Frapporti Giulia, Colombo Eleonora, Ahmed Hazem, Assoni Giulia, Polito Laura, Randazzo Pietro, Arosio Daniela, Seneci Pierfausto, Piccoli Giovanni
Department of Cellular, Computational and Integrative Biology (CIBIO), Via Sommarive 9, Povo, I-38123 Trento, Italy.
Chemistry Department, Università Statale di Milano, Via Golgi 19, I-20133 Milan, Italy.
Pharmaceutics. 2022 Apr 14;14(4):862. doi: 10.3390/pharmaceutics14040862.
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.
二糖海藻糖是一种公认的自噬诱导剂，但其治疗应用因效力低和药代动力学特性差而受到严重阻碍。因此，我们致力于基于海藻糖的小分子和纳米物体的合理设计与合成，以克服这些问题。在几种合理设计的以海藻糖为中心的假定自噬诱导剂中，我们通过合适的间隔基将海藻糖与已知的自组装诱导剂角鲨烯偶联，得到了两种纳米脂质 - 海藻糖缀合物。角鲨烯因其一旦与生物活性化合物连接，就倾向于在受控条件下在水性介质中组装，内化其负载并形成具有更好药代动力学的纳米组装体而闻名。我们组装角鲨烯缀合物以产生相应的纳米组装体，其流体动力学直径分别为188和184 nm，并且如所测的Z电位所示，在水性介质中具有高稳定性。此外，对纳米组装体的毒性及其在体外诱导自噬的能力进行了表征。
