of human cancers [23] and support the rationale of the synthetic approach, in accordance with the ability of the disulfide-containing bivalent conjugates to release the active drug inside cells, as already reported [3,11].…”

“…For several years we have been interested in using this kind of NPs to improve the properties of both anticancer and neuroprotective drugs [3][4][5][6][7][8][9][10][11][12][13][14]. We designed conjugates able to form NPs that can release the drug in cellular media, [3,8,11,14] hetero-NPs bearing Based on the above statements, we considered CBD for its potential dual activity (cytotoxic compound and self-assembly inducer) and to conjugate it to well-known tubulin binder drugs, N-desacetyl thiocolchicine (2), podophyllotoxin (3), and paclitaxel (4), through two different linkers, 5a and 5b (Figure 1). The synthesis and characterization of the planned conjugates and their ability to form self-assembled NPs are here reported.…”

Trehalose-Bearing Carriers to Target Impaired Autophagy and Protein Aggregation Diseases

“…Unfortunately, none of the nanoassemblies induced autophagy in vitro , likely because of insufficient concentration of free trehalose resulting from the limited hydrolysis of ester linkage in the cell environment. In the next attempt, squalene–trehalose conjugates were bound via a biologically labile disulfide bond . Two nanoassemblies from trehalose–monosqualene and trehalose–disqualene conjugates were fabricated.…”

Folic acid functionalization for targeting self-assembled paclitaxel-based nanoparticles

“…This kind of conjugates is capable to spontaneously assemble in water, forming NPs able to release a payload drug in cellular media. [4][5][6][7][8] Additional modications can be made on this simple design in order to obtain hetero-NPs bearing two different drugs (combining different conjugates that present the same lipidic self-assembling inducer); 9,10 single and dual drug uorescent hetero-NPs (where in one of the conjugates the drug is substituted by a uorescent moiety) 11,12 and NPs formed by selfassembling conjugate dual drugs (in which also the selfassembly inducer is pharmaceutically active). 13,14 Recently, we focused on further improving these NPs, by exploiting targeted drug delivery through folate-containing hetero-NPs.…”