Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria.
Department of Pharmaceutical Technology, University of Navarra, 31008 Pamplona, Spain.
Int J Pharm. 2019 Feb 10;556:1-8. doi: 10.1016/j.ijpharm.2018.11.070. Epub 2018 Dec 6.
The present study evaluates the potential of encapsulated doxorubicin to reduce both the viability of melanoma cells and the tumor growth in a mouse melanoma model. The prepared doxorubicin loaded chitosan/alginate nanoparticles possessed mean diameter around 300 nm and negative zeta-potential. Classical molecular dynamic simulations revealed that the high encapsulation efficiency (above 90%) was mainly due to electrostatic interaction between doxorubicin and sodium alginate, although dipole-dipole and hydrophobic interactions might also contribute. The in vitro dissolution tests showed slower doxorubicin release in slightly alkaline medium (pH = 7.4) and faster release in acid one (pH = 5.5), indicating that higher concentration of doxorubicin might reach the acidic tumor tissue. The free and the encapsulated doxorubicin decreased the viability of melanoma cell lines (B16-F10 and B16-OVA) in a similar degree. However, the cytotoxic effect of the encapsulated doxorubicin still occurred in the more resistant B16-F10 cells even after removing the extracellular drug. The experiments on a syngeneic melanoma mouse model revealed that free and encapsulated doxorubicin elicited the control of the tumor growth (dose of 3 mg/kg). Thus, the encapsulation of doxorubicin into chitosan/alginate nanoparticles could be considered advantageous because of the better intracellular accumulation and longer cytotoxic effect on the investigated melanoma cells.
本研究评估了包载阿霉素的纳米粒在减少黑素瘤细胞活力和小鼠黑素瘤模型中肿瘤生长的潜力。所制备的载阿霉素壳聚糖/海藻酸钠纳米粒的平均直径约为 300nm，具有负的 zeta 电位。经典分子动力学模拟表明，高包封效率（超过 90%）主要归因于阿霉素与海藻酸钠之间的静电相互作用，尽管偶极-偶极和疏水相互作用也可能有一定贡献。体外溶出试验表明，在略碱性介质（pH=7.4）中阿霉素释放更慢，在酸性介质（pH=5.5）中释放更快，表明更高浓度的阿霉素可能到达酸性肿瘤组织。游离和包载的阿霉素以相似的程度降低了黑素瘤细胞系（B16-F10 和 B16-OVA）的活力。然而，即使在去除细胞外药物后，包载的阿霉素的细胞毒性作用仍在更耐药的 B16-F10 细胞中发生。在同种异体黑素瘤小鼠模型上的实验表明，游离和包载的阿霉素均能控制肿瘤生长（剂量为 3mg/kg）。因此，将阿霉素包封到壳聚糖/海藻酸钠纳米粒中可能是有利的，因为其可以更好地在细胞内积累，对所研究的黑素瘤细胞产生更长的细胞毒性作用。
