Nonshrinkable Thermosensitive Hydrogels Combined with Bispecific Anti-PSMA/CD3 T-Cell Engager for Effective Against
Pu-Sheng Wei1, Po-Yu Chou1, Hao-Yi Hsu2
1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Purpose:
CD3-based Bispecific T-cell engagers (BiTEs) are effective for solid tumors due to their tumor specificity and tissue penetration, but they face challenges like short half-lives and narrow therapeutic windows. Innovative delivery systems, like thermosensitive hydrogels, show the potential to enhance stability, sustained release, and therapeutic efficacy.
Methods:
We developed PEGylated PLGA (PEG-PLGA) thermosensitive hydrogels with a nonshrinkable property (nsTPPgels) for effective controlled release and loaded them with bispecific anti-prostate surface membrane antigen (PSMA) F /anti-CD3 T-cell engager (BiPTE) to form in situ drug deposits with a sustained-release profile after subcutaneous injection. Each group of hydrogels was first tested for differences in properties through rheological and in vitro drug release profiles. Meanwhile, in vivo pharmacokinetics, anti-tumor efficacy studies, and T-cell tracking studies were conducted to analyze the advantages of nsTPPgels included D2gel and DTgels.
Results:
The cytotoxicity of BiPTE against PSMA-overexpressing tumor cells and the drug release functionality of nsTPPgels were validated in vitro. Rheological studies showed that both D2gel and DTgels remained in solution below 27 °C for easy injection and solidified at physiological temperatures to form localized depots for sustained BiPTE release. All nsTPPgels demonstrated a 5-day in vitro sustained release, prolonged elimination half-life, steady plasma BiPTE levels, and extended mean residence time. In an LNCaP-xenograft mouse model, tumor growth inhibition rates for BiPTE/DTgel-2, BiPTE/DTgel-2S, and BiPTE/D2gel were 74.3%, 96.1%, and 113.1%, respectively, compared to 35.6% for intravenous and 46% for subcutaneous BiPTE administration. Furthermore, all nsTPPgels effectively achieved T-cell recruitment to lymph nodes and tumor sites in tracking studies.
Conclusion:
In conclusion, we developed relatively convenient injectable thermosensitive D2gel with a desirable gelation temperature window, which have the potential to be used for antibody drug delivery in several biomedical applications.
Insights
Thermosensitive hydrogels loaded with bispecific T-cell engagers (BiTEs) improve prostate cancer treatment by enabling sustained drug release and enhancing T-cell activity. This delivery system offers a promising approach for solid tumor therapies.
Area of Science:
- Biomedical Engineering
- Drug Delivery Systems
- Immunotherapy
Background:
- Bispecific T-cell engagers (BiTEs) show promise for solid tumors but face challenges like short half-lives.
- Thermosensitive hydrogels offer a potential solution for enhanced stability and sustained release of BiTEs.
Purpose of the Study:
- To develop and evaluate PEGylated PLGA thermosensitive hydrogels (nsTPPgels) for controlled subcutaneous delivery of a bispecific anti-prostate surface membrane antigen (PSMA) /anti-CD3 T-cell engager (BiPTE).
- To assess the in vitro and in vivo performance of nsTPPgels for sustained BiPTE release and enhanced anti-tumor efficacy.
Main Methods:
- PEGylated PLGA thermosensitive hydrogels (nsTPPgels) were developed and characterized for rheological properties and in vitro drug release.
- Hydrogels loaded with BiPTE were evaluated for in vivo pharmacokinetics, anti-tumor efficacy in an LNCaP-xenograft mouse model, and T-cell recruitment.
Main Results:
- nsTPPgels demonstrated injectable properties below 27 °C and formed localized depots at physiological temperatures for sustained BiPTE release.
- In vivo studies showed significant tumor growth inhibition (up to 113.1%) with nsTPPgels, prolonged drug half-life, and effective T-cell recruitment to tumors.
- Compared to conventional administration, nsTPPgels significantly improved anti-tumor efficacy and T-cell localization.
Conclusions:
- Injectable thermosensitive D2gel offers a convenient and effective platform for sustained delivery of antibody-based therapeutics like BiPTE.
- This hydrogel system holds potential for improving antibody drug delivery and treating solid tumors.
More Related Videos
10:19Tracking Bispecific Antibody-Induced T Cell Trafficking Using Luciferase-Transduced Human T Cells
Published on: May 12, 2023
07:47Custom-designed Laser-based Heating Apparatus for Triggered Release of Cisplatin from Thermosensitive Liposomes with Magnetic Resonance Image Guidance
Published on: December 13, 2015
