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.
|出版狀態||已發佈 - 11月 2021|
ASJC Scopus subject areas