Fallacara Anna Lucia, Mancini Arianna, Zamperini Claudio, Dreassi Elena, Marianelli Stefano, Chiariello Mario, Pozzi Gianni, Santoro Francesco, Botta Maurizio, Schenone Silvia
Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy.
Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy; Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, IT, Italy.
Bioorg Med Chem Lett. 2017 Jul 15;27(14):3196-3200. doi: 10.1016/j.bmcl.2017.05.015. Epub 2017 May 17.
Pyrazolo[3,4-d]pyrimidine derivatives 1-5, active as c-Src inhibitors, have been selected to be formulated as drug-loaded human serum albumin (HSA) nanoparticles, with the aim of improving their solubility and pharmacokinetic properties. The present study includes the optimization of a desolvation method-based procedure for preparing HSA nanoparticles. First, characterization by HPLC-MS and Dynamic Light Scattering (DLS) showed a good entrapment efficacy, a controllable particle size (between 100 and 200nm) and an optimal stability over time, confirmed by an in vitro drug release assay. Then, 1-4 and the corresponding NPs were tested for their antiproliferative activity against neuroblastoma SH-SY5Y cell line. Notably, 3-NPs and 4-NPs were identified as the most promising formulation showing a profitable balance of stability, small size and a similar activity compared to the free drugs in cell-based assays. In addition, albumin formulations increase the solubility of pyrazolo[3,4-d]pyrimidine avoiding the use of DMSO as solubilizing agent.
作为c-Src抑制剂具有活性的吡唑并[3,4-d]嘧啶衍生物1-5已被选定制成载药人血清白蛋白（HSA）纳米颗粒，目的是改善其溶解性和药代动力学性质。本研究包括对基于去溶剂化方法制备HSA纳米颗粒的程序进行优化。首先，通过HPLC-MS和动态光散射（DLS）进行表征，结果显示包封效率良好、粒径可控（在100至200nm之间）且经体外药物释放试验证实具有最佳的长期稳定性。然后，测试了1-4以及相应的纳米颗粒对神经母细胞瘤SH-SY5Y细胞系的抗增殖活性。值得注意的是，3-纳米颗粒和4-纳米颗粒被确定为最有前景的制剂，在基于细胞的试验中，它们在稳定性、小尺寸和与游离药物相似的活性之间展现出有利的平衡。此外，白蛋白制剂提高了吡唑并[3,4-d]嘧啶的溶解性，避免了使用二甲基亚砜作为增溶剂。
