Abstract
Limited drug loading capacity (LC), mostly below 5% w/w, is a significant drawback of nanoparticulate drug delivery systems (DDS). Squalenoylation technology, which employs bioconjugation of squalenyl moiety and drug, allows self-assemble of nanoparticles (NPs) in aqueous media with significantly high LC (>30% w/w). The synthesis and particle preparation of squalenoylated prodrugs are, however, not facile for molecules with multiple reactive groups. Taking a different approach, we describe the synthesis of amphiphilic squalenyl derivatives (SqDs) as well as the physicochemical and biopharmaceutical characterizations of their self-assembled NPs as DDSs. The SqDs included in this study are (i) cationic squalenyl diethanolamine (ii) PEGylated SqD (PEG 750 Da), (iii) PEGylated SqD (PEG 3,000 Da), and (iv) anionic squalenyl hydrogen sulfate. All four SqDs self-assemble into NPs in a size range from 100 to 200 nm in an aqueous solution. Furthermore, all NP derivatives demonstrate appropriate biocompatibility and adequate colloidal stability in physiological relevant pH environments. The mucoprotein binding of PEGylated NPs is reduced compared to the charged NPs. Most importantly, this technology allows excellent LC (at maximum of 45% w/w) of a wide range of multifunctional compounds, varying in physicochemical properties and molecular weight. Interestingly, the drug release profile can be tuned by different loading methods. In summary, the SqD-based NPs appear as versatile drug delivery platforms.
Highlights
Nano-sized drug delivery systems (DDS) having the size range from 10 to 1,000 nm have been investigated intensively to improve the treatment efficacy of severe diseases (Bobo et al, 2016; Ho et al, 2019)
The cationic squalenyl derivative (cSq) and PEGylated squalenyl derivative (SqD) were straightforwardly obtained by simple reductive amination reaction from 1,1′,2-trisnorsqualenic aldehyde
The successful synthesis and purification of all SqDs were confirmed by 1H-NMR and 13C-NMR (Supplementary Figures 1–8)
Summary
Nano-sized drug delivery systems (DDS) having the size range from 10 to 1,000 nm have been investigated intensively to improve the treatment efficacy of severe diseases (Bobo et al, 2016; Ho et al, 2019). With the aim to formulate nanomedicines having a maximized LC, Couvreur et al (2006) invented the squalenoylation approach. This unique technique creates a prodrug by bioconjugation of a drug molecule and a hydrophobic squalenyl moiety. The squalenoylated prodrug could self-assemble into uniform and stable nanoparticles (NPs) in aqueous solution without using additional surfactants (Desmaële et al, 2012), which cannot be achieved by other lipid prodrugs, e.g., employing stearyl moiety (Couvreur et al, 2006). Using squalenyl derivatives in developing DDS is favorable (Reddy and Couvreur, 2009)
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