Department of Biomedical Engineering and Environmental Sciences , National Tsing Hua University , Hsinchu 30013 , Taiwan.
Department or Radiology , National Taiwan University Hospital Hsin-Chu Branch , Hsinchu 30013 , Taiwan.
Biomacromolecules. 2018 Sep 10;19(9):3825-3839. doi: 10.1021/acs.biomac.8b00942. Epub 2018 Aug 9.
Radiotherapy is one of the general approaches to deal with malignant solid tumors in clinical treatment. To improve therapeutic efficacy, chemotherapy is frequently adopted as the adjuvant treatment in combination with radiotherapy. In this work, a reactive oxygen species (ROS)-responsive nanoparticle (NP) drug delivery system was developed to synergistically enhance the antitumor efficacy of radiotherapy by local ROS-activated chemotherapy, taking advantages of the enhanced concentration of reactive oxygen species (ROS) in tumor during X-ray irradiation and/or reoxygenation after X-ray irradiation. The ROS-responsive polymers, poly(thiodiethylene adipate) (PSDEA) and PEG-PSDEA-PEG, were synthesized and employed as the major components assembling in aqueous phase into polymer NPs in which an anticancer camptothecin analogue, SN38, was encapsulated. The drug-loaded NPs underwent structural change including swelling and partial dissociation in response to the ROS activation by virtue of the oxidation of the nonpolar sulfide residues in NPs into the polar sulfoxide units, thus leading to significant drug unloading. The in vitro performance of the chemotherapy from the X-ray irradiation preactivated NPs against BNL 1MEA.7R.1 murine carcinoma cells showed comparable cytotoxicity to free drug and appreciably enhanced effect on killing cancer cells while the X-ray irradiation being incorporated into the treatment. The in vivo tumor growth was fully inhibited with the mice receiving the local dual modality treatment of X-ray irradiation together with SN38-loaded NPs administered by intratumoral injection. The comparable efficacy of the local combinational treatment of X-ray irradiation with SN38-loaded NPs to free SN38/irradiation dual treatment corroborated the effectiveness of ROS-mediated drug release from the irradiated NPs at tumor site. The IHC examination of tumor tissues confirmed the significant reduction of VEGFA and CD31 expression with the tumor receiving the local dual treatment developed in this work, thus accounting for the absence of tumor regrowth compared to other single modality treatment.
放射疗法是临床治疗恶性实体肿瘤的一般方法之一。为了提高治疗效果，常采用化疗作为辅助治疗，与放射疗法联合使用。在这项工作中，开发了一种活性氧（ROS）响应纳米颗粒（NP）药物递送系统，通过局部 ROS 激活化疗，利用 X 射线照射期间肿瘤中活性氧（ROS）的浓度增加和/或 X 射线照射后再氧化，协同增强放射疗法的抗肿瘤疗效。ROS 响应聚合物，聚（硫代二乙撑酯）（PSDEA）和 PEG-PSDEA-PEG，被合成并用作主要成分，在水溶液中组装成聚合物 NPs，其中包裹了一种抗癌喜树碱类似物，SN38。载药 NPs 发生结构变化，包括肿胀和部分解离，这是由于 NPs 中非极性的硫醚残基氧化成极性的亚砜单元，从而导致药物的显著释放。体外性能对 BNL 1MEA.7R.1 鼠肝癌细胞的化疗作用表明，与游离药物相比，具有相当的细胞毒性，并且在 X 射线照射被纳入治疗时，对杀伤癌细胞具有明显的增强作用。接受局部 X 射线照射与瘤内注射 SN38 载药 NPs 联合治疗的小鼠完全抑制了肿瘤生长。局部联合治疗 X 射线照射与 SN38 载药 NPs 与游离 SN38/照射双重治疗的疗效相当，证实了 ROS 介导的从照射 NPs 中释放药物在肿瘤部位的有效性。肿瘤组织的 IHC 检查证实，与其他单一治疗模式相比，接受本工作中开发的局部双重治疗的肿瘤中 VEGFA 和 CD31 的表达显著减少，因此没有肿瘤复发。
