School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Ph.D. Program in Clinical Drug Development of Herbal Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan.
Biomaterials. 2021 Nov;278:121166. doi: 10.1016/j.biomaterials.2021.121166. Epub 2021 Oct 5.
In this study, PEGylated poly (lactide-co-glycolide) (PLGA) thermosensitive composite hydrogels (DTgels) loaded with bispecific anti-cluster of differentiation 3 (CD3) scFv T-cell/anti-epidermal growth factor receptor (EGFR) Fab engager (BiTEE) were subcutaneously (s.c.) injected for the in situ formation of a drug deposit to resolve limitations of the clinical application of the BiTEE of a short half-life and potential side effects. Three kinds of DTgels prepared with different ratios of methoxy poly (ethylene glycol) (mPEG)-PLGA (diblock copolymer, DP) and PLGA-PEG-PLGA (triblock copolymer, TP) were designated DTgel-1, DTgel-2, and DTgel-2S. All three DTgel formulations showed thermosensitive properties with a sol-gel transition temperature at 28-34 °C, which is suitable for an injection. An in vitro release study showed that all DTgel formulations loaded with stabilized BiTEE extended the release of the BiTEE for up to 7 days. In an animal pharmacokinetics study, an s.c. injection of BiTEE/DTgel-1, BiTEE/DTgel-2, or BiTEE/DTgel-2S respectively prolonged the half-life of the BiTEE by 3.5-, 2.0-, and 2.2-fold compared to an intravenous injection of the BiTEE solution. Simultaneously, BiTEE/DTgel formulations showed almost no proinflammatory cytokine release in mice injected with T cells after s.c. administration. Results of an animal antitumor (MDA-MB-231) study indicated that an s.c. injection of the BiTEE/DTgel formulations significantly improved the antitumor efficacy compared to an intravenous (i.v.) or s.c. injection of the BiTEE solution. Moreover, BiTEE/DTgel formulations led to enhanced T-cell recruitment to solid-tumor sites. In conclusion, the in situ formation of injectable PEGylated PLGA thermosensitive hydrogels loaded with the BiTEE was successfully carried out to increase its half-life, maintain a constant blood level within therapeutic windows, and enhance T-cell recruitment to solid-tumor sites resulting in exceptional treatment efficacy.
在这项研究中，聚乙二醇化聚（乳酸-共-乙醇酸）（PLGA）温敏复合水凝胶（DTgels）负载双特异性抗分化簇 3（CD3）scFv T 细胞/抗表皮生长因子受体（EGFR）Fab 接头（BiTEE）被皮下（s.c.）注射，以原位形成药物沉积，解决 BiTEE 半衰期短和潜在副作用的临床应用限制。三种不同比例的甲氧基聚（乙二醇）（mPEG）-PLGA（嵌段共聚物，DP）和 PLGA-PEG-PLGA（三嵌段共聚物，TP）制备的 DTgels 分别命名为 DTgel-1、DTgel-2 和 DTgel-2S。所有三种 DTgel 制剂均表现出温敏特性，具有 28-34°C 的溶胶-凝胶转变温度，适合注射。体外释放研究表明，所有负载稳定 BiTEE 的 DTgel 制剂均将 BiTEE 的释放延长至 7 天。在动物药代动力学研究中，与 BiTEE 溶液的静脉内注射相比，s.c.注射 BiTEE/DTgel-1、BiTEE/DTgel-2 或 BiTEE/DTgel-2S 分别将 BiTEE 的半衰期延长了 3.5、2.0 和 2.2 倍。同时，s.c.给药后，在注射 T 细胞的小鼠中，BiTEE/DTgel 制剂几乎没有引起促炎细胞因子的释放。动物抗肿瘤（MDA-MB-231）研究结果表明，与静脉内（i.v.）或 s.c.注射 BiTEE 溶液相比，s.c.注射 BiTEE/DTgel 制剂显著提高了抗肿瘤疗效。此外，BiTEE/DTgel 制剂导致 T 细胞向实体瘤部位的募集增强。总之，成功地进行了原位形成可注射聚乙二醇化 PLGA 温敏水凝胶，负载 BiTEE，以增加其半衰期，在治疗窗内维持恒定的血药水平，并增强 T 细胞向实体瘤部位的募集，从而产生卓越的治疗效果。
