Ugur Esma, Tidim Gökçe, Gundogdu Dilara, Alemdar Cemre, Oral Goksu, Husnugil H Hazal, Banerjee Sreeparna, Erel-Goktepe Irem
Department of Chemistry, Middle East Technical University, 06800 Cankaya, Ankara, Türkiye.
Department of Biology, Middle East Technical University, 06800 Cankaya, Ankara, Türkiye.
ACS Omega. 2024 Sep 11;9(38):39626-39642. doi: 10.1021/acsomega.4c03977. eCollection 2024 Sep 24.
This study reports, first, on the preparation and cross-linking of multilayers composed of poly(2-isopropyl-2-oxazoline--ethyleneimine) (PiPOX-PEI) and tannic acid (TA). PiPOX was synthesized by cationic ring-opening polymerization (CROP) and partially hydrolyzed, yielding a random copolymer PiPOX-PEI. It was then coassembled at the surface with TA using the layer-by-layer (LbL) technique. Multilayers were exposed to NaIO solution to induce covalent bond formation between PEI units of PiPOX-PEI and TA. Cross-linking with NaIO enhanced the stability of the multilayers, especially under basic conditions. Second, the potential of PiPOX-PEI and TA multilayers as a stimuli-responsive dual drug-releasing platform was examined using curcumin (CUR) and doxorubicin (DOX) as model drugs. These drugs were chosen as they can act in a combinatorial manner to increase cell death. The surface of CUR-containing CaCO microparticles was modified with PiPOX-PEI and TA multilayers and postloaded with DOX. We found that LbL particles could release DOX in a pH-responsive manner, whereas temperature-induced release was observed only when the temperature was raised above 40 °C. The DOX and CUR released from the LbL particles could act synergistically on HCT-116 cells. Cross-linking increased the DOX release from LbL particles but decreased the CUR release from the core. Corroborating the release data, the synergy observed with the non-cross-linked particles was lost with the cross-linked particles, and the decrease in the viability of HCT-116 cells was attributed mainly to the release of DOX. Overall, we describe here NaIO-induced cross-linking of PiPOX-PEI/TA LbL films, the effects of pH, temperature, and cross-linking on DOX and CUR release from multilayers, and comparison of the combinatorial effect of DOX and CUR for cross-linked and non-cross-linked LbL microparticles through cell viability assays.
本研究首先报道了由聚（2-异丙基-2-恶唑啉-乙烯亚胺）（PiPOX-PEI）和单宁酸（TA）组成的多层膜的制备和交联。PiPOX通过阳离子开环聚合（CROP）合成并部分水解，得到无规共聚物PiPOX-PEI。然后使用逐层（LbL）技术将其与TA在表面共组装。将多层膜暴露于NaIO溶液中，以诱导PiPOX-PEI的PEI单元与TA之间形成共价键。用NaIO交联增强了多层膜的稳定性，尤其是在碱性条件下。其次，以姜黄素（CUR）和阿霉素（DOX）作为模型药物，研究了PiPOX-PEI和TA多层膜作为刺激响应性双药物释放平台的潜力。选择这些药物是因为它们可以联合作用以增加细胞死亡。用PiPOX-PEI和TA多层膜修饰含CUR的CaCO微粒表面，并后负载DOX。我们发现LbL微粒可以以pH响应方式释放DOX，而仅当温度升高到40°C以上时才观察到温度诱导释放。从LbL微粒释放的DOX和CUR可以对HCT-116细胞产生协同作用。交联增加了DOX从LbL微粒中的释放，但减少了核心中CUR的释放。与释放数据一致，交联微粒失去了非交联微粒所观察到的协同作用，并且HCT-116细胞活力的降低主要归因于DOX的释放。总体而言，我们在此描述了NaIO诱导的PiPOX-PEI/TA LbL膜的交联、pH、温度和交联对多层膜中DOX和CUR释放的影响，以及通过细胞活力测定比较交联和非交联LbL微粒中DOX和CUR的联合作用。
