Ultrasound targeting of microbubble-bound anti PD-L1 mAb to enhance anti-tumor effect of cisplatin in cervical cancer xenografts treatment

Ma, Yao; Han, Jiahuai; Jiang, Jianhai; Zheng, Zhiwei; Tan, Yandi; Liu, Chaoqi; Zhao, Yun

doi:10.1016/j.lfs.2020.118565

Cited by 11 publications

(6 citation statements)

References 45 publications

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“…The PD-L1-targeted microbubbles prepared by our group in the early stage have shown good targeting aggregation and antitumor effects. 36 , 37 Ultrasound-triggered, microbubble-targeted drug delivery can not only increase drug accumulation in tumors and prolong their retention time but also limit drug uptake in normal tissues, thereby reducing systemic toxicity and drug side effects. 38 Additionally, ultrasound irradiation enhanced cellular uptake and increased drug accumulation at the tumor site by 1.85-fold.…”

Section: Discussionmentioning

confidence: 99%

Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma

Chen¹,

Luo²,

Liu³

et al. 2022

IJN

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Purpose Ultrasound nanobubbles (NBs) can kill tumor cells, mediated by their effects of cavitation and acoustic perforation through ultrasound, while as novel drug carriers, biomaterial-modified NBs release drugs at a target region. In this work, the ultrasound NBs bridged by biotin-streptavidin were prepared simultaneously to be loaded with both programmed death ligand 1 monoclonal antibody (PD-L1 mAb) and doxorubicin (DOX), which are immune checkpoint inhibitors (ICIs) and chemotherapeutic agents, to synergize immunotherapy and chemotherapy combined with sonodynamic therapy (SDT). Methods The PD-L1 mAb/DOX NBs, using bridging affinity biotin (BRAB) technology as a bridge, were prepared by thin-film hydration and mechanical oscillation for the targeted delivery of biotinylated PD-L1 mAb and DOX. Characterization and pharmacokinetic studies of PD-L1 mAb/DOX NBs were performed in vitro and in vivo. The antitumor effect of ultrasound-mediated PD-L1 mAb/DOX-NBs was studied in the subcutaneously transplanted tumor of the H22 hepatoma model, and the mechanism of synergistic tumor repression was investigated. Results The data of in vitro targeting experiments, contrast-enhanced ultrasound imaging (CEUS), in vivo imaging of the small animals imaging system (IVIS), and frozen sections showed that PD-L1 mAb/DOX-NBs have well-targeted aggregation in the tumor. By observing tumor inhibition rate, tissue cell apoptosis, and apoptosis-related gene and protein expression, the PD-L1 mAb/DOX-NBs group showed the best immunotherapy effects, and its tumor volume and mass inhibition rates were about 69.64% and 75.97%, respectively ( P < 0.01). Therefore, blocking the PD-1/PD-L1 pathway could improve immune cells’ tumor-killing ability. Antitumor immune cytokines were further enhanced when combined with DOX-induced tumor cell apoptosis and immunogenic cell death (ICD). Conclusion In summary, ultrasound-mediated PD-L1 mAb/DOX-NBs showed significant synergistic antitumor effects, providing a potential combined immunotherapy strategy for HCC.

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Section: Discussionmentioning

confidence: 99%

Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma

Chen¹,

Luo²,

Liu³

et al. 2022

IJN

Self Cite

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“…However, a shortcoming of our NBs is the absence of active targeting, which has been improved by other members in our group. 22 They designed an actively targeted microbubbles conjugated with anti-PD-L1 mAb, which can target the PD-L1 site on the tumor cells. NBs in our study had both positive charge and lipid, which could result in a simultaneous loading of negatively charged sPD-1 plasmid and lipid-soluble Ce6, thus providing a necessary condition for synergetic immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Nanobubbles Containing sPD-1 and Ce6 Mediate Combination Immunotherapy and Suppress Hepatocellular Carcinoma in Mice

Tan¹,

Yang²,

Ma³

et al. 2021

IJN

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Immune checkpoint inhibitors (ICIs) and sonodynamic therapy (SDT) are types of immunotherapy. In order to combine soluble programmed cell death protein 1 (sPD-1)mediated immune checkpoint therapy and chlorin e6 (Ce6)-assisted SDT, nanobubbles (NBs) were generated to simultaneously load sPD-1 and Ce6. Materials and Methods: The sPD-1/Ce6-NBs, which were prepared by thin-film hydration and mechanical oscillation, had a stable physical condition, and delivered sPD-1 and Ce6 in a targeted manner. NBs could strengthen tumor suppression by increasing tumor-targeting accumulation of Ce6 and sPD-1, and by inducing ultrasound-targeted NB destruction. A mouse H22 cell hepatoma xenograft model was used to evaluate the synergetic immunotherapeutic effect and mechanism of sPD-1/Ce6-NBs. Results: By observing the tumor inhibition rate, tissue and cell apoptosis, apoptosis-related genes and protein expression, the best immunotherapeutic effect was exhibited by the sPD-1/ Ce6-NBs group. The immunotherapeutic mechanism initially demonstrated that when tumor cells were transfected by sPD-1 delivered by NBs, which downregulated the expression of programmed death-ligand 1 (PD-L1) in tumor cells, and blocked the PD-1/PD-L1 signaling pathway, which improved T-cell-mediated tumor inhibition. Furthermore, ICIs combined with SDT induced immunogenic cell death by translocating calreticulin to the cell surface and then synergistically enhancing antitumor immune responses. Conclusion:In conclusion, sPD-1/Ce6-NBs were successfully designed. Ultrasoundmediated sPD-1/Ce6-NBs are potentially effective delivery systems for combination immunotherapy of hepatocellular carcinoma.

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“…Today, many patients have been treated with a synergistic combination of checkpoint blocking inhibitors and chemotherapeutics or other immunotherapy strategies [374][375][376][377]. Microbubbles and ultrasound have been used to locally enhance the penetration of these checkpoint inhibitors in the TME and also display comparable synergistic effects [383,384]. Additionally, Eranki, et al show great potential in combining mechanical HIFU and checkpoint-inhibitors PD-L1 and CTLA-4 as this significantly improved survival in a previously immunologically unresponsive neuroblastoma [362].…”

Section: Immunological Barriermentioning

confidence: 99%

Opening doors with ultrasound and microbubbles: Beating biological barriers to promote drug delivery

Deprez

Lajoinie

Engelen

et al. 2021

Advanced Drug Delivery Reviews

135

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Ultrasound targeting of microbubble-bound anti PD-L1 mAb to enhance anti-tumor effect of cisplatin in cervical cancer xenografts treatment

Cited by 11 publications

References 45 publications

Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma

Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma

Nanobubbles Containing sPD-1 and Ce6 Mediate Combination Immunotherapy and Suppress Hepatocellular Carcinoma in Mice

Opening doors with ultrasound and microbubbles: Beating biological barriers to promote drug delivery

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