Abstract
The disaccharide trehalose is an autophagy inducer, but its pharmacological application is severely limited by its poor pharmacokinetics properties. Thus, trehalose was coupled via suitable spacers with squalene (in 1:2 and 1:1 stoichiometry) and with betulinic acid (1:2 stoichiometry), in order to yield the corresponding nanolipid-trehalose conjugates 1-Sq-mono, 2-Sq-bis and 3-Be-mono. The conjugates were assembled to produce the corresponding nano-assemblies (NAs) Sq-NA1, Sq-NA2 and Be-NA3. The synthetic and assembly protocols are described in detail. The resulting NAs were characterized in terms of loading and structure, and tested in vitro for their capability to induce autophagy. Our results are presented and thoroughly commented upon.
Highlights
Nano-vectors are used as therapeutics and diagnostics [1,2]
33..11.c.SoSnyynjuntgthhaeestseisi)soaofnfTTdaarraggeebtti1s1---smmquooannlooenaaynnlddat22e--dbbiitssreSShqqauulaoallseeenneec-oTnreshtraulocste(Ctaorngjeutgcaotems pound 2-Sq-bis, 2:1 squalenetrehalose conjugate), we focused our attention onto the hexaTMS-protected trehalose derivative 5 [3I8In]naonordrddetehrretoctaorbbtooabxiyntalaeintiethdesirtqhauemarleonaneo-m-li(ntoaknregore-a(ttdcadorgumecptt o6cu[o3nm1d]p1(Fo-Siugqnu-drme o21)n-.Soq, 1-m:1osnqou,ale1n:1e-tsrqeuhaloensee-ctorenhjuagloaste) caonndjugaabteis)-saqnudalaenbyisl-astqeudalterenhyalalotesde tcroenhsatlrouscet c(otanrsgtreut ccto(mtaprgoeutncdom2-pSoqu-bnids,22-S:1q-sbqius,al2e:n1es-tqrueahlaelnoes-e tcroehnajulogsaetec),ownjeugfoacteu)s,ewd eouforcautstendtioounroanttoenthtieonheoxnatToMthSe-phroexteacTteMdSt-rperhoatleocsteddetrievhaatliovsee5d[e3r8i]vaantidveth5e
We could not rule out the presence of trehalose at lower, nM concentrations that would not elicit an autophagy-inducing effect in cells, due to its detection LC-MS limits; and we suggest that highly lipophilic lipid-trehalose intermediates 1-Sq-Pmhaornmoaceauntidcs 320-B19e, -1m1, o42n2o remain trapped within the protein pellet
Summary
Nano-vectors are used as therapeutics and diagnostics [1,2]. Iron-based [3], gold-based [4] and silica-based inorganic nano-vectors [5] were tested as being a diagnostic (magnetic resonance imaging reagents/MRIs [6]), or as therapeutics (hyperthermia against tumors [7], iron replacement therapies [8]). Trehalose [15,16] is a non-reducing disaccharide made by a 1,1 linkage between two d-glucose molecules. Trehalose induces autophagy in vitro and in vivo [19] and reduces protein misfolding and aggregation in vitro [20] by acting as a chemical chaperone and solvating them [20]. Nano lipid-drug conjugates [24], obtained by the covalent coupling of a drug to bio-compatible lipids, improve pharmacokinetics, decrease toxicity and increase the therapeutic index of the associated. Nano lipid-drug conjugates [24], obtained by the covalent coupling of a drug to bio-compatible lipids, improve pharmacokinetics, decrease toxicity and increase the therapeutic index of the dasrusogcsi.aItnedpadrrtuicgusl.arI,nsqpuaartliecnuel-abra, sseqduaamlepneh-ibpahsileidc caomnjpuhgiapthesilihcacvoenajupgroatveesnhtaravcekarepcroorvdefnortrtahcekrarpeecuotridc afoprptlhiceartaiponeust[i2c5a]p.
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