TY - JOUR
T1 - In situ subcutaneously injectable thermosensitive PEG-PLGA diblock and PLGA-PEG-PLGA triblock copolymer composite as sustained delivery of bispecific anti-CD3 scFv T-cell/anti-EGFR Fab Engager (BiTEE)
AU - Wei, Pu Sheng
AU - Chen, Yi Jou
AU - Lin, Shyr Yi
AU - Chuang, Kuo Hsiang
AU - Sheu, Ming Thau
AU - Ho, Hsiu O.
N1 - Funding Information:
This work was financially supported by the Ministry of Science and Technology , Taiwan ( 108-2320-B038-039-MY3 ; 109-3111-8-038-001 ; 111-2628-B-038-007 ) and Health and welfare surcharge of tobacco products (MOHW110-TDU-B-212-144014). The authors would like to acknowledge the Laboratory Animal Center at TMU for technical support in in vivo imaging studies and professor Hsin-Cheng Chiu for technical support in gel permeation chromatography studies.
Funding Information:
This work was financially supported by the Ministry of Science and Technology, Taiwan (108-2320-B038-039-MY3; 109-3111-8-038-001; 111-2628-B-038-007) and Health and welfare surcharge of tobacco products (MOHW110-TDU-B-212-144014). The authors would like to acknowledge the Laboratory Animal Center at TMU for technical support in in vivo imaging studies and professor Hsin-Cheng Chiu for technical support in gel permeation chromatography studies.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
KW - Anti-EGFR
KW - Bispecific T-cell engager
KW - In situ formation
KW - T-cell recruitment
KW - Thermosensitive hydrogel
UR - http://www.scopus.com/inward/record.url?scp=85116562956&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85116562956&partnerID=8YFLogxK
U2 - 10.1016/j.biomaterials.2021.121166
DO - 10.1016/j.biomaterials.2021.121166
M3 - Article
AN - SCOPUS:85116562956
SN - 0142-9612
VL - 278
JO - Biomaterials
JF - Biomaterials
M1 - 121166
ER -