Enhanced biocompatibility of PAMAM dendrimers benefiting from tuning their surface charges
Enhanced biocompatibility of PAMAM dendrimers benefiting from tuning their surface charges
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得益于调整表面电荷，PAMAM 树枝状聚合物的生物相容性得到增强
DOI：
10.1016/j.msec.2018.07.070
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发表时间：
2018-12-01
影响因子：
7.9
通讯作者：
Chen, Shengfu
中科院分区：
文献类型：
--
作者：
Cui, Yanshuai;Liang, Bo;Chen, Shengfu
树枝状大分子的表面电荷是决定其在纳米医学中应用的关键因素之一。研究了荧光素钠包覆的第五代聚酰胺胺树枝状大分子(G5 PAMAM)的表面电荷调节方法。首先，表面伯胺与顺丁烯二酸酐反应，引入双键。然后，L-半胱氨酸和半胱胺分别在水中通过硫醇-烯加成反应连接到这两个双键上。通过调节L-半胱氨酸与半胱胺的摩尔比，成功地控制了改性G5 PAMAM的表面电荷。在生理pH下，修饰后的G5 PAMAM的表面电荷在-16.0 mV到-3.7 mV之间变化。此外，与G5 PAMAM相比，它们与蛋白质和细胞具有良好的相容性。修饰后的G5 PAMAM和纤维蛋白原在溶液中共存，不会产生明显的聚集，而G5 PAMAM可以诱导明显的聚集，表明这些修饰可以有效地降低G5 PAMAM与蛋白质之间的相互作用力。此外，经修饰的G5 PAMAM的溶血作用可忽略不计，而G5 PAMAM可引起严重的溶血。细胞毒性实验表明，在高达2 mg/mL的浓度下，修饰的G5 PAMAM对HUVEC细胞和KB细胞都表现出很低的细胞毒性(细胞存活率为90%)。与G5 PAMAM相比，它们的细胞摄取效率要低得多。此外，静脉注射修饰的G5 PAMAM经肾脏排泄，在肝脏中蓄积较少，证实了它们在体内具有良好的生物相容性。改性后的G5 PAMAM有望成为未来造影剂载体的理想候选材料。
The surface charge of dendrimers is one of the key factors that determine their use in nanomedicine. Generation 5 poly(amido amine) dendrimers (G5 PAMAM) encapsulating with fluorescein sodium were employed to study the method to tune surface charge. Firstly, the surface primary amines were reacted with maleic anhydride to introduce double bonds. Then, L-cysteine and cysteamine were conjugated to these double bonds via thiol-ene additions in water, respectively. The surface charges of modified G5 PAMAMs were successfully controlled by tuning the molar ratio of L-cysteine to cysteamine. The surface charges of the resulting modified G5 PAMAMs varied from -16.0 mV to -3.7 mV at physiological pH. In addition, they showed good compatibility with proteins and cells compared with G5 PAMAM. Modified G5 PAMAMs and fibrinogen could coexist in solution without generating noticeable aggregation, while G5 PAMAM induces significant aggregation, indicating these modifications can effectively reduce the interaction force between G5 PAMAM and proteins. Furthermore, modified G5 PAMAMs exhibited negligible hemolysis, while G5 PAMAM caused severe hemolysis. The cytotoxicity assay demonstrated that modified G5 PAMAMs exhibited very low cytotoxicity to both HUVEC cells and KB cells (> 90% cell viability) at high concentrations up to 2 mg/mL. The cellular uptake of them was much less efficient compared with that of G5 PAMAM. Moreover, the intravenous injected modified G5 PAMAMs were excreted by kidney with a relatively little accumulation in liver, confirming their good biocompatibility in viva. It is expected that the modified G5 PAMAMs could be an excellent candidate for contrast agent carriers in the future.