Drug-loaded microbubble delivery system to enhance PD-L1 blockade immunotherapy with remodeling immune
Jun Zheng1, Ju Huang1, Liang Zhang2,3
1State Key Laboratory of Ultrasound in Medicine and Engineering, Institute of Ultrasound Imaging, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, People's Republic of China.
Background:
Although programmed cell death protein 1 (PD-1)/ programmed cell death-ligand protein 1 (PD-L1) checkpoint blockade immunotherapy demonstrates great promise in cancer treatment, poor infiltration of T cells resulted from tumor immunosuppressive microenvironment (TIME) and insufficient accumulation of anti-PD-L1 (αPD-L1) in tumor sites diminish the immune response. Herein, we reported a drug-loaded microbubble delivery system to overcome these obstacles and enhance PD-L1 blockade immunotherapy.
Methods:
Docetaxel (DTX) and imiquimod (R837)-loaded microbubbles (RD@MBs) were synthesized via a typical rotary evaporation method combined with mechanical oscillation. The targeted release of drugs was achieved by using the directional "bursting" capability of ultrasound-targeted microbubble destruction (UTMD) technology. The antitumor immune response by RD@MBs combining αPD-L1 were evaluated on 4T1 and CT26 tumor models.
Results:
The dying tumor cells induced by DTX release tumor-associated antigens (TAAs), together with R837, promoted the activation, proliferation and recruitment of T cells. Besides, UTMD technology and DTX enhanced the accumulation of αPD-L1 in tumor sites. Moreover, RD@MBs remolded TIME, including the polarization of M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, and reduction of myeloid-derived suppressor cells (MDSCs). The RD@MBs + αPD-L1 synergistic therapy not only effectively inhibited the growth of primary tumors, but also significantly inhibited the mimic distant tumors as well as lung metastases.
Conclusion:
PD-L1 blockade immunotherapy was enhanced by RD@MBs delivery system.
Insights
This study developed a drug-loaded microbubble system to enhance programmed cell death-ligand 1 (PD-L1) blockade immunotherapy by improving T cell infiltration and drug accumulation in tumors. The novel system effectively inhibited tumor growth and metastasis.
Area of Science:
- Biomedical Engineering
- Cancer Immunotherapy
- Drug Delivery Systems
Background:
- Programmed cell death protein 1 (PD-1)/programmed cell death-ligand protein 1 (PD-L1) checkpoint blockade immunotherapy shows promise but is limited by poor T cell infiltration and low anti-PD-L1 accumulation in the tumor microenvironment.
- Tumor immunosuppressive microenvironment (TIME) hinders effective cancer treatment, necessitating strategies to enhance immunotherapy efficacy.
Purpose of the Study:
- To develop a novel drug-loaded microbubble delivery system to overcome the limitations of PD-1/PD-L1 blockade immunotherapy.
- To enhance T cell infiltration and anti-PD-L1 accumulation within tumor sites.
- To improve the overall antitumor immune response and therapeutic outcomes.
Main Methods:
- Docetaxel (DTX) and imiquimod (R837)-loaded microbubbles (RD@MBs) were synthesized using rotary evaporation and mechanical oscillation.
- Ultrasound-targeted microbubble destruction (UTMD) technology was employed for targeted drug release.
- Antitumor immune responses were evaluated in 4T1 and CT26 tumor models using RD@MBs combined with anti-PD-L1 (αPD-L1).
Main Results:
- DTX-induced tumor cell death released tumor-associated antigens (TAAs), promoting T cell activation, proliferation, and recruitment, while R837 further enhanced immune response.
- UTMD and DTX facilitated increased accumulation of αPD-L1 in tumor sites.
- RD@MBs remodeled the TIME by shifting M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype and reducing myeloid-derived suppressor cells (MDSCs).
- The synergistic therapy of RD@MBs + αPD-L1 significantly inhibited primary tumor growth, distant tumors, and lung metastases.
Conclusions:
- The developed RD@MBs delivery system effectively enhances PD-L1 blockade immunotherapy.
- This approach offers a promising strategy for improving cancer treatment by overcoming tumor immunosuppression and improving drug delivery.
