Department of Pharmacy, Medical School, University of Patras, 26504, Patras, Greece.
Department of Materials Science, University of Patras, 26504, Patras, Greece.
AAPS PharmSciTech. 2018 Feb;19(2):621-633. doi: 10.1208/s12249-017-0874-2. Epub 2017 Sep 18.
In solid tumors, hypoxia (lack of oxygen) is developed, which leads to the development of resistance of tumor cells to chemotherapy and radiotherapy through various mechanisms. Nevertheless, hypoxic cells are particularly vulnerable when glycolysis is inhibited. For this reason, in this study, the development of magnetically targetable nanocarriers of the sodium-glucose transporter protein (SGLT2) inhibitor dapagliflozin (DAPA) was developed for the selective delivery of DAPA in tumors. This nanomedicine in combination with radiotherapy or chemotherapy should be useful for effective treatment of hypoxic tumors. The magnetic nanoparticles consisted of a magnetic iron oxide core and a poly(methacrylic acid)-graft-poly(ethyleneglycol methacrylate) (PMAA-g-PEGMA) polymeric shell. The drug (dapagliflozin) molecules were conjugated on the surface of these nanoparticles via in vivo hydrolysable ester bonds. The nanoparticles had an average size of ~ 70 nm and exhibited a DAPA loading capacity 10.75% (w/w) for a theoretical loading 21.68% (w/w). The magnetic responsiveness of the nanoparticles was confirmed with magnetophoresis experiments. The dapagliflozin-loaded magnetic nanoparticles exhibited excellent colloidal stability in aqueous and biological media. Minimal (less than 15% in 24 h) drug release from the nanoparticles occurred in physiological pH 7.4; however, drug release was significantly accelerated in pH 5.5. Drug release was also accelerated (triggered) under the influence of an alternating magnetic field. The DAPA-loaded nanoparticles exhibited higher in vitro anticancer activity (cytotoxicity) against A549 human lung cancer cells than free DAPA. The application of an external magnetic field gradient increased the uptake of nanoparticles by cells, leading to increased cytotoxicity. The results justify further in vivo studies of the suitability of DAPA-loaded magnetic nanoparticles for the treatment of hypoxic tumors.
在实体肿瘤中，会出现缺氧（缺乏氧气）的情况，这会通过各种机制导致肿瘤细胞对化疗和放疗产生耐药性。然而，当糖酵解被抑制时，缺氧细胞会变得特别脆弱。出于这个原因，在这项研究中，开发了可靶向磁纳米载体来输送钠-葡萄糖协同转运蛋白（SGLT2）抑制剂达格列净（DAPA），以实现肿瘤内的选择性药物输送。这种纳米药物与放疗或化疗结合使用，应该对治疗缺氧肿瘤非常有用。这些磁性纳米颗粒由一个磁性氧化铁核心和一个聚（甲基丙烯酸）-接枝-聚（乙二醇甲基丙烯酸酯）（PMAA-g-PEGMA）聚合壳组成。药物（达格列净）分子通过体内可水解酯键连接在这些纳米颗粒的表面上。这些纳米颗粒的平均尺寸约为 70nm，并表现出 10.75%（w/w）的 DAPA 载药量，理论载药量为 21.68%（w/w）。通过磁泳实验证实了纳米颗粒的磁响应性。载达格列净的磁性纳米颗粒在水相和生物介质中表现出极好的胶体稳定性。在生理 pH 7.4 下，纳米颗粒中药物的释放最小（24 小时内小于 15%）；然而，在 pH 5.5 下，药物的释放明显加速。在交变磁场的影响下，药物的释放也会加速（触发）。载达格列净的纳米颗粒在体外对 A549 人肺癌细胞的抗癌活性（细胞毒性）高于游离的 DAPA。施加外部磁场梯度会增加细胞对纳米颗粒的摄取，从而导致细胞毒性增加。这些结果证明了载有 DAPA 的磁性纳米颗粒在治疗缺氧肿瘤方面的进一步体内研究的适用性。
