Institut Galien Paris-Saclay, UMR 8612, CNRS, Université Paris-Saclay, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, F-92296 cedex Châtenay-Malabry, France.
Laboratoire de Physique de la Matière Condensée (PMC), CNRS, Ecole Polytechnique, Institut Polytechnique de Paris, 91120 Palaiseau, France.
Bioconjug Chem. 2021 Apr 21;32(4):782-793. doi: 10.1021/acs.bioconjchem.1c00051. Epub 2021 Apr 2.
A small library of amphiphilic prodrugs has been synthesized by conjugation of gemcitabine (Gem) (a hydrophilic nucleoside analogue) to a series of lipid moieties and investigated for their capacity to spontaneously self-assemble into nanosized objects by simple nanoprecipitation. Four of these conjugates formed stable nanoparticles (NPs), while with the others, immediate aggregation occurred, whatever the tested experimental conditions. Whether such capacity could have been predicted based on the prodrug physicochemical features was a matter of question. Among various parameters, the hydrophilic-lipophilic balance (HLB) value seemed to hold a predictive character. Indeed, we identified a threshold value which well correlated with the tendency (or not) of the synthesized prodrugs to form stable nanoparticles. Such a hypothesis was further confirmed by broadening the analysis to Gem and other nucleoside prodrugs already described in the literature. We also observed that, in the case of Gem prodrugs, the lipid moiety affected not only the colloidal properties but also the anticancer efficacy of the resulting nanoparticles. Overall, this study provides a useful demonstration of the predictive potential of the HLB value for lipid prodrug NP formulation and highlights the need of their opportune in vitro screening, as optimal drug loading does not always translate in an efficient biological activity.
已经通过将吉西他滨（Gem）（一种亲水核苷类似物）与一系列脂质部分缀合来合成了一个小型的两亲前药库，并通过简单的纳米沉淀研究了它们自发自组装成纳米尺寸物体的能力。这四种缀合物形成了稳定的纳米颗粒（NPs），而对于其他缀合物，无论测试的实验条件如何，都会立即发生聚集。这种能力是否可以基于前药的物理化学特性来预测是一个问题。在各种参数中，亲水-亲脂平衡（HLB）值似乎具有预测特征。实际上，我们确定了一个阈值，该阈值与合成前药形成稳定纳米颗粒的趋势（或不）很好地相关。通过将分析扩展到已在文献中描述的 Gem 和其他核苷前药，进一步证实了这一假设。我们还观察到，对于 Gem 前药，脂质部分不仅影响胶体性质，而且影响所得纳米颗粒的抗癌功效。总的来说，这项研究为脂质前药 NP 制剂的 HLB 值的预测潜力提供了有用的证明，并强调了对其进行适当的体外筛选的必要性，因为最佳药物载量并不总是转化为有效的生物活性。
