CQM-Centro de Química da Madeira, MMRG, Universidade da Madeira, Campus Universitário da Penteada, 9020-105 Funchal, Portugal.
Department of Bioinformatics, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio Avenue 7, LT-10257 Vilnius, Lithuania.
Biomacromolecules. 2022 Jan 10;23(1):20-33. doi: 10.1021/acs.biomac.1c00455. Epub 2021 Dec 6.
Although doxorubicin (DOX) is one of the most used chemotherapeutic drugs due to its efficacy against a wide group of cancer types, it presents severe side effects. As such, intensive research is being carried out to find new nanoscale systems that can help to overcome this problem. Polyester dendrimers based on the monomer 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) are very promising systems for biomedical applications due to their biodegradability properties. In this study, bis-MPA-based dendrimers were, for the first time, evaluated as DOX delivery vehicles. Generations 4 and 5 of bis-MPA-based dendrimers with hydroxyl groups at the surface were used (B-G4-OH and B-G5-OH), together with dendrimers partially functionalized with amine groups (B-G4-NH/OH and B-G5-NH/OH). Partial functionalization was chosen because the main purpose was to compare the effect of different functional groups on dendrimers' drug delivery behavior without compromising cell viability, which is often affected by dendrimers' cationic charge. Results revealed that bis-MPA-based dendrimers were cytocompatible, independently of the chemical groups that were present at their surface. The B-G4-NH/OH and B-G5-NH/OH dendrimers were able to retain a higher number of DOX molecules, but the in vitro release of the drug was faster. On the contrary, the hydroxyl-terminated dendrimers exhibited a lower loading capacity but were able to deliver the drug in a more sustained manner. These results were in accordance with the cytotoxicity studies performed in several models of cancer cell lines and human mesenchymal stem cells. Overall, the results confirmed that it is possible to tune the drug delivery properties of bis-MPA-based dendrimers by modifying surface functionalization. Moreover, molecular modeling studies provided insights into the nature of the interactions established between the drug and the bis-MPA-based dendrimers─DOX molecules attach to their surface rather than being physically encapsulated.
尽管多柔比星（DOX）因其对广泛类型癌症的疗效而被广泛用作化疗药物，但它也存在严重的副作用。因此，正在进行大量研究以寻找新的纳米系统来帮助克服这一问题。基于单体 2,2-双（羟甲基）丙酸（bis-MPA）的聚酯树突状聚合物由于其生物降解性能，是非常有前途的生物医学应用系统。在这项研究中，首次将基于 bis-MPA 的树突状聚合物评估为 DOX 递药载体。使用了具有表面羟基的基于 bis-MPA 的第 4 代和第 5 代树突状聚合物（B-G4-OH 和 B-G5-OH），以及部分官能化有胺基的树突状聚合物（B-G4-NH/OH 和 B-G5-NH/OH）。选择部分官能化是因为主要目的是比较不同官能团对树突状聚合物递药行为的影响，而不会损害细胞活力，因为细胞活力常常受到树突状聚合物的正电荷影响。结果表明，基于 bis-MPA 的树突状聚合物具有细胞相容性，与其表面存在的化学基团无关。B-G4-NH/OH 和 B-G5-NH/OH 树突状聚合物能够保留更多的 DOX 分子，但药物的体外释放速度更快。相反，羟基封端的树突状聚合物的载药量较低，但能够以更持续的方式递药。这些结果与在几种癌细胞系和人骨髓间充质干细胞模型中进行的细胞毒性研究一致。总体而言，结果证实通过修饰表面官能化，可以调节基于 bis-MPA 的树突状聚合物的药物递药特性。此外，分子模拟研究提供了关于药物与基于 bis-MPA 的树突状聚合物之间建立的相互作用性质的见解——DOX 分子附着在其表面上，而不是物理包裹。
