Department of Chemistry and Biochemistry , University of Texas at Dallas , Richardson , Texas 75080 , United States.
Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences , University of Nebraska Medical Center , Omaha , Nebraska 68198 , United States.
Biomacromolecules. 2018 Mar 12;19(3):1082-1089. doi: 10.1021/acs.biomac.8b00221. Epub 2018 Feb 27.
The short chain fatty acid, 4-phenylbutyric acid (PBA), is used for the treatment of urea cycle disorders and sickle cell disease as an endoplasmic reticulum stress inhibitor. PBA is also known as a histone deacetylase inhibitor (HDACi). We report here the effect of combination therapy on HeLa cancer cells using PBA as the HDACi together with the anticancer drug, doxorubicin (DOX). We synthesized γ-4-phenylbutyrate-ε-caprolactone monomer which was polymerized to form poly(γ-4-phenylbutyrate-ε-caprolactone) (PPBCL) homopolymer using NdCl·3TEP/TIBA (TEP = triethyl phosphate, TIBA = triisobutylaluminum) catalytic system. DOX-loaded nanoparticles were prepared from the PPBCL homopolymer using poly(ethylene glycol) as a surfactant. An encapsulation efficiency as high as 88% was obtained for these nanoparticles. The DOX-loaded nanoparticles showed a cumulative release of >95% of DOX at pH 5 and 37 °C within 12 h, and PBA release was monitored by H NMR spectroscopy. The efficiency of the combination therapy can notably be seen in the cytotoxicity study carried out on HeLa cells, where only ∼20% of cell viability was observed after treatment with the DOX-loaded nanoparticles. This drastic cytotoxic effect on HeLa cells is the result of the dual action of DOX and PBA on the DNA strands and the HDAC enzymes, respectively. Overall, this study shows the potential of combination treatment with HDACi and DOX anticancer drug as compared to the treatment with an anticancer drug alone.
短链脂肪酸 4-苯丁酸（PBA）被用作治疗尿素循环障碍和镰状细胞病的内质网应激抑制剂。PBA 也被称为组蛋白去乙酰化酶抑制剂（HDACi）。我们在这里报告了使用 PBA 作为 HDACi 与抗癌药物阿霉素（DOX）联合治疗 HeLa 癌细胞的联合治疗效果。我们合成了γ-4-苯丁酸-ε-己内酯单体，然后使用 NdCl·3TEP/TIBA（TEP = 三乙基磷酸酯，TIBA = 三异丁基铝）催化体系聚合形成聚（γ-4-苯丁酸-ε-己内酯）（PPBCL）均聚物。使用聚乙二醇作为表面活性剂从 PPBCL 均聚物中制备 DOX 负载的纳米颗粒。这些纳米颗粒的包封效率高达 88%。DOX 负载的纳米颗粒在 pH 5 和 37°C 下在 12 小时内显示出 >95%的 DOX 累积释放，并且通过 1H NMR 光谱监测 PBA 释放。在对 HeLa 细胞进行的细胞毒性研究中，可以明显看出联合治疗的效果，其中用载有 DOX 的纳米颗粒处理后，细胞活力仅观察到约 20%。这种对 HeLa 细胞的剧烈细胞毒性作用是 DOX 和 PBA 分别对 DNA 链和 HDAC 酶的双重作用的结果。总的来说，与单独使用抗癌药物相比，这项研究表明 HDACi 和 DOX 抗癌药物联合治疗的潜力。
