Biologically activatable azobenzene polymers targeted at drug delivery and imaging applications
Biologically activatable azobenzene polymers targeted at drug delivery and imaging applications
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DOI：
10.1016/j.biomaterials.2018.09.020
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发表时间：
2018-12-01
期刊：
影响因子：
14
通讯作者：
Khan, Anzar
中科院分区：
文献类型：
--
作者：
Eom, Taejun;Yoo, Wonjae;Khan, Anzar
分子设计的概念，描述了制备偶氮苯聚合物能够显示出可调的反应，大鼠肝微粒体诱导的侧链自焚过程中缺氧条件下。结果表明，偶氮苯核携带的供体/受体取代模式是最活跃的系统对酶促触发偶氮苯裂解反应（半衰期= t（1/12）= 6分钟）。它们的活性随后是偶氮苯核携带供体/供体（t（1/2）= 20 min）、电子非取代（t（1/2）= 72 min）和受体（t（1/2）= 78 min）系统。当化学刺激物连二亚硫酸钠取代生物还原条件时，这种趋势得以保留，并证明了研究结果的普遍性及其在蛋白质组学程序中的潜力。此外，已建立的设计概念还允许聚合物结构和拓扑结构的变化，同时仍然保持电子取代模式。然而，偶氮苯的空间限制或固有特性（亲水/疏水）不会改变断裂反应的命运。在所有情况下，自分解过程允许聚合物链从化学中性转化为阳离子状态。这种结构转化可以用作激活机制（体外），通过与带相反电荷的细胞膜的静电相互作用进入细胞，并递送抗癌药物。有趣的是，聚合物结构现在起作用，并且瓶刷状共聚物显示出更高的选择性和更快的细胞摄取。最后，性能最好的聚合物允许结构调制成荧光成像探针。对患有结肠炎的小鼠的体内应用证实了成像探针在身体的患病结肠和盲肠部分中的积累，其中已知内源性微生物植物群产生活化酶。因此，这项工作建立了适用于递送和成像应用的生物可活化和可裂解的偶氮苯基聚合物支架的分子设计的一般原则。
Molecular design concepts are described for the preparation of azobenzene polymers capable of showing a tunable response to the rat liver microsome-induced side-chain self-immolation process under hypoxic conditions. It is shown that azobenzene nuclei carrying a donor/acceptor substitution pattern are the most active system towards the enzymatically triggered azobenzene cleavage reaction (half-life = t(1/12) = 6 min). Their activity is followed by azobenzene nuclei carrying donor/donor (t(1/2) = 20 min), electronically non-substituted (t(1/2) = 72 min), and acceptor (t(1/2) = 78 min) systems. This trend is preserved when a chemical stimulus, sodium dithionite, replaces the biological reducing conditions and demonstrates generality of the findings, and their potential in proteomics procedures. Furthermore, the established design concepts also permit for variation in polymer structure and topology while still maintaining the electronic substitution pattern. The steric constraints or the inherent character (hydrophilic/hydrophobic) of the azobenzene, however, does not alter the fate of the scission reaction. In all cases, the self-immolation process allows the polymer chain to convert from a chemically neutral to a cationic state. This structural transformation can be used as an activation mechanism (in vitro) to gain entry into cells through electrostatic interactions with the oppositely charged cell membrane and to deliver an anticancer drug. Interestingly, polymer structure now plays a role and bottlebrush-like copolymer show higher selectivity and faster cellular uptake. Finally, the best performing polymer allows for structural modulation into a fluorescent imaging probe. In vivo application to mice suffering from colitis confirms accumulation of the imaging probe in the diseased colon and cecum parts of the body where the endogenous microbial flora is known to produce the activation enzyme. This work, therefore, establishes general principles for the molecular design of biologically activatable and cleavable azobenzene-based polymeric scaffolds applicable to delivery and imaging applications.