Abstract

A library of arginine-like surface modifiers was tested to improve the targetability of DOPE:DOPC liposomes towards myofibroblasts in a tumour microenvironment. Liposomes were characterised using zeta potential and dynamic light scattering. Cell viability remained unchanged for all liposomes. Liposomes were encapsulated using doxorubicin (DOX) with an encapsulation efficiency >94%. The toxicity of DOX-loaded liposomes was calculated via half-maximal inhibitory concentration (IC₅₀) for fibroblasts and myofibroblasts. These liposomes resulted in significantly lower IC₅₀-values for myofibroblasts compared to fibroblasts, making them more toxic towards the myofibroblasts. Furthermore, a significant increase in cell internalisation was observed for myofibroblasts compared to fibroblasts, using fluorescein-loaded liposomes. Most importantly, a novel regression model was constructed to predict the IC₅₀-values for different modifications using their physicochemical properties. Fourteen modifications (A–N) were used to train and validate this model; subsequently, this regression model predicted IC₅₀-values for three new modifications (O, P and Q) for both fibroblasts and myofibroblasts. Predicted and measured IC₅₀-values showed no significant difference for fibroblasts. For myofibroblasts, modification O showed no significant difference. This study demonstrates that the tested surface modifications can improve targeting to myofibroblasts in the presence of fibroblasts and hence are suitable drug delivery vehicles for myofibroblasts in a tumour microenvironment.

摘要

测试了一个精氨酸样表面修饰剂库，以提高 DOPE:DOPC 脂质体在肿瘤微环境中对肌成纤维细胞的靶向性。脂质体使用 zeta 电位和动态光散射进行表征。所有脂质体的细胞活力保持不变。使用多柔比星 (DOX) 封装脂质体，封装效率 > 94%。通过成纤维细胞和肌成纤维细胞的半数最大抑制浓度 (IC _{50 ) 计算载有 DOX 的脂质体的毒性。}这些脂质体导致显着降低 IC ₅₀-肌成纤维细胞与成纤维细胞相比的值，使它们对肌成纤维细胞更具毒性。此外，与成纤维细胞相比，使用负载荧光素的脂质体观察到肌成纤维细胞的细胞内化显着增加。最重要的是，构建了一种新的回归模型来使用它们的物理化学性质来预测不同修饰的IC _50值。使用了 14 次修改 (A-N) 来训练和验证该模型；随后，该回归模型预测了成纤维细胞和肌成纤维细胞的三种新修饰（O、P和Q）的IC _50值。预测和测量 IC ₅₀值显示成纤维细胞没有显着差异。对于肌成纤维细胞，修饰O没有显示出显着差异。该研究表明，所测试的表面修饰可以在成纤维细胞存在的情况下提高对肌成纤维细胞的靶向性，因此是肿瘤微环境中肌成纤维细胞的合适药物递送载体。