School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia.
School of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia.
J Labelled Comp Radiopharm. 2023 Aug;66(10):308-320. doi: 10.1002/jlcr.4046. Epub 2023 Jun 7.
Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) are promising treatments for unresectable liver tumours. Some recent studies suggested that combining TACE and TARE in one treatment course might improve treatment efficacy through synergistic cytotoxicity effects. Nonetheless, current formulations do not facilitate a combination of chemo- and radio-embolic agents in one delivery system. Therefore, this study aimed to synthesise a hybrid biodegradable microsphere loaded with both radioactive agent, samarium-153 ( Sm) and chemotherapeutic drug, doxorubicin (Dox) for potential radio-chemoembolization of advanced liver tumours. Sm and Dox-loaded polyhydroxybutyrate-co-3-hydroxyvalerate (PHBV) microspheres were prepared using water-in-oil-in-water solvent evaporation method. The microspheres were then sent for neutron activation in a neutron flux of 2 × 10 n/cm /s. The physicochemical properties, radioactivity, radionuclide purity, Sm retention efficiency, and Dox release profile of the Dox- Sm-PHBV microspheres were analysed. In addition, in vitro cytotoxicity of the formulation was tested using MTT assay on HepG2 cell line at 24 and 72 h. The mean diameter of the Dox- Sm-PHBV microspheres was 30.08 ± 2.79 μm. The specific radioactivity was 8.68 ± 0.17 GBq/g, or 177.69 Bq per microsphere. The Sm retention efficiency was more than 99%, tested in phosphate-buffered saline (PBS) and human blood plasma over 26 days. The cumulative release of Dox from the microspheres after 41 days was 65.21 ± 1.96% and 29.96 ± 0.03% in PBS solution of pH 7.4 and pH 5.5, respectively. The Dox- Sm-PHBV microspheres achieved a greater in vitro cytotoxicity effect on HepG2 cells (85.73 ± 3.63%) than Sm-PHBV (70.03 ± 5.61%) and Dox-PHBV (74.06 ± 0.78%) microspheres at 300 μg/mL at 72 h. In conclusion, a novel biodegradable microspheres formulation loaded with chemotherapeutic drug (Dox) and radioactive agent ( Sm) was successfully developed in this study. The formulation fulfilled all the desired physicochemical properties of a chemo-radioembolic agent and achieved better in vitro cytotoxicity on HepG2 cells. Further investigations are needed to evaluate the biosafety, radiation dosimetry, and synergetic anticancer properties of the formulation.
经动脉化疗栓塞术（TACE）和经动脉放射性栓塞术（TARE）是治疗不可切除肝肿瘤的有前途的治疗方法。一些最近的研究表明，在一次治疗过程中联合使用 TACE 和 TARE 可能通过协同细胞毒性作用提高治疗效果。尽管如此，目前的制剂并不利于在一个输送系统中结合化疗和放射栓塞剂。因此，本研究旨在合成一种载有放射性钐-153（Sm）和化疗药物阿霉素（Dox）的混合可生物降解微球，用于治疗晚期肝肿瘤的放射化学栓塞。采用水包油包水溶剂蒸发法制备载有 Sm 和 Dox 的聚羟基丁酸酯-3-羟基戊酸酯（PHBV）微球。然后将微球送入中子通量为 2×10 n/cm /s 的中子中进行活化。分析了 Dox-Sm-PHBV 微球的理化性质、放射性、放射性核素纯度、Sm 保留效率和 Dox 释放曲线。此外，还通过 MTT 测定法在 HepG2 细胞系上在 24 和 72 h 时测试了该制剂的体外细胞毒性。Dox-Sm-PHBV 微球的平均直径为 30.08±2.79 μm。比活度为 8.68±0.17 GBq/g，即每个微球 177.69 Bq。Sm 保留效率在磷酸盐缓冲盐水（PBS）和人血浆中超过 26 天均大于 99%。Dox 从微球中的累积释放率在 pH 7.4 和 pH 5.5 的 PBS 溶液中分别为 41 天后的 65.21±1.96%和 29.96±0.03%。Dox-Sm-PHBV 微球在 300μg/mL 时对 HepG2 细胞的体外细胞毒性作用（85.73±3.63%）大于 Sm-PHBV（70.03±5.61%）和 Dox-PHBV（74.06±0.78%）微球在 72 h。总之，本研究成功开发了一种载有化疗药物（Dox）和放射性药物（Sm）的新型可生物降解微球制剂。该制剂满足了化学放射栓塞剂的所有理想理化性质，并在 HepG2 细胞上实现了更好的体外细胞毒性。需要进一步研究来评估该制剂的生物安全性、辐射剂量学和协同抗癌特性。
